Poster presentation will take place during coffee breaks. See in the attached file (pdf file below) the presenting day for each poster. Presenting day 1: Tuesday 11th June 2019 Presenting day 2 : Wednesday 12th June 2019 Presenting day 3: Thursday 13th June 2019 Posters in red have been selected for short talks. Poster size: A0 (Max width 1 meter, Max height 2 meters; No landscape format please!)
| Presenting
Day |
Poster Number |
First Name |
Last Name |
Affiliation |
Title |
Authors |
Abstract (250 words max) |
Email address |
| 1 |
1 |
Rita |
Soares |
Instituto de Medicina
Molecular | João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa,
Lisboa and Instituto de Farmacologia e Neurociências, Faculdade de Medicina,
Universidade de Lisboa, Lisboa. |
Characterizing the role of
mitochondrial dynamics in adult neural stem cells differentiation |
Rita Soares, Ana M.
Sebastião, Sara Xapelli, Vanessa A. Morais |
Neural
stem/progenitor cells (NSPCs) are found in discrete regions of the mammalian
brain. During adulthood, NSCs can be a source of new neurons in neurological
disorders, such as Parkinson’s disease and Alzheimer’s disease, and
oligodendrocytes in demyelinating disorders such as Multiple Sclerosis.
However, these newborn cells are not sufficient to overcome the neurological
deficits involved by neuronal loss. Therefore, the identification of novel
mechanisms responsible for modulating NSC fate represents a key issue for
future brain repair strategies. Several studies suggest that mitochondria
have an important role in regulating NSC differentiation and lineage
determination. However, the molecular mechanisms involved in this regulation
remain unknown. Hence, our work aims to dissect how mitochondria biogenesis,
morphology and bioenergetics can modulate the NSC differentiation into
neuronal or oligodendroglial lineages. For this, NSPCs were obtained by
isolating subventricular zone (SVZ) and dentate gyrus (DG) cells from P1-3
mouse models. The isolated cells, grown in neurospheres, were plated under
specific differentiation conditions giving raise to neurons, astrocytes and
oligodendrocytes. Different parameters namely seeding density, culture conditions
and number of passages were determined. Moreover, the multipotency of
SVZ/DG-derived NSPCs, obtained from different passages, was also accessed. At
present, our data reveals that expression of proteins involved in
mitochondrial biogenesis and fusion/fission tend to change during NSPC
differentiation, while mitochondrial network appears to become more
fragmented with NSPCs differentiation. These results will pave the road
towards novel findings concerning the role of mitochondrial dynamics in NSC
fate. |
ritasoares@medicina.ulisboa.pt |
| 1 |
2 |
Annina |
Denoth-Lippuner |
Brain
Research Institute, University of Zurich, Zurich, Switzerland |
The
iCOUNT: a novel tool to study the division history of stem cells |
Denoth-Lippuner
A., Liang T., Jaeger B. N., Jessberger S. |
Cell
proliferation is required for organ development, tissue homeostasis and
repair. To allow for visualization and counting of previous cell divisions on
a single cell level, we developed the iCOUNT: a system that is based on the
recombination-induced tag exchange (RITE) of a stable and cell
cycle-dependent protein. Using CRISPR/Cas9 we endogenously tagged different
proteins with the iCount cassette encoding an inducible color switch.
Thereby, the cells change their color in a cell cycle-dependent manner,
allowing for live analysis of individual cell division history.
Testing the iCOUNT system in mouse and human embryonic and neural stem
cells revealed a robust color exchange enabling precise counting for several
cell divisions. Therefore, we generated a CRISPR knock-in mouse expressing
the iCOUNT. Inducing Cre led to a change in color in all tissues analyzed. In
the embryonic brain a gradual change was observed corresponding to the
localization of the cells. Therefore, the iCOUNT provides a novel technique
to analyze the division history of stem cells in vivo.
Using the iCount, we sorted neural stem cells based on their division
history and used single nuclei RNA sequencing to identify transcriptional
changes that occur with progressive cell divisions. Furthermore, we will use
the iCOUNT mouse to study other stem cell compartments.
Taken together, the iCOUNT-system is a unique genetic tool that will not
only allow to count divisions of somatic stem cells but also to identify
cellular changes occurring with cell divisions and to compare those changes
among different types of stem cells.
|
denoth@hifo.uzh.ch |
| 1 |
3 |
Aixa V. |
Morales |
Instituto Cajal
(CSIC) |
SOXD TRANSCRIPTION
FACTORS PROMOTE ACTIVATION OF QUIESCENT NEURAL STEM CELLS IN THE ADULT
HIPPOCAMPUS |
Lingling Li1, Sara
Muñoz1, Cristina Medina1, Carmen Córdoba1,María Ciorraga1, Elena Calleja1,
Silvia Nicolis4, Véronique Lefebvre3, Helena Mira2 and Aixa V.
Morales1.
1Instituto Cajal, (C.S.I.C), Madrid, Spain.
2Instituto de Biomedicina de Valencia, (C.S.I.C), Valencia, Spain.
3Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
4University of Milano-Bicocca, Milano, Italy.
|
Adult neurogenesis, a
process of generating functionally integrated neurons throughout life,
constitutes an important strategy to generate plasticity in the mature
central nervous system. In the adult subgranular zone (SGZ) of the
hippocampus, neural stem cells (NSCs) generate new granule cells via a well
characterized cell lineage that includes a succession of intermediate
progenitor cells (IPCs). The majority of NSCs in the SGZ niche are in a
reversible state of quiescence, a situation that protects the cells from DNA
damage and the population from depletion. However, little is known, of how
the transition from quiescence to an active mitotic state is regulated.
Genes of the Sox family of transcription factors are essential during
neurogenesis. In the developing spinal cord, Sox5 controls cell cycle exit of
neural progenitors and dorsal interneurons specification, counteracting the
Wnt signalling pathway. More recently, we have characterized that both SoxD
genes (Sox5 and Sox6) are expressed in the majority of NSCs and in IPCs in
the SGZ of adult mouse hippocampus and that Sox5 levels are increased in the
activated proliferating NSCs.
Using inducible conditional mutant mice to specifically delete Sox5 and
Sox6 expression in the adult neurogenic niches, we have determined that both
factors are required for radial glial-like NSCs proliferation/activation and
for the generation of new neurons in the adult SGZ. Moreover, we have
determined that proneural gene Ascl1 (esential for NSCs activation) is
severly downregulated in NSCs of the SGZ in Sox5 or Sox6 adult mutant
hippocampus and that could be directly controlled by SoxD transciption
factors. In summary, SoxD genes are required in NSCs for the transition from
the quiescence to the activated mitotic state, an step essential to promote
neurogenesis in a tightly regulated manner throughout adulthood.
|
aixamorales@cajal.csic.es |
| 1 |
4 |
Lachlan |
Harris |
The
Francis Crick Institute |
Progressive
changes to hippocampal neural stem cell quiescence ensure lifelong
neurogenesis |
Lachlan
Harris*, Marco Ortiz*, Francois Guillemot
*equal contributions
|
In
most mammals, neural stem cells (NSCs) persist in the hippocampus where they
continue to generate neurons (neurogenesis). The general pattern of
hippocampal neurogenesis is that it occurs at high levels in young animals,
rapidly declines and then is maintained at low levels throughout life. In mice, the rapid decline in neurogenesis
in juveniles, is due to the self-consuming divisions of NSCs. However, the
mechanisms that underpin the relative maintenance of NSCs and neurogenesis in
older animals are unknown. Here, we demonstrate that with age, NSCs acquire
the capacity to return to quiescence – instead of differentiating. And
secondly, NSCs that have never activated, progress into a deeper state of
quiescence. Both of these processes are controlled by a common mechanism: the
relative abundance of the transcription factor Ascl1, which in turn, is
controlled by sonic hedgehog signalling and the activity of the ubiquitin
ligase Huwe1. In the absence of these cellular and molecular changes, the NSC
pool exhausts and neurogenesis ends prematurely. Together, these findings
provide insights into how the regulation of NSC quiescence ensures lifelong
neurogenesis. |
lachlan.harris@crick.ac.uk |
| 1 |
5 |
Dorothea |
Schulte |
Institute
of Neurology, University Hospital Frankfurt, Goethe University |
Posttranslational
control of a neuronal fate determinant in the SVZ adult neurogenic niche |
Jasmine
Kolb, Tanja Müller, Ann-Christin Hau, Marie Anders-Maurer, Christian Behrends
and Dorothea Schulte |
Adult
neurogenesis is regulated by stem cell niche-derived extrinsic factors and
cell-intrinsic regulators, yet the mechanisms by which niche signals impinge
on the activity of intrinsic neurogenic transcription factors remain poorly
defined. The atypical TALE-homeodomain transcription factor MEIS2 is an
essential regulator of adult subventricular zone (SVZ) neurogenesis that
enables chromatin decompaction and effective transcription of neuron-specific
genes by facilitating the assembly of a PBX1-PAX6-PARP1/ARTD1 containing
complex at promoter-proximal regions of these genes. Here we show that MEIS2
itself is under dual posttranslational regulation in the SVZ / olfactory bulb
neurogenic system. Firstly, MEIS2 protein is cytoplasmic in undifferentiated neural
cells but accumulates in the cell nucleus in response to down-regulation of
EGFR signaling. Nuclear accumulation is mediated by methylation of MEIS2 on a
conserved arginine and involves direct competition between the nuclear export
receptor CRM1 and the MEIS dimerization partner PBX1 for association with
MEIS2. Secondly, cytoplasmic MEIS2 is fragmented in a process that is
sensitive to phosphorylation at several positions within the MEIS2
polypeptide and blocked by heterodimer formation with PBX1. We further link
these processes to the formation of glioma, highly aggressive glial tumors
that are thought to originate from the SVZ stem cell niche. Collectively, our
results establish MEIS2 as a hub that integrates extrinsic signals and
translates them into a neurogenic transcriptional program in the SVZ and
suggest that MEIS2 deactivation may indirectly favor gliomagenesis. |
dorothea.schulte@kgu.de |
| 1 |
6 |
Nathalie |
Coré |
CNRS
UMR7288 |
Control
of neural stem cell specification in the postnatal forebrain by antagonist
function of Vax1 and Pax6 |
Nathalie
Coré, Andrea Erni, Christophe Beclin, Eva Hennen and Harold Cremer |
Neural
stem cells (NSCs) in the postnatal mouse ventricular/subventricular zone
(V/SVZ), that generate different types of interneurons for the olfactory
bulb, are highly heterogeneous. Depending on their location along the
ventro-dorsal axis of the lateral ventricles, they preferentially give rise
to distinct neuronal subclasses with defined positions, connectivity or
neurotransmitter phenotypes. Understanding the molecular mechanisms that
determine the generation of the distinct neuron populations at the NSC level
will be essential for directing the differentiation of NSCs into defined
neuronal cell populations in therapeutic contexts.
We found that the homeodomain transcription factor (TF) Vax1 is expressed
in the lateral V-SVZ stem cell compartment in a ventro-dorsal gradient,
suggesting a role in stem cell patterning and determination of neuronal
phenotype. We used postnatal in vivo electroporation to miss-express Vax1 in
the dorsal NSC aspects of the V-SVZ. Overexpressing Vax1 in dorsal or
dorso-lateral NSCs led to a decrease in the dopaminergic interneuron
population in the olfactory bulb. This phenotype is accompanied by a
reduction of the pro-dopaminergic TF Pax6 in the stem cell compartment,
suggesting that dopaminergic fate repression by Vax1 occurs through
repression of Pax6. Moreover, conditional inactivation of Vax1 in NSCs along
the lateral SVZ led to a reduced number of Calbindin+ neurons, showing that
Vax1 is necessary for the production of this sub-set of OB neurons.
This shows that antagonistic interactions between Vax1 and Pax6 control
neuronal phenotype along the dorso-ventral axis of the forebrain stem cell
compartment. If these interactions are direct or implicate intermediate
regulators like, for example, miR-7a is currently under investigation.
|
nathalie.core@univ-amu.fr |
| 1 |
7 |
Luca |
Bonfanti |
University
of Turin |
Greater
occurrence of cortical layer II “immature” neurons in mammals with expanded
neocortex |
Chiara
La Rosa, Francesca Cavallo, Alessandra Pecora, Ugo Ala, Juan Nacher, Bruno
Cozzi, Chet Sherwood, Irmgard Amrein, Luca Bonfanti |
Doublecortin-positive
(DCX+), PSA-NCAM+ cortical neurons were discovered in the rodent piriform
cortex. They are generated pre-natally, then continue to express markers of
immaturity (non-newly generated immature neurons, nng-INs), thus potentially
representing a reservoir of young neurons in the adult brain (Gomez-Climent
et al, 2008; Piumatti et al, 2018). In some mammals, they extend into
neocortex; the hypothesis has been advanced that nng-INs might be more
important in large-brained mammals characterized by decline of active adult
neurogenesis (Palazzo et al., 2018; Parolisi et al. 2018).
We collected brains from 12 mammals (4 entire hemispheres in 10 animal
species, at different ages; total: 84 brains) belonging to 8 orders and
endowed with different neuroanatomy, lifespan, ecological niche. Occurrence
of nng-INs in paleo- and neo-cortex, their morphology (type 1, small-bipolar;
type 2 cells, large-ramified), and amount (linear density: cells/mm of
cortical layer II perimeter) were evaluated at 4 representative brain levels,
previously established to be comparable. Cell proliferation (Ki-67 antigen,
PCNA, BrdU), and immaturity/maturity markers (DCX, PSA-NCAM, NeuN) were also
employed. All non-rodents species hosted nng-INs in the neocortex, with
remarkable heterogeneity as to their relative amount: cortical layer II
linear densities increase in neocortex more than in paleocortex in mammals
with a large, gyrencephalic brain (almost an order of magnitude from mice to
chimpanzee). By contrast, morphology, phenotype, non-proliferative and
immaturity features were rather constant. We show that nng-INs are a well
preserved feature in mammals, with far higher importance in the expanded
cortex of large-brained species.
|
luca.bonfanti@unito.it |
| 1 |
8 |
Farah |
Alammari |
Department
of Physiology, Anatomy and Genetics, University of Oxford, Sherrington
Building, S Parks Road, Oxford OX1 3PT, UK |
The
role of the transcription co-regulator KAP1 and the lncRNA Paupar in
postnatal/adult subventricular zone development |
Farah
Alammari, Francis Szele |
The
function of many transcriptional regulators and of long non-coding RNAs in
neural development and in the SVZ are poorly understood. KAP1 is an important
transcriptional and epigenetic regulator that mediates silencing and
heterochromatin formation. Here, we studied the function of KAP1 on postnatal
and adult SVZ neurogenesis. We showed that knockdown of KAP1 in vivo
disrupted normal SVZ neurogenesis and reduced the number of newborn neurons
in the olfactory bulb. We also showed
that KAP1 directly binds to Paupar, a vertebrate conserved lncRNA and forms a
trimeric complex with Pax6. Similar to Kap1, we showed that Paupar is
necessary for OB neurogenesis as Paupar knockdown decreased the number of
newborn OB neurons. In both loss-of-function studies newborn OB granule
neurons appeared to have delayed morphological differentiation. Neither Kap1
or Paupar loss affected cell death. We have however generated data suggesting
Paupar and Kap1 may regulate stem cell maintenance and self-renewal in vivo.
Finally, we found that KAP1 and Paupar co-regulated genes important in
self-renewal and differentiation. Together, these results provide
understanding about the role of the transcription coregulator KAP1 and the lncRNA
Paupar in SVZ neurogenesis. |
farah.alammari@dpag.ox.ac.uk |
| 1 |
9 |
Isabelle |
Blomfield |
The
Francis Crick Institute |
Id4
eliminates the pro-activation factor Ascl1 to maintain quiescence of adult
hippocampal stem cells |
Isabelle
Blomfield, Brenda Rocamonde, Maria del Mar Masdeu, Eskeatnaf Mulugeta,
Stefania Vaga, Debbie L. C. van den Berg, Emmanuelle Huillard, François
Guillemot, Noelia Urbán |
Quiescence
is essential for the long-term maintenance of adult stem cells and tissue
homeostasis. However, how stem cells maintain quiescence is still poorly
understood. Here we show that neural stem cells in the dentate gyrus of the
adult hippocampus actively transcribe the pro-activation factor Ascl1
regardless of their activated or quiescent states. We found that the
Inhibitor of DNA binding protein Id4 eliminates Ascl1 protein in neural stem
cell cultures. Id4 sequesters Ascl1 heterodimerisation partner E47, promoting
Ascl1 protein degradation and neural stem cell quiescence. Accordingly,
elimination of Id4 from stem cells in the adult hippocampus results in
abnormal accumulation of Ascl1 protein and premature stem cell activation.
Our results highlight the importance of non-transcriptional mechanisms for
the maintenance of neural stem cell quiescence and reveal a crucial role for
Id4 as a quiescence-inducing factor, in sharp contrast with its role of
promoting the proliferation of embryonic neural progenitors. |
isabelle.blomfield@crick.ac.uk |
| 1 |
10 |
Sebastian |
Arredondo |
Institute
of Biomedical Biosciences, Universdad Andrés Bello |
Wnt5a
promotes adult hippocampal neurogenesis by non-canonical Wnt signaling |
Sebastian
B. Arredondo, Fernanda G. Guerrero, Andrea Herrera-Soto, Joaquin
Jensen-Flores, Daniel B. Bustamante, Alejandro Oñate-Ponce, Pablo Henny,
Manuel Varas-Godoy, Nibaldo C. Inestrosa and Lorena Varela-Nallar |
Adult
hippocampal neurogenesis is regulated by the Wnt signaling pathway, but
little is known about the endogenous Wnt ligands involved. The binding of a
Wnt ligand to its receptor and co-receptor can trigger the canonical
Wnt/β-catenin signaling pathway or the non-canonical Wnt/PCP or Wnt/Ca+2
signaling cascades. Here, we investigated the role of Wnt5a on adult
hippocampal neurogenesis. This ligand is present in the adult hippocampus and
is required to maintain dendritic architecture of hippocampal neurons. We
determined that Wnt5a knockdown in the adult mouse dentate gyrus by
lentivirus-mediated shRNA reduced neurogenesis and impaired dendritic
development of adult-born neurons. In addition, in cultured adult neural
progenitor cells (aNPCs) isolated from the hippocampus of adult mice, Wnt5a
knockdown reduced neuronal differentiation and morphological development of
aNPCs-derived neurons, while treatment with recombinant Wnt5a promoted
neuronal differentiation and induced morphological development of newborn
neurons. Interestingly, astrocytic differentiation was not affected by
expression of shWnt5a or by treatment with recombinant Wnt5a, suggesting that
Wnt5a does not affect fate commitment. By using specific inhibitors, we
determined that Wnt5a signals through CaMKII to induce neurogenesis, and
promotes dendritic development of newborn neurons through activating Wnt/JNK
and Wnt/CamKII signaling. Our results indicate that Wnt5a ligand is a niche
factor in the adult dentate gyrus that promotes neuronal differentiation and
development through activation of non-canonical Wnt signaling pathways.
Supported by: Fondecyt 1190461 and Núcleo UNAB DI-4-17/N (LVN); Conicyt
21151115 (SBA). |
siarredo@gmail.com |
| 1 |
11 |
Diogo |
Lourenço |
(1)
Instituto de Farmacologia e Neurociências, Faculdade de Medicina,
Universidade de Lisboa, Lisboa, Portugal;
(2) Instituto de Medicina Molecular | João Lobo Antunes, Faculdade de
Medicina, Universidade de Lisboa, Lisboa, Portugal; |
Cannabidivarin
and Capsaicin promote neuronal differentiation of neural stem cells |
Diogo
M. Lourenço (1,2), R. Soares (1,2), Rui S. Rodrigues (1,2), A. M. Sebastião
(1,2), S. Xapelli (1,2) |
Adult
neural stem/progenitor cells (NSPC) with multipotent and self-renewing
properties can be mostly found in two neurogenic niches, the Subventricular
Zone (SVZ) and the Dentate Gyrus (DG) of the hippocampus. Cannabinoids have
been shown to play pivotal roles in different neurogenic stages, namely in
differentiation and maturation of NSPC. In this work we aimed at unravelling
the role of cannabidivarin (CBDV), a non-psychoactive phytocannabinoid,
homolog of cannabidiol, with high affinity for the vanilloid receptor 1
(TRPV1), on SVZ postnatal neurogenesis.
SVZ neurospheres were prepared from C57BL/6J (WT) mice pups (P1-3) and were
incubated for 2 days with CBDV and Capsaicin (TRPV1 agonist). Three groups
were tested: 1) control (no drugs); 2) CBDV (100nM; 300nM; 1µM); 3) Capsaicin
(3µM; 10µM; 30µM). Immunocytochemistry against mature neurons (NeuN) and
oligodendrocyte progenitor cells (NG2) was used to evaluate the effect of
CBDV and Capsaicin on neuronal differentiation.
Here we show that SVZ neurospheres treated for 2 days in vitro (n=4) with
1µM of CBDV or 30µM Capsaicin show a significant increase in the number of
NeuN-positive cells (p<0.05). No differences were found regarding the
number of NG2-positive cells at any concentration when compared with the
control condition. These results show that CBDV and Capsaicin promote
neuronal differentiation at 2 days in vitro in SVZ cultures.
This work will allow determining whether CBDV or Capsaicin, most probably
trough the activation of TRPV1, can modulate postnatal neurogenesis or
oligodendrogenesis and will be important for future brain repair
strategies. |
diogo.lourenco@medicina.ulisboa.pt |
| 1 |
12 |
Alexandra |
Pötzsch |
DZNE |
L-lactate
acts as a pro-proliferative cue for adult hippocampal precursor cells in
vitro |
Alexandra
Pötzsch, Odette Leiter, Sara Zocher, Stefanie Bernas, Gerd Kempermann |
We add new evidence to the hypothesis that in the adult brain, the
metabolite L-lactate can influence cellular homeostasis by proposing such a
role in the context of adult hippocampal neurogenesis. Neural precursor cells
(NPCs) in the adult hippocampus can adapt their behavior upon changes in
their microenvironment, for instance the availability of metabolites.
L-lactate has both energetic and signaling properties and shows locally
fluctuating concentrations governed by diverse stimuli (i.e. exercise,
neuronal excitation), which also regulate adult neurogenesis. Studying how
L-lactate affects NPCs in vitro, we demonstrated that L-lactate had a
pro-proliferative effect on NPCs that depended on both active transport via
monocarboxylate transporters (MCTs) and the activation of lactate receptor
HCAR1. The increased proliferation was not linked to amplified mitochondrial
respiration. Instead, L-lactate deviated glucose metabolism in that
glycolysis was decreased and G6PD activity increased indicating augmented
pentose phosphate pathway action. Furthermore, Erk1/2 phosphorylation and
HCAR1 dependent PI3K/Akt signaling were induced by L-lactate. Our results
show that L-lactate availability is linked to the proliferative potential of
NPCs and demonstrate that a broader understanding of metabolite signaling
properties is crucial to comprehend the link between metabolism, signaling,
cellular behavior and plasticity in the adult hippocampus. |
alexandra.poetzsch@dzne.de |
| 1 |
13 |
Gontzal |
García
del Caño |
Universidad
del País Vasco / Euskal Herriko Unibertsitatea |
Silencing
of Phospholipase C-β1 expression impairs AraC-induced neuronal
differentiation of NT2 cells |
Isasti
A, González-Burguera I, Borrega L, Saumell M, Barrondo S, Sallés J, García
del Caño G, López de Jesús M |
Phospholipase
C-β1 (PLCβ1) is the predominant PLCβ1 in human cerebral cortex. The time
course of PLCβ1 expression in the human cortex during pre- and postnatal
development (1) and the fact that knocking out Plcb1 gene in mice disrupts
cortical development and alters neurogenesis and migration of new born
granule neurons of the adult hippocampus (2,3) indicates a critical role for
PLCβ1 in neuronal development and differentiation. Using the NT2 cell line as
a well characterized model of neuronal differentiation (4), we have recently
shown that acquisition of neuronal fate and upregulation of the
neuron-specific markers NF200 and β-III-tubulin after exposure to
cytosine-β-D-arabinofuranoside (AraC) is preceded by a drastic increase of
PLCβ1 protein expression levels (5), suggesting that neuronal differentiation
of NT2 progenitors requires PLCβ1 upregulation. To test this hypothesis, we
have investigated the effects of PLCβ1 silencing on the expression of
neuronal markers during AraC-induced neuronal differentiation. Our results
show that knocking down of PLCB1 gene, using either shRNAs or siRNAs, impairs
AraC-induced cell morphological differentiation and upregulation of NF200 and
β-III-tubulin proteins, which demonstrates that PLCβ1 is necessary for AraC-induced
neuronal differentiation of NT2 cells.
1. López De Jesús et al. (2006). Neurochem Int, 49:72-79.
2. Spires et al. (2005). Cerebral Cortex, 15:385.393.
3. Manning et al (2012). Hippocampus, 22:309-319.
4. Gonzalez-Burguera et al. (2015). Stem Cell Res, 16:541-551.
5. Gonzalez-Burguera et al. (2011). SENC congress, 28-30 september 2011. |
gontzal.garcia@ehu.eus |
| 1 |
14 |
Gregor-Alexander |
Pilz |
University
of Zurich |
Diversity
of neural stem cells in the adult hippocampus |
Gregor-Alexander
Pilz1, Sara Bottes1, Baptiste N. Jaeger1, David J. Jörg2, John D. Cole1,
Merit Kruse1, Fritjof Helmchen3, Benjamin D. Simons2, Sebastian
Jessberger1#
1Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain
Research Institute, University of Zurich, 8057 Zurich, Switzerland.
3Cavendish Laboratory, Department of Physics, University of Cambridge,
Cambridge CB3 0HE, UK; Wellcome Trust/Cancer Research UK Gurdon Institute,
University of Cambridge, Cambridge CB2 1QN, UK; Wellcome Trust-Medical
Research Council Cambridge Stem Cell Institute, University of Cambridge,
Cambridge CB2 1QR, UK. 3Laboratory of Neural Circuit Dynamics, Faculties of
Medicine and Science, Brain Research Institute, University of Zurich, 8057
Zurich, Switzerland. |
Neural
stem cells (NSCs) generate new granule neurons throughout life in the
mammalian hippocampus. However, the potential for long-term self-renewal of
individual NSCs within the adult brain remains unclear. To address this stem
cell property, we here used chronic in vivo 2-photon microscopy and followed
single NSCs that were genetically labeled through conditional recombination
driven by the regulatory elements of the stem cell-expressed genes GLI Family
Zinc Finger 1 (Gli1) or Achaete-scute homolog 1 (Ascl1). Through intravital
imaging of NSCs and their progeny for up to 3 months, we identify a
population of Gli1-targeted NSCs showing long-term self-renewal. In contrast,
Ascl1-targeted NSCs undergo limited cell divisions before they become
exhausted, as previously described by our lab. Using protein expression
profiling (4i iterative stainings) and single cell RNA sequencing (sc-RNAseq)
we show that Gli1- and Ascl1-targeted NSCs and their progeny have highly
similar transcriptional profiles, supporting the presence of heterogeneous
NSC populations with distinct behavioral properties. Using longitudinal
observations of single NSCs and their progeny we here identify functional
diversity of NSCs and provide the cellular framework how NSCs generate new
neurons throughout life in the adult hippocampus. |
pilz@hifo.uzh.ch |
| 1 |
15 |
Filippo |
Michelon |
1
Neuroscience Institute Cavalieri Ottolenghi (NICO), Orbassano (Turin), Italy;
Department of Life Sciences and Systems Biology (DBIOS), University of Turin,
Turin, Italy
2 Université de Lille, Inserm, CHU Lille, UMR-S 1172, laboratoire du
développement et plasticité du cerveau neuroendocrine, centre de recherche
Jean-Pierre Aubert, Lille, France
3 Université Côte d’Azur (UCA), CNRS, Inserm, iBV, Nice, France
|
COUP-TFI/Nr2f1
overexpression in the GLAST-lineage perturbs the migration and morphology of
a subpopulation of hippocampal granule neurons |
Michelon
F 1,2*, Bonzano S 1*, Crisci I 1, Ternier G 2, Giacobini P 2, Studer M 3, De
Marchis S 1 *equal contribution |
In
the mammalian brain, newborn granule neurons develop throughout life from
multipotent adult neural stem cells (NSCs) located in the subgranular zone of
the dentate gyrus. Intrinsic/extrinsic factors and external cues control
their multistep developmental process, eventually leading to their functional
integration in hippocampal circuits. Among the intrinsic factors regulating
this process, we recently demonstrated that the transcriptional regulator
COUP-TFI (also known as Nr2f1) acts as a central player in controlling adult
hippocampal NSC fate choice. Here we used a tamoxifen-inducible mouse line to
study the phenotype of newborn neurons following conditional COUP-TFI
overexpression in the GLAST-lineage. Our data suggest that COUP-TFI regulates
migration and dendritic development of newborn neurons within the adult mouse
dentate gyrus. Indeed, COUP-TFI overexpression results in the mislocalization
of a subpopulation of newborn Prox1+ granule neurons that migrate to ectopic
sub-regions (i.e. the outer granule cell layer and the hilus). Moreover,
morphological analysis showed that misplaced cells bear an altered dendritic
architecture compared to “normotopic” granule cells. Overall, these findings
indicate a new role of COUP-TFI in adult neurogenesis by controlling the
proper positioning and morphological maturation of newborn granule neurons.
Future studies will be aimed to dissect the molecular mechanisms through
which COUP-TFI exerts its role and to investigate the possible involvement of
COUP-TFI in neurological disorders (e.g. epilepsy) characterized by ectopic
granule cell migration and alterations in granule neuron morphological
features. |
filippo.michelon@inserm.fr |
| 1 |
16 |
Sophie |
Austin |
The
Francis Crick Institute |
Dose
Dependent Effects of Canonical Wnt Signalling in Quiescent Adult Hippocampal
Stem Cells |
Sophie
Austin, Noelia Urbán, Isabelle Blomfield, François Guillemot |
Adult
hippocampal stem cells (AHSCs) generate new neurons that integrate into
existing hippocampal networks and modulate mood/memory. AHSCs are largely
quiescent and stimulated to activate and produce neurons by surrounding
signals. Although canonical Wnt signalling modulates adult neurogenesis it is
unclear if/how it directly affects AHSCs. Our aim is to characterise the role
of canonical Wnt signalling in active and quiescent AHSCs.
Using BATGAL Wnt reporter mice we find that both active and quiescent AHSCs
respond heterogeneously to Wnt signalling in vivo. Similarly, using an in
vitro model of active and quiescent AHSCs, we find that AHSCs in both states
respond heterogeneously to Wnt. This suggests that AHSCs’ response to Wnt
signaling is independent of their activation state both in vivo and in vitro.
In vitro we find that intact canonical Wnt signaling is not essential for
quiescent AHSC activation or for the maintenance of their quiescent state.
Strong Wnt activation initiates neuronal differentiation in both active and
quiescent culture conditions. Milder Wnt activation also promotes
differentiation of active AHSCs but, interestingly stimulates proliferation
in quiescent AHSCs. Thus, lower levels of Wnt signalling can promote quiescence
exit. Overall this indicates that levels of canonical Wnt signalling are
important in determining proliferation vs neuronal differentiation responses
in quiescent AHSCs. We are now investigating the molecular mechanisms driving
these differential effects in response to different canonical Wnt signalling
levels. We are also currently modulating Wnt in AHSCs in vivo to determine
how active and quiescent AHSCs are affected by different Wnt levels. |
sophie.austin@crick.ac.uk |
| 1 |
17 |
Miguel
V. |
Guerra |
1Instituto
de Ciencias Biomedicas, Facultad de Medicina y Facultad de Ciencias de la
Vida, Universidad Andres Bello, Santiago, Chile. 2Centro de Envejecimiento y
Regeneración (CARE-UC), Facultad de Ciencias Biológicas, P. Universidad
Católica de Chile |
Epigenetic
changes during adult hippocampal neurogenesis |
Miguel
V. Guerra 1, Brigitte van Zundert 1,2* and Lorena Varela-Nallar 1* |
In
the dentate gyrus of the adult hippocampus, the generation of new neurons
from neural stem cells (NSCs) involves proliferation, differentiation and
maturation of newborn cells. These stages are controlled by transcriptional
and epigenetic mechanisms. Regarding the latter, little is known about the
role of histone post-translational modifications (HPTMs) during hippocampal
neurogenesis. HPTMs can either promote or inhibit transcription depending on
the modification, and the histone residue being modified. Here we studied
HPTMs during the stages of neurogenesis in the dentate gyrus of 2 month-old
mice. A strong increase in epigenetic repressive marks was observed in
progenitor cells and proliferating neuroblasts compared to quiescent NSCs and
mature neurons. No changes were observed in histone activation marks studied.
In addition, HPTMs were evaluated in proliferating and differentiated
cultured adult neural progenitor cells (aNPCs), isolated from adult mouse
hippocampus. A decrease in repressive marks was observed during neuronal
differentiation by immunostaining and immunoblot. Interestingly, no changes
in repressive histone marks were observed in aNPC-derived astrocytes.
Finally, we determined a significant decrease in neuronal differentiation of
aNPCs in the presence of a small molecule that inhibits histone
methyltransferases. Our results suggest that epigenetic repression through
HPTMs regulates early stages of adult hippocampal neurogenesis.
Supported by: Fondecyt 1190461 (LVN), Fondecyt 1181645 and CARE-UC AFB
170005 (BvZ), Nucleo UNAB DI-4-17/N, Conicyt 21181497 (MGV). |
guerra.miguelv@gmaill.com |
| 1 |
18 |
Sofia |
Madsen |
Department
of Physiology, University of Lausanne |
Generating
an endogenous reporter mouse to study lipid droplets in neural stem cells |
Sofia
Madsen, Mergim Ramosaj, Denise Tavel and Marlen Knobloch |
Lipid
metabolism plays an important role in the regulation of neural stem cells
(NSCs): Build-up of lipids through de novo lipogenesis seems to be crucial
for NSC proliferation (Knobloch et al. 2013), whereas the break-down of
lipids via fatty acid beta-oxidation has recently been shown to regulate NSC
quiescence (Knobloch et al 2017). Lipid droplets (LDs) are the intracellular
organelles that store lipids, mainly triacylglycerols and sterol esters. LDs
have classically been seen as inert storage organelles, however studies over
the recent years have revealed them as highly dynamic organelles that fulfil
crucial metabolic functions. How LDs are involved in the regulation of adult
NSCs is currently poorly understood.
We are investigating the role of LDs in NSCs during development and in
adulthood, both in vitro and in vivo. As LDs are very sensitive to the common
staining methods used for visualization, we are using CRISPR/Cas9 to create
an endogenous LD reporter mouse. This mouse will allow us to visualize LDs in
a staining-free manner and will also enable us to follow LD dynamics using
live imaging. Here we present the target selection, validation and tagging
approach for this novel endogenous LD reporter mouse.
|
sofia.madsen@unil.ch |
| 1 |
19 |
Sara |
Bonzano |
NICO
- University of Turin |
The
transcriptional regulator COUP-TFI/Nr2f1 exerts an anti-astrogliogenic
function on adult mouse hippocampal NSCs/progenitors enabling adult
neurogenesis |
Bonzano
Sara 1,4, Crisci Isabella 1, Stajano Daniele 1, Podlesny-Drabiniok Anna 2,
Rolando Chiara 3, Krezel Wojciech 2, Studer Michèle 4, De Marchis Silvia
1
1 Neuroscience Institute Cavalieri Ottolenghi (NICO), Orbassano (Turin),
Italy; Department of Life Sciences and Systems Biology (DBIOS), University of
Turin, Turin, Italy;
2 Université de Strasbourg, CNRS, Inserm, IGBMC, Illkirch, France;
3 Department of Biomedicine, University of Basel, Basel, Switzerland;
4 Université Côte d’Azur (UCA), CNRS, Inserm, iBV, Nice, France.
|
In
the adult hippocampal dentate gyrus (DG), radial glial-like neural stem cells
(NSCs) are multipotent (generating both neurons and astrocytes) while
progenitors are fate-restricted to the neuronal lineage. Despite the
importance of a tight control of neurogenic versus astrogliogenic potential,
the underlying transcriptional program is still largely unknown.
In this study, we found that a large subset of NSCs/progenitors
co-expressed the transcription factor COUP-TFI (also known as Nr2f1) in the
healthy DG, whereas neuroinflammation led to its downregulation. By combining
inducible knockouts to fate mapping approaches we showed that COUP-TFI
deletion from adult DG NSCs reduced neurogenesis and increased astrocyte
production likely by inducing the pro-astrogliogenic factor NFIA. Remarkably,
this shift also occurred upon COUP-TFI loss by retroviral targeting of
mitotic progenitors, indicating that these cells might still be bipotent and
need COUP-TFI to limit their potential to the neuronal fate. Moreover,
complementary experiments clearly demonstrated that COUP-TFI overexpression
abolished the production of new astrocytes under physiological conditions and
was sufficient to abate the inflammation-induced gain in astrogliogenesis and
to restore proper neurogenesis levels, thus revealing a crucial function for
COUP-TFI in protecting the DG niche from inflammatory insults. Finally,
downregulation of COUP-TFI takes place within the mouse hippocampal niche
early during physiological aging concomitantly with the drop in neurogenesis,
further supporting COUP-TFI as a central regulator of the adult DG neurogenic
niche. |
sara.bonzano@unito.it |
| 1 |
20 |
Ariane |
Sharif |
UMRS1172
JPArc Development and Plasticity of the Neuroendocrine Brain Lab, 1 place de
Verdun 59045 Lille France |
Characterization
of the neural stem cell niche in the adult human hypothalamus |
Giuliana
Pellegrino, Claire Trubert, Jérémy Terrien, Fabien Pifferi, Danièle Leroy,
Anne Loyens, Martine Migaud, Marc Baroncini, Claude-Alain Maurage, Christian
Fontaine, Vincent Prévot, Ariane Sharif |
The
adult brain contains niches of neural stem cells that continuously add new
neurons to selected circuits throughout life. Besides the subventricular zone
of the lateral ventricles and the subgranular zone of the hippocampal dentate
gyrus, which have been extensively studied in various mammalian species
including humans, a third neurogenic niche has recently been identified in
the adult hypothalamus of several animal models, mostly rodents. To evaluate
whether a neural stem cell niche also exists in the adult hypothalamus in
humans, we performed multiple immunofluorescent stainings to assess the
expression of a panel of neural stem/progenitor cell (NPC) markers (Sox2,
nestin, vimentin, GLAST, GFAP) in the human hypothalamus in comparison with
the mouse, rat and a non-human primate species, the grey mouse lemur
(Microcebus murinus). Our results show that the adult human hypothalamus
contains four populations of cells co-expressing the five NPC markers: i) a
ribbon of small stellate cells that lines the third ventricular wall behind a
hypocellular gap and is similar to that found along the lateral ventricles,
ii) ependymal cells, iii) tanycytes, which line the floor of the third
ventricle in the tuberal region, and iv) a population of small stellate cells
in the suprachiasmatic nucleus. In the mouse, rat and mouse lemur
hypothalamus, co-expression of NPC markers is essentially restricted to
tanycytes and these species lack a ventricular ribbon. Altogether, we
identify in the adult human hypothalamus four distinctive cell populations
harbouring an antigenic profile of neural stem cells, three of which appear
specific to humans. |
ariane.sharif@inserm.fr |
| 1 |
21 |
Anja |
Urbach |
Jena
University Hospital, Dept. for Neurology |
Differential
effects of cyclin D2 ablation on the self-renewal capacity of postnatal and
adult hippocampal stem cells and dynamic expression of D-cyclins during
precursor differentiation in vitro |
Syeda
A. Zahra, Otto W. Witte, Anja Urbach |
The
neurogenic potential of the adult dentate gyrus (DG) relies on a pool of
quiescent neural stem cells (NSCs) that become activated to generate new
granule cells on demand. Our studies on cyclin D2 knockout (D2KO) mice
suggest that cyclin D2 is required for the establishment of the adult NSC
pool during the second to third postnatal week, and that cyclin D2 becomes
increasingly important for hippocampal neurogenesis during this period. We
showed that cyclin D2 is the only D-type cyclin of adult NSCs, suggesting an
important role for their proliferation and self-renewal. On the contrary,
developmental NSCs in the postnatal hilar germinative matrix as well as in
the emerging subgranular zone also express cyclin D1, which might compensate
for the loss of cyclin D2 during postnatal neurogenesis. To further examine these findings, we
isolated neural precursors from postnatal day 7 (P7) and adult mouse dentate
gyri and cultured them as neurospheres. We found that neurospheres could be
established from both, P7 and adult D2KO precursors. However, precursors from
D2KO mice formed less and in adults also smaller spheres during primary
culture as compared to wildtype mice. The spheres of P7 D2KO mice were able
to expand exponentially over at least ten passages, demonstrating that their
DG contains bona fide self-renewing NSCs that do not require D2 for
proliferation. On the contrary, the precursor population from adult D2KO mice
displayed no long-term neurosphere-forming capacity and stopped growing after
the third passage, suggesting that it is composed of only progenitor cells.
Proliferation of D2KO precursors is likely accomplished by cyclin D1 which is
expressed in spheres of both, P7 and adult mice (qRT-PCR and Western blot).
To further evaluate the dynamics of D-cyclin expression during adult
neurogenesis, we cultured DG precursors from wildtype mice as monoadherent
cultures (with FGF2 and EGF) and differentiated them in mitogen-free media
for 96 hrs. We observed similar quantities of cyclin D1 and D2 transcripts
and proteins which were high in proliferating cultures and sharply decreased
during the first 24 hrs of differentiation, simultaneously with a drop of the
proliferation marker Ki67 and increasing levels of differentiation markers
DCX, Fox3 and GFAP. Together, these findings confirm our in vivo data
suggesting that cyclin D2 is dispensable for proliferation of developmental
NSCs but required for the formation and maintenance of the adult NSC
population. |
anja.urbach@med.uni-jena.de |
| 1 |
22 |
Iris |
Schäffner |
Universität
Erlangen |
FoxO-dependent
control of lysosome function in adult neurogenesis |
Iris
Schäffner, Georgia Minakaki, Ursula Schlötzer-Schrehardt, Jihye Paik,
Wolfgang Wurst, Jochen Klucken, and D. Chichung Lie |
The
Autophagy-Lysosome Pathway (ALP) is a highly conserved catabolic pathway with
emerging functions in adult neurogenesis. The mechanisms controlling ALP
activity in adult neural stem cells and subsequent generated neurons are
largely unknown. We recently identified transcription factors of the FoxO
family as central regulators of ALP activity in adult hippocampal
neurogenesis. Conditional deletion of FoxO transcription factors led to a
progressing loss of adult neural stem cells and strongly impaired autophago-lysosomal
flux in developing neurons of the adult hippocampus. Furthermore,
FoxO-deficiency altered dendritic morphology, elevated spine density and led
to aberrant spine positioning in adult-generated hippocampal neurons. How
FoxOs impact on autophago-lysosomal flux remains to be determined. We now
observed insufficient acidification of lysosomes in FoxO-deficient cells,
which in turn lead to the accumulation of fused autophagolysosomes and the
block of the following degradation process. Additional data point to a
decreased expression of Tfeb, a master regulator of lysosomal biogenesis, and
of specific subunits of the vacuolar-ATPase (v-ATPase) – a multiple-subunit
composed proton pump residing in the lysosomal membrane, which is responsible
for the acidification of lysosomes. Collectively, our new findings suggest a
new link between FoxO transcription factors and v-ATPase-dependent
acidification of lysosomes in adult neurogenesis. |
iris.schaeffner@fau.de |
| 1 |
23 |
Carmen |
Castro |
University
of Cadiz |
NOVEL
PROTEIN KINASE C ACTIVATION PROMOTES MIGRATION OF NEUROBLASTS TOWARD BRAIN
INJURIES: A ROLE IN NEUREGULIN RELEASE |
Ricardo
Gómez-Oliva1,6, Noelia Geribaldi-Doldán 1,6, Samuel Domínguez-García1,6,
Felix A. Ruiz2,6, Pedro A. Nunez-Abades3,6, Livia Carrascal3,6, Jorge
Bolívar-Pérez 4,6, Antonio J. Macías-Sánchez5,6, Rosario Hernández-Galán5,6
and Carmen Castro1,6
1 Área de Fisiología, Facultad de Medicina, Universidad Cádiz, Spain;
2 Área de Nutrición, Facultad de Medicina, Universidad Cádiz, Spain;
3 Departamento Fisiología, Facultad de Farmacia, Universidad Sevilla,
Spain;
4 Área de Bioquímica y Biología Molecular. Facultad de Ciencias,
Universidad de Cádiz, Spain;
5 Departamento de Química Orgánica, Facultad de Ciencias, Universidad de
Cádiz, Spain;
6 Instituto de Investigación Biomédica de Cádiz (INIBICA), Cádiz,
Spain.
|
Neural
stem cells (NSC) are activated within neurogenic niches in response to brain
injuries. These response results in the production of neuroblasts, which
attempt to migrate towards the injured area, yet this neuroblast do not
contribute to the generation of new neurons within the damaged tissue.
Injuries constitute a gliogenic/non-neurogenic niche in which neuronal
production is impaired. Signaling molecules within the injury released in
response to inflammation prevent neuroblast migration, differentiation and/or
survival. The introduction of neurogenic signaling molecules in injuries may
facilitate neuronal enrichment. Kinases of the protein kinase C (PKC) family
mediate the release of growth factors that participate in different steps of
the neurogenic process. Activation of novel PKC isozymes facilitates release
of neurogenic growth factors such as neuregulin, however, specific novel PKC
activators have not been described so far. We have isolated a plant derived
diterpene, 7,8,12-tri-O-acetyl-3-O-(4-methoxyphenyl) acetylingol (EOF2; CAS
number 944799-48-8), with the capacity to specifically activate novel PKC. We
have found in here that in mice with controlled mechanical injuries,
intranasal administration of EOF2 facilitates migration of neuroblasts from
neurogenic regions towards the perilesional area. We also demonstrated, using
fusion proteins in which membrane-anchored growth factors neuregulin 1 and
transforming growth factor a (TGFα) were fused to a mCherry and GFP in both
N-terminal and C-terminal ends, that EOF2 selectively mediated the release of
neuregulin 1 without affecting the release of TGFα. Our findings highlight
the role of novel PKC in brain injury regeneration. Funded by Spanish
Ministerio de Ciencia, Innovación y Universidades (BFU2015-68652-R). |
carmen.castro@uca.es |
| 1 |
24 |
David |
Morizet |
Institut
Pasteur |
Unveiling
the heterogeneity of vertebrate adult Neural Stem Cells |
David
Morizet, Alessandro Alunni, Laure Bally-Cuif |
The
vertebrate brain harbors neural stem cells (NSCs) that persist into adulthood
to ensure the life-long production of functional neurons. These NSCs are
mainly quiescent, a feature important for their maintenance into old age.
NSCs however do not constitute a homogeneous population and different
subtypes can contribute differently to maintaining long-term neurogenic
ability.
The adult zebrafish pallium hosts NSCs with similar characteristics to
their mammalian counterparts but present in large number, making it a
powerful model to unravel NSC properties. Using this model, our lab recently
demonstrated the existence of subpopulations of NSCs that differ in their
quiescence depths and/or are hierarchically organized along a cascade leading
to activation and neuronal production. However the molecular signature and
functionally relevant markers for these subpopulations remain unknown.
In order to get a better description of the heterogeneity of quiescent NSCs
we used single-cell RNA-sequencing with the 10x Genomics platform. We enriched for NSCs via flow-assisted
cell-sorting with a transgenic line and obtained over 17k cells, with over 3k
of them being quiescent NSCs. Our analysis confirms the existence of
different clusters of quiescent NSCs and highlights markers that can be used
to study these cells in situ. These results also allow us to order the cells
along a differentiation trajectory using pseudotime and obtain insights about
the physiological functions of these clusters. We are in the process of
validating in situ the expression of diagnostic markers prior to initiating
functional assays. My most recent results on these fronts will be
presented.
|
david.morizet@pasteur.fr |
| 1 |
25 |
Fabienne |
Grolig |
University
Erlangen |
FoxO
transcription factors and mitophagy in adult neural stem cells |
Fabienne
Grolig, Ursula Schlötzer-Schrehardt, D.Chichung Lie, Iris Schäffner |
Maintenance
of the adult neural stem cell pool is crucial to sustain
neurogenesis-dependent plasticity throughout life.
The FoxO transcription factors serve as regulators of adult neural stem
cell maintenance at least in part through the control of autophago-lysosomal
activity in adult neural stem/progenitor cells (NSPC). In general,
degradation of aged or damaged mitochondria via the autophago-lysosomal
pathway - a process termed mitophagy - is critical for mitochondrial
homeostasis. Interestingly, it was recently found that mitochondrial function
is vital to maintain NSPC proliferation and neurogenesis.
We hypothesize that mitochondria homeostasis in NSPCs is dependent on
FoxO-mediated mitophagy. Preliminary results revealed differences in number,
size and morphology of mitochondria between wildtype and FoxO cKO NSPCs.
Additionally, mitochondrial membrane potential was reduced in FoxO cKO cells,
indicating an accumulation of a fraction of aged or damaged mitochondria.
Furthermore, markers involved in the induction of mitophagy, as e.g. PINK1,
were down-regulated in FoxO cKO NSPCs.
These preliminary data support the hypothesis, that the FoxO transcription
factors might be involved in the regulation of mitophagy in adult NSPCs.
|
fabienne.grolig@fau.de |
| 1 |
26 |
Aneta |
Grymanowska |
Mossakowski
Medical Research Centre, PAS, 02-106 Warsaw, 5 Pawińskiego Str., Poland |
Distinct
nuclear architecture of neural stem cells among other neural cell types in
adult hippocampal neurogenesis |
Aneta
W. Grymanowska, Ana Martin, Krzysztof H. Olszyński, Krzysztof Nowiński,
Bartosz Borucki, Piotr Majka, Sylwia Bednarek, Grzegorz M. Wilczyński,
Adriana Magalska, Robert K. Filipkowski |
Three-dimensional
reconstruction of the nuclear shape of every cell type in adult hippocampal
neurogenesis was performed along with semi-automated shape analysis that
quantitatively measures volume, height, surface area and additional metrics
of nuclear morphology such as the density of nuclear DNA. Also, we are
introducing a novel, high throughput nuclear shape analysis with automatic
nuclei segmentation and cellular type classification, with the application of
U-Net based Deep Convolutional Neural Network (DCNN), modified to accommodate
3D multichannel images.
Four channels correspond to four types of staining used: GFP-Nestin, NeuN,
DAPI and DCX. Cells are assigned probabilities of belonging to each of five
possible types: type 1 (GFP-Nestin+/neural process), type 2a (GFP-Nestin+),
type 2b (GFP-Nestin+/DCX+), type 3 (DCX+), type 4 (NeuN). We are showing that
neural stem cells in the dentate gyrus of adult murine hippocampus exhibit a
distinct nuclear architecture. Obtained results also show that the chromatin
in the nucleus of cell type 1 and type 2 is more condensed compared to other
neural cell types in the dentate gyrus. This work was supported by National
Science Centre, Poland, grant no. 2014/14/M/NZ4/00561 (for RKF) |
agrymanowska@imdik.pan.pl |
| 1 |
27 |
Nesrin |
Sharif |
Institute
of Physiological Chemistry, University Medical Center, Mainz |
Neurogenin2-induced
neurons under the scope: from activity-dependent gene regulation to synaptic
plasticity |
Nesrin
Sharif, Filippo Calzolari, Nicolas Marichal, Benedikt Berninger |
Recovery
of brain function following damage depends on the successful functional
integration of newly generated neurons and their ability to plastically
contribute to pre-existing neuronal network activity. Direct
astroglia-to-neuron conversion by ectopic expression of the neuronal fate
determining transcription factor neurogenin-2 has emerged as a powerful tool
to generate induced glutamatergic cortical neurons (iNs) in vitro as well as
in vivo. However, the extent to which iNs may display long-term synaptic
plasticity as well as contribute to homeostatic synaptic scaling in
comparison to endogenous neurons has not yet been investigated. This study
aims to investigate the extent to which iNs undergo transcriptional
modulation in an activity-dependent manner, in comparison to primary cortical
neurons in vitro. My current results demonstrate that functionally active
synaptic connections can be established among iNs. iNs can be stimulated by
several stimulation paradigms, resulting in upregulation of multiple
immediate-early genes in vitro. Motivated by these findings, I am modulating
activity (e.g. long-term exposure to or complete blockage of activity) in
cultures of iNs with cortical neurons in order to investigate
activity-dependent transcriptomic changes by performing RNA-sequencing on
FACS-sorted iN nuclei. These data will provide a clearer understanding of the
authenticity of iNs, potentially paving the way for further improvements of
the astroglia-to-neuron conversion process. |
nesharif@uni-mainz.de |
| 1 |
28 |
Jorge |
Valero |
Achucarro
Basque Center for Neuroscience | Ikerbasque Basque Foundation for Science |
Microglia
actively remodels adult hippocampal neurogenesis through the phagocytosis
secretome |
J.
Valero(1,2,8), I. Diaz-Aparicio(1,2), I. Paris(1,2), V. Sierra-Torre(1,2), A.
Plaza-Zabala(1), N. Rodríguez-Iglesias(1,2), M. Márquez-Ropero(1,2), S.
Beccari(1,2), O. Abiega(1,2), E. Alberdi(1,2), C. Matute(1,2), I.
Bernales(2), A. Schulz(3), L. Otrokocsi(4), B. Sperlagh(4), K. E.
Happonen(5), G. Lemke(5), M. Maletic-Savatic(6,7), A. Sierra(1,2,8)
1 Achucarro Basque Center for Neuroscience, Leioa, Bizkaia, Spain.
2 University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
3 University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
4 Institute of Experimental Medicine, Hungarian Academy of Sciences,
Budapest, Hungary.
5 Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
6 Jan and Dan Duncan Neurological Research Institute at Texas Children's
Hospital, Houston, TX, USA.
7 Baylor College of Medicine, Houston, TX, USA.
8 Ikerbasque Foundation, Bilbao, Bizkaia, Spain.
|
During
adult hippocampal neurogenesis, the majority of newborn cells undergo
apoptosis and are rapidly phagocytosed by resident microglia in order to
avoid disturbing the surrounding neurons. Here, we propose that phagocytosis
is not merely a passive process of corpse removal but has an active role in
maintaining adult hippocampal neurogenesis. First, we found that neurogenesis
was disrupted in mice chronically deficient for two microglial phagocytosis
pathways (P2Y12, MerTK/Axl), but was transiently increased in mice in which
MerTK expression was conditionally downregulated. We then followed an in
vitro approach to perform a transcriptomic analysis of microglial
phagocytosis and identified genes involved in metabolism, chromatin
remodeling, and neurogenesis-related functions. Finally, we determined that
the phagocytic microglia secretome limits the production of new neurons both
in vivo and in vitro. Our data suggest that reprogrammed phagocytic microglia
acts as a sensor of local cell death, modulating the balance between cell
proliferation and cell survival in the neurogenic niche, supporting the
long-term maintenance of adult hippocampal neurogenesis.
This work was supported by grants from the Spanish Ministry of Economy and
Competitiveness with FEDER funds to AS (BFU2012-32089 and RYC-2013-12817), to
AS and JV (BFU2015-66689); a Leonardo Award from the BBVA Foundation to AS; a
Basque Government project (PI_2016_1_0011); a Hungarian Research and
Development Fund Grant (K116654) to B.S; a Hungarian Brain Research Program
grant (2017-1.2.1-NKP-2017-00002) to B.S. and Ikerbasque start-up funds to
JV.
|
jorge.valero@achucarro.org |
| 1 |
29 |
Luke |
Foulser |
Wellcome
Sanger Institute |
Dechiphering
Developmental Disorders |
Sebastian
Gerety, Andy Day, Adam Hunter, Luke Foulser, Neophytos Kouphou, Alex
Neaverson and Malin Andersson |
The
deciphering developmental disorders project aims to advance clinical genetic
practice for children with developmental disorders by the systematic
application of the latest microarray and sequencing methods. This has led to
the identification of a number of implicated genes which have since sought to
be explored. CRISPR/Cas9 KO iPSCs are
used to produce homozygous and heterozygous mutations of 100 genes of known
importance in biological duplicate. Here, we attempt to understand the
biological function of these mutations potentially leading to these
disorders. The KO iPSCs will be used to model brain development by
differentiating to a neural stem cell population in vitro. These NSCs will
then be characterised by immunocytochemistry for NSC markers to ensure a
successful differentiation and homogenous population. NSCs with mutations in
these developmental genes will then be used to analyse the genome-wide
expression profile to identify disrupted signalling pathways underlying the
disorders observed in children. Moreover, future differentiation into
cortical neurons may prove key, due to high prevalence of cognitive disorders
within the cohort. In turn, this may
lead to future target pathways that could be treated to obviate the
disorder’s phenotype. |
lf11@sanger.ac.uk |
| 1 |
30 |
Giuseppe |
Lupo |
Sapienza
University of Rome |
Epigenomic
profiling of aged mouse neural stem/progenitor cells identifies Dbx2 as a
candidate regulator of age-associated neurogenic decline |
Giuseppe
Lupo, Paola S. Nisi, Mario Fiore, Pilar Esteve, Yu-Lee Paul, Clara Lopes
Novo, Ben Sidders, Muhammad A. Khan, Stefano Biagioni, Hai-Kun Liu, Paola
Bovolenta, Emanuele Cacci, Peter J. Rugg-Gunn |
Rodent
adult neurogenesis declines with ageing, but the underlying molecular
mechanisms are poorly understood. To investigate the intrinsic molecular
changes that occur upon neural stem/progenitor cell (NSPC) ageing, we
compared the transcriptional, histone methylation and DNA methylation
signatures of NSPCs derived from the subventricular zone (SVZ) of young adult
(3 months old) and aged (18 months old) mice. Surprisingly, the genome-wide
transcriptional and epigenetic profiles of SVZ-derived NSPCs were largely
unchanged in aged cells. Despite the global similarities, we detected robust
age-dependent changes at several genes and their regulatory elements, thereby
identifying putative regulators of neurogenic decline. Among them, the
homeobox gene Dbx2 was upregulated in vitro and in vivo, and its promoter
region had altered histone and DNA methylation levels, in aged NSPCs. Using
functional in vitro assays, we found that elevated Dbx2 expression in adult
NSPCs promotes age-related phenotypes. In particular, Dbx2 overexpression
reduced NSPC proliferation by impairing the G1/S and G2/M cell cycle
transitions, and caused the dysregulation of age-associated modulators of
NSPC self-renewal and differentiation. Depleting Dbx2 in aged NSPCs led to
the reverse gene expression changes. Taken together, these results provide
new insights into the molecular programmes that are affected during NSPC
ageing, and uncover a new functional role for Dbx2 in promoting age-related
neurogenic decline. |
giuseppe.lupo@uniroma1.it |
| 1 |
31 |
Hyunah |
Lee |
Department
of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and
Neuroscience, King's College London, LONDON, SE5 9RX, UK ¹ | Laboratory of
Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA ² |
The
effects of apolipoprotein E (APOE) polymorphism on human hippocampal
neurogenesis |
Hyunah
Lee ¹, Graham Cocks ¹, Lucia Dutan Polit ¹, Maria Carolina Marchetto ², Fred
H. Gage ², Jack Price ¹, Deepak Srivastava ¹, Sandrine Thuret ¹ |
Apolipoprotein
E4 (APOE4) allele is the most common genetic risk factor for Alzheimer's
disease, which is known to both increase the overall onset of the disease and
decrease the age of onset. Growing body of evidence suggests that APOE4 may
negatively affect adult hippocampal neurogenesis in the dentate gyrus, which
has been implicated in AD progression. However, the impact of APOE isoforms
on hippocampal neurogenesis at a cellular/molecular level is not fully
understood. In this study, time-course characterization of neurogenic
properties was performed on human isogenic APOE induced pluripotent stem
cells (iPSCs). Using an in vitro model of hippocampal neurogenesis that was
previously optimized in the lab, isogenic APOE iPSCs were differentiated to hippocampal
neural progenitors and dentate gyrus granule cell-like neurons. Compared to
neutral APOE3 homozygous cells, APOE4 homozygous cells showed significantly
different expression patterns for markers of hippocampal neural progenitors,
and PROX1, the marker for mature dentate gyrus granule cells. The gene
expression pattern of APOE and protein expression patterns of MAP2 and DCX
were comparable between APOE3 and APOE4 cells. The isogenic lines also showed
differential phenotypes for the expression of Ki-67, a marker for cell
proliferation, during neuronal differentiation. Taken together, our findings
suggest that APOE genotype can impact the course of hippocampal neurogenesis,
and that sustaining normal hippocampal neurogenesis can be a potential target
for early intervention against AD. Whether APOE genotype interacts with
environmental factors to either exacerbate or ameliorate the phenotypes we
have characterized thus far is currently under investigation. |
|
| 2 |
1 |
Curie |
Kim |
King's
College London |
Investigating the
impact of intermittent energy restriction and mastication on adult
hippocampal neurogenesis-associated cognition in an ageing population |
Curie Kim, Sophie Miquel, Wendy Hall and
Sandrine Thuret |
Adult
hippocampal neurogenesis (AHN) is needed for pattern separation, the ability
to differentially encode small changes derived from similar inputs, and
recognition memory, the ability to recognise previously encountered stimuli.
Intermittent energy restriction (IER) may increase neurogenesis as a
“cellular relic” of feeding patterns during evolution in response to
alternating famine and abundant food. Human trials have found significant
improvements in verbal recognition memory after 30% calorie reduction. IER
has been associated with significant increases in human brain activation
volume in areas involved in brain function control and plasticity. Food
texture and mastication have also been implicated. Decreased mastication in
humans and animals have a negative impact on AHN and associated cognition.
There is a close association between masticatory function, cognitive status
and age-related neurodegeneration in human elderly. Previous findings show
that a 4-week IER intervention can improve pattern separation performance in
43 individuals aged 35-75 years. It also resulted in increased levels of
serum α-klotho, an anti-ageing protein. A mastication intervention carried
out in 54 individuals aged 45-70 years old required participants to consume
chewing gum for 10 minutes, 3 times a day over 3 months. There was a
significantly bigger improvement in recognition memory compared to a
non-chewing control group. Following on from these findings, a 3-month
intermittent ER and mastication intervention trial is being carried out on
healthy human participants aged 60 years and older. The impact of IER and
mastication, independently and synergistically, on AHN-associated factors is
measured using the mnemonic similarity task and serum α-klotho. |
curie.kim@kcl.ac.uk |
| 2 |
2 |
Shane
Marie |
Ohline |
Department
of Psychology, University of Otago, Dunedin, New Zealand |
Adult-born
dentate granule cell excitability depends on the interaction of neuron age,
ontogenetic age and experience |
S.M.
Ohline1,3, K.L. Wake1,3, M.-V. Hawkridge4, M.F. Dinnunhan1,3, R.U.
Hegemann1,3, A. Wilson1,3, L. Schoderboeck1,2,3, B.J. Logan1,3, T.
Jungenitz4, S.W. Schwarzacher4, S.M.
Hughes2,3 and W.C. Abraham1,3
1Department of Psychology, and 2Department of Biochemistry, 3Brain Health
Research Centre and Brain Research New Zealand, University of Otago, Dunedin,
New Zealand
4Institute of Clinical Neuroanatomy, Goethe-University of Frankfurt,
Frankfurt am Main, Germany
|
Early
during their maturation, adult-born dentate granule cells (aDGCs) are
particularly excitable, but eventually develop the electrophysiologically
quiet properties of mature cells. However, the stability versus plasticity of
this quiet state across time and experience remains unresolved. By
birthdating two populations of aDGCs across different animal ages, we found
for 10-month-old rats the expected reduction in excitability across cells
aged 4-12 weeks, as determined by Egr1 immunoreactivity. Unexpectedly, cells
35 weeks old (after genesis at an animal age of 2 months) were as excitable
as 4-week-old cells, in the dorsal hippocampus. This high level of
excitability at maturity was specific for cells born in animals 2 months of
age, as cells born later in life did not show this effect. Importantly,
excitability states were not fixed once maturity was gained, but were
enhanced by enriched environment exposure or LTP induction, indicating that
any maturational decrease in excitability can be compensated by experience.
These data reveal the importance of the animal’s age for aDGC excitability,
and emphasize their prolonged capability for plasticity during
adulthood.
This work was made possible by a grant from the Marsden Fund administered
by the Royal Society of NZ. |
shane@psy.otago.ac.nz |
| 2 |
3 |
Rupert |
Overall |
DZNE
(German Center for Neurodegenerative Diseases) |
The
Adult Neurogenesis Map |
Rupert
W Overall |
The
hippocampus is a key brain structure for learning and memory. It not only
processes input from the environment, but also fundamentally influences
behaviour. This means that the neural network in the hippocampus is a core
part of an information loop connecting environmental stimulus and response.
It is particularly intriguing that this special brain region is also home to
a population of neural stem cells which allow the environmentally-regulated
creation of new neurons, throughout the life of the organism, that add an
extra level of flexibility to hippocampal performance. We have previously
shown that the regulation of the stem cell pool and the generation of new
neurons are under complex genetic control. We also maintain a structured
database of all genes reported to affect adult hippocampal neurogenesis in
some way. We are now extending this effort to encompass behavioural
phenotypes and environmental stimuli. The resulting information is being
organised into a structured SBML map to enable interactive browsing and
complex searching of the knowledgebase, as well as to provide a platform for
predictive modelling. We present here an outline and working draft of the
Adult Neurogenesis Map and look forward to community feedback as the project
expands. |
rupert.overall@dzne.de |
| 2 |
4 |
Julia |
Schneider |
Institute
of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg |
Astrogenesis
and dynamic of astrocytes in the mouse hippocampus |
Julia
Schneider, Julian Karpf, Ruth Beckervordersandforth |
The
brain comprises two broad classes of cells: neurons and glia cells.
Astrocytes are ranked to the glial family and fulfil a variety of functions.
In the dentate gyrus (DG) of the hippocampus, specialized astrocytes, known
as radial glia-like cells, function as neural stem cells and generate new
neurons and astrocytes. Non-radial astrocytes, which are major components of
the DG, contribute to the generation and survival of newborn neurons.
Astrocytes were believed to be homogenous within one region, but recent
events suggest that astrocytes are molecularly and functionally different.
Using a genetic labelling strategy, we found that the adult hippocampal
dentate gyrus is populated by morphologically distinct astrocytes that are
localized to specific compartments and associated to diverse processes.
Surprisingly, experiments revealed the proliferation of non-radial
astrocytes, which is in contrast to the prevailing assumption that astrocytes
are postmitotic in the non-injured brain. Based on these findings we aim to
describe hippocampal astrogenesis not only in the adult but also during
embryonic and fetal states. We attempt to answer the following questions:
What is the origin of embryonic and adult-born astrocytes? When does
astrogenesis start during embryogenesis? How do hippocampal astrocytes
develop and become morphologically and functionally different? In addition to
the proliferation potential of non-radial astrocytes, we could observe that
the proliferation could be influenced by the DG is composed of
morphologically and functionally distinct astrocytes, whose dynamics are
critical modulators for hippocampal adaption to changing conditions. Further
analysis revealed that adult astrogenesis and the survival of adult-born
astrocytes are increased under exercising conditions. As adult neurogenesis
is important for brain plasticity, a contributing role of adult astrogenesis
has to be investigated with an in vivo knock out model of dividing
astrocytes. Collectively, our study revealed structural heterogeneity and
subtype-specific dynamics of hippocampal astrocytes in response to
physiological stimuli. It will also enlighten the role of adult astrogenesis
on hippocampal plasticity. Furthermore, we aim to be the first who will
investigate adult and embryonic astrogenesis in the hippocampal neurogenic
niche. |
julia.js.schneider@fau.de |
| 2 |
5 |
Jariya |
Welbat |
Department
of Anatomy, Faculty of Medicine, Khon
Kaen University |
Effects
of Hesperidin on oxidative stress and hippocampal neurogenesis treatment in
adult rats treated with methotrexate |
Jariya
Umka Welbat, Salinee Naewla, Kornrawee Suwannakot, Anusara Aranarochana,
Apiwat Sirichoat, Wanassanan Pannangrong |
Methotrexate
(MTX) is a folic acid antagonist widely used a chemotherapeutic agent. MTX
induces formation of reactive oxygen species (ROS) and leads to
neurotoxicity, which is associated with a reduction neurogenesis. Hesperidin
(Hsd) is a flavanone glycoside found in citrus fruits. Hsd has antioxidant
activities and consequently prevent neuronal cell death. This study was
designed to evaluate the neuroprotective effect of Hsd against MTX-induced
oxidative stress and reductions of neurogenesis in adult rats. Sprague Dawley
rats were randomly divided into four groups. The vehicle group received
saline and propylene glycol. The Hsd group received Hsd (100 mg/kg) by oral
gavage for 21 days. The MTX group received MTX (75 mg/kg intravenous) by
intravenous injection on day 8 and 15 of the study and the MTX+Hsd group
received both MTX and Hsd. After treatment, oxidative stress [malondialdehyde
(MDA)] and antioxidant activities [superoxide dismutase (SOD), glutathione
peroxidase (GPx), and catalase (CAT)] were determined. Cell proliferation,
survival and immature neurons in the hippocampal dentate gyrus were
quantified using Ki67 and bromodeoxyuridine (BrdU) and doublecortin (DCX),
respectively. Increases in MDA and decreases in the antioxidant activities in
the hippocampus and prefrontal cortex were significantly observed in the
MTX-treated rats. In addition, MTX significantly reduced neurogenesis,
including cell proliferation, survival and immature neurons. However,
co-treatment with Hsd ameliorated the negative effects of MTX on oxidative
stress, antioxidant enzymes and neurogenesis. These findings suggest that Hsd
could prevent neurotoxicity effect of MTX by inhibiting oxidative stress and
increasing neuroprotective properties. |
jariya@kku.ac.th |
| 2 |
6 |
Apiwat |
Sirichoat |
Department
of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002,
Thailand |
Neuroprotective
effect of melatonin on impairments of spatial working memory and neurogenesis
caused by 5-fluorouracil in adult rats. |
Apiwat
Sirichoat, Kornrawee Suwannakot, Pornthip Chaisawang, Wanassanun Pannangrong,
Peter Wigmore, Jariya Umka Welbat |
Melatonin
is a hormone originally produced by the pineal gland. Melatonin can modulate
neurogenesis both in vitro and in vivo and protect deterioration of neurons
in the hippocampus. The objective of the present study was to investigate the
neuroprotective effects of melatonin on a reduction of spatial memory and
hippocampal neurogenesis caused by 5-fluorouracil chemotherapy in male
Spraque-Dawley rats. Animals were separated into 6 groups, including vehicle,
melatonin, 5-FU and co-administration with melatonin and 5-FU (preventive,
recovery and throughout) groups. 5-FU (25 mg/kg/day) was administered by i.v.
injection 5 times every 3 days, whereas melatonin (8 mg/kg/day) was given 1
time/day by intraperitoneal (i.p.) injection for 21 days and 42 days. Spatial
memory test was determined using the novel object location (NOL) test. Ki-67,
bromodeoxyuridine (BrdU) and doublecortin (DCX) were used to quantify the
numbers of cell proliferation, cell survival and immature neurons,
respectively. The results demonstrated that 5-FU-treated animals did not
prefer either objects in familiar or novel locations. Moreover, 5-FU
significantly reduced numbers of Ki-67, BrdU and DCX positive cells. These
results indicate that 5-FU treatment caused impairments of spatial working
memory, cell proliferation, survival and immature neurons in the SGZ of the
hippocampal DG. However, these aberrations were restored to control levels by
co-treatment with melatonin in all time periods. These data suggest that
melatonin could prevent and restore the spatial working memory and
neurogenesis impairments caused by 5-FU. |
apiwsi@kku.ac.th |
| 2 |
7 |
Odette |
Leiter |
The
University of Queensland; Technische Universität Dresden |
Exercise-induced
activated platelets increase adult hippocampal neurogenesis |
Odette
Leiter, Suse Seidemann, Rupert W. Overall, Beáta Ramasz, Nicole Rund, Sonja
Schallenberg, Tatyana Grinenko, Ben Wielockx, Gerd Kempermann and Tara L.
Walker |
Systemic
factors contribute to the regulation of adult hippocampal neural precursor
cells. Physical exercise is associated with systemic changes and represents a
strong positive physiological stimulus of neural precursor cell
proliferation. However, the mechanisms underlying these effects are largely
unknown. We show that dentate gyrus primary cultures form significantly more
neurospheres when treated with serum from running mice. Using proteomic
screening of mouse plasma following exercise, we identified platelets and
their released factors as potential mediators of this effect. We found that
platelets are activated after short periods of exercise and that activated
platelets promote neurogenesis. Similarly, treatment with platelet factor 4,
a protein released after platelet activation and elevated in the plasma of
running mice, increased neurogenesis. Ex vivo, the neurogenesis-promoting
effects of activated platelets and platelet factor 4 were exclusively
observed in dentate gyrus primary cultures but not in cultures derived from
the subventricular zone. Moreover, in mice depleted of circulating platelets,
the dentate gyrus-specific running-induced increase in precursor cell
proliferation was absent. Our data demonstrate that platelets and their released
factors can modulate adult neural precursor cells under physiological
conditions and provide an intriguing link between running-induced platelet
activation and the regulation of neural precursor cells following exercise. |
o.leiter@uq.edu.au |
| 2 |
8 |
Victor |
Luna |
Columbia
University/RFMH |
Adult-born
Neurons Monosynaptically Inhibit and Excite Mature Granule Cells in the
Dentate Gyrus |
Victor
M. Luna, Christoph Anacker, Nesha S. Burghardt, Hameda Khandaker, Valentine
Andreu, Amira Millette, Paige Leary, Rebecca Ravenelle, Jessica C. Jimenez,
Alessia Mastrodonato, Christine A. Denny, Andre A. Fenton, Helen E.
Scharfman, Rene Hen |
Young
adult-born granule cells (abGCs) in the dentate gyrus (DG) of the hippocampus
have a profound impact on cognition and mood. However, it remains unclear how
abGCs uniquely contribute to local DG information processing. Using a
combination of electrophysiology, optogenetics, pharmacology, and behavior,
we show that the actions of abGCs in the DG depend on the origin of incoming
afferents. In response to lateral entorhinal cortex (LEC) inputs, abGCs
surprisingly exert monosynaptic inhibition of developmentally-born mature
granule cells (mGCs) via group II metabotropic glutamate receptors. In
contrast, in response to medial entorhinal cortex (MEC) inputs, abGCs
directly excite mGCs via glutamatergic N-methyl-D-aspartate receptors likely
containing the atypical NR3 subunit. These modulatory mechanisms are utilized
exclusively by abGCs and not mGCs. Moreover, we find that
neurogenesis-dependent inhibition and excitation appear to contribute to the
differences in sub-regional activity levels within the DG during an active
place avoidance task and a novel object recognition task. Our results suggest
that a critical function of abGCs may be to regulate the relative synaptic
strengths of LEC-driven contextual information versus MEC-driven spatial
information to shape distinct neural representations in the DG. We therefore
propose that abGC-driven inhibition and excitation depends on the demands of
the environment, which can be reflected in the activity of cortical as well
as sub-cortical regions sending inputs to the DG. |
vl2323@cumc.columbia.edu |
| 2 |
9 |
Jadna |
Bogado
Lopes |
German
Center for Neurodegenerative Diseases (DZNE) Dresden, Center for Regenerative
Therapies TU Dresden (CRTD), Technische Universität Dresden, Dresden,
Germany. |
What
is the role of new-neurons in the development of individual behaviour? |
J
Bogado-Lopes, F Ehret, AN Grzyb, AE Rünker, G Kempermann |
The
interaction of individuals with their environment leads to the development of
distinct behavioural patterns. Previously, we showed that isogenic mice kept
in an enriched environment (ENR) established divergent and stable social and
exploratory trajectories. Remarkably, the amount of exploratory activity,
measured as roaming entropy (RE), correlated positively with adult
hippocampal neurogenesis (AHN), a cellular plasticity mechanism in the
hippocampus. We hypothesised that the feedback between activity (and hence
experience of the environment) and brain plasticity, including AHN, is a core
mechanism underlying brain individualization in ENR. To investigate whether
disruption of AHN would compromise the exploratory activity and
individualisation processes, we here used cyclin D2-ko mice with
constitutively suppressed AHN (but normal hippocampal development), and their
wild-type littermates (n = 40). Animals were housed together for 3-months in
a novel large ENR enclosure consisting of 70 connected cages equipped with
radio antennae for longitudinal tracking. Their cognitive performance was
evaluated in the Morris Water Maze task (MWM) and AHN levels were assessed
using BrdU labeling. We confirmed that the number of BrdU positive cells
correlated with RE in the wild-type animals, and cyclinD2-ko mice had
impaired performance in the reversal phase of MWM. Whereas wild-type animals
developed stable exploratory trajectories, the behaviour of cyclinD2-ko mice
remained more random. Furthermore, different patterns of correlations between
exploratory behaviour, cognitive performance and AHN were observed in
wild-type and knockout mice. Together, these results suggest that adult
neurogenesis may have a crucial role at the individualisation of brain-related
phenotypes. |
jadna.bogado_lopes@tu-dresden.de |
| 2 |
10 |
Tara |
Walker |
The
University of Queensland |
Selenium
increases hippocampal neurogenesis and rescues the age-related cognitive
decline |
Tara
L Walker, Ruslan Rust, Lisa Grönnert, Joanna M Wasielewska, Susann Ruhwald,
Rupert W Overall, Vijay S Adusumilli, Daniel G Blackmore, Nicole Rund,
Alexander M Sykes, Annette E Rünker, Odette Leiter, Perry F Bartlett and Gerd
Kempermann |
Adult
hippocampal neurogenesis, the lifelong generation of new neurons decreases
with age, and results in a concomitant decline in particular forms of
learning and memory. This process can be positively regulated by a wide range
of external stimuli, one of which is diet. We show that the trace element
selenium increased the number of proliferating neural precursor cells and
newly born neurons in the hippocampus of young adult and aged mice.
Importantly, dietary selenium supplementation also rescued the age-related
decline in hippocampus-associated learning and memory. Selenium is the core
regulator of the ferroptotic cell death pathway. We found that selenium
treatment reduced levels of intracellular reactive oxygen species and blocked
lipid peroxidation, hallmarks of ferroptotic cell death, specifically in
nestin+ precursor cells. In addition, in vivo infusion of the ferroptosis
inhibitor liproxstatin-1 significantly increased the number of proliferating
hippocampal precursor cells.
Conversely, infusion of the ferroptosis inducer RSL-3 reduced
precursor proliferation, and imaging by electron microscopy revealed
alterations in mitochondrial morphology that are characteristic of cells
undergoing ferroptotic cell death. Together this data suggests that selenium
acts to increase hippocampal neurogenesis via a reduction in ferroptotic cell
death at the precursor cell stage. |
t.walker1@uq.edu.au |
| 2 |
11 |
Thomas |
Kerloch |
Neurocentre
Magendie INSERM U1215 |
Rnd2:
a new player in the regulation of adult hippocampal neurogenesis |
Thomas
Kerloch, Fanny Farrugia, Marlène Maître, Muriel Koehl, Mylène Blanchard,
Hélène Doat, Thierry Leste-Lasserre, Julian Ik-Tsen Heng, Adeline Goron,
Delphine Gonzales, François Guillemot, Djoher Nora Abrous, Emilie Pacary |
In
most areas of the brain, neurons are born during embryogenesis. In contrast,
the majority of granule neurons in the dentate gyrus (DG) of the hippocampus
are born postnatally and their generation continues throughout adulthood.
This finding that new neurons are generated in the adult mammalian brain has
opened novel avenues for brain repair and has initiated, in the last 20
years, tremendous efforts to characterize how new neurons differentiate and
integrate into adult neural circuitries. However, further studies are needed
to better understand the mechanisms and signaling cascades involved in this
process.
Although neurogenesis is a highly choreographed process that requires an
extensive and dynamic remodeling of the cytoskeleton, very little is known
about the role of cytoskeletal regulators during adult neurogenesis. In
particular, few studies have addressed the roles played by RhoGTPases, the
master regulators of cytoskeleton rearrangements. In this context, we focused
on Rnd2, a Rho GTPase particularly enriched in the temporal part of the adult
mouse DG and expressed in endosomes. We found, using retrovirus in vivo, that
the deletion of Rnd2 specifically in adult-born hippocampal neurons decreases
the survival of these cells, and in the surviving ones, leads to soma
hypertrophy, increases dendritic arborization and induces mispositioning.
Moreover, we show that Rnd2 is critical for adult hippocampal newborn neuron
survival, only during a defined period of their development at the immature
stage when they integrate the hippocampal circuitry. Importantly, Rnd2
deletion in adult-born hippocampal neurons also increases anxiety-like
behavior in mice, thus identifying Rnd2 as a potential novel target for
anxiety disorders. In addition, our data show that Rnd2 does not play the
same functions in granule neurons born at P0, highlighting a differential
regulation of developmental and adult neurogenesis in the DG and
demonstrating that Rnd2 has specific functions in adult-born neurons.
Altogether our data demonstrate that Rnd2 is a critical regulator of adult
newborn neuron development and function in the hippocampus and highlight new
important functions for this RhoGTPase in vivo.
|
emilie.pacary@inserm.fr |
| 2 |
12 |
Elena
P. |
Moreno
Jiménez |
Centro
de Biología Molecular Severo Ochoa (CBMSO) |
ADULT
HIPPOCAMPAL NEUROGENESIS IS A ROBUST PHENOMENON DURING PHYSIOLOGICAL AGING IN
HUMANS |
E. P.
Moreno-Jiménez, M. Flor-García, J. Terreros-Roncal and M. Llorens-Martín |
The
hippocampus hosts one of the most unique phenomena of the adult mammalian
brain, namely, the addition of new neurons throughout life. This process,
named adult hippocampal neurogenesis (AHN), confers an unparalleled degree of
plasticity to the entire hippocampal circuitry. Nonetheless, direct evidence
of AHN in humans has remained elusive. Thus, determining whether new neurons
are continuously incorporated into the human dentate gyrus (DG) during
physiological aging is a crucial question with outstanding therapeutic
potential. By combining brain samples from neurologically healthy subjects
(between 42 and 87 years of age) obtained under tightly controlled
conditions, and state-of-the-art tissue processing methods, we identified
thousands of immature neurons in the DG of neurologically healthy human
subjects up to the ninth decade of life. Our results strongly support the
persistence of AHN during physiological aging in humans. Therefore, we
addressed whether cell subpopulations at distinct stages of maturity could
also be distinguished among DCX+ cells in the human DG. To this end, we first
analyzed the expression of cell markers characteristic of different
maturation stages of AHN in human DCX+ cells. Moreover, we analyzed
morphometric features of double-labeled cells. Based on both the percentages
of double-labeled cells and their morphological features, we have outlined
the first proposed model of the differentiation stages of AHN in humans. Our
data bring to light the existence of a dynamic population of immature neurons
in the human DG throughout physiological aging until the tenth decade of
life. These findings point to unexplored mechanisms of circuit plasticity in
the aging human hippocampus. |
elena.moreno@cbm.csic.es |
| 2 |
13 |
Vanessa |
Charrier |
Neurocentre
Magendie INSERM U1215 |
Influence
of spatial learning on the connectome of adult-born neurons in rats |
Charrier
V, Masachs N, Farrugia F, Blin N, Proton V, van Praag H, Gage FH, Callaway
ME, Abrous DN. |
Experience
such as learning enhances adult hippocampal neurogenesis in the dentate
gyrus, a brain region essential for learning and memory, by promoting newborn
neurons integration into the established network and by increasing the
complexification of their dendritic arborisation. In return, adult-born
neurons play an important role in the encoding of new memories, especially
during spatial learning. Yet, it is still unknown how the connectome of
adult-born neurons is influenced by spatial learning, though these
connections are the source of their activation and role in memory. Here,
using an approach allowing the visualization of the glutamatergic
post-synaptic densities and a retroviral retrograde monosynaptic tracing
method, we characterized the connectome of adult-born neurons following
spatial learning at different time points of their maturation. First, we
showed that the total glutamatergic post-synaptic density of immature
adult-born neurons as well as the one of each sub-part of the molecular layer
increased following spatial learning, suggesting an enhanced excitatory
innervation. We demonstrated that this enhancement first corresponds to a
transient increase in the innervation from other mature granule cells during
the first days of life of newborn neurons and would be needed for a
successful integration into the network. This transient increase is followed
later in the maturation process by an enhanced innervation from the lateral
entorhinal cortex and then from the CA3 region. Once adult-born neurons reach
full maturity, we showed that spatial learning similarly increased their
glutamatergic innervation. Our results suggest a modulation by spatial
learning of the adult-born neurons connectome during their maturation. |
vanessa.charrier@inserm.fr |
| 2 |
14 |
Miguel |
de la
Flor García |
Centro
de Biología Molecular Severo Ochoa (CBMSO) |
UNMASKING
NEWBORN DENTATE GRANULE CELLS IN ADULT HUMANS |
M.
Flor-García, J. Terreros-Roncal, E. P. Moreno-Jiménez and M. Llorens-Martín |
Hippocampal
dentate gyrus (DG) hosts one of the most unique phenomena of the adult
mammalian brain, namely adult hippocampal neurogenesis (AHN). AHN results in
the generation of dentate granule cells (DGCs). However, direct evidence of
human AHN remains elusive. Thus, we sought to determine the existence of AHN
in human samples. To this end, we tested different combinations of NaBH4,
glycine and heat-mediated citrate buffer antigen retrieval (HC-AR) using
brain samples obtained from neurologically healthy subjects until 87 years of
age. We chose 0.5% NaBH4 plus a HC-AR as the best sample treatment to unmask
newborn DGCs in immunofluorescence assays. Then, we performed stereological
counts of DGCs positive for validated doublecortin (DCX) and polysialylated-neural
cell adhesion molecule (PSA-NCAM) markers in 4 non-unmasked control samples
fixed during 1, 2, 4, 6, 12, 24 and 48 hours in 4% PFA. We observed that the
density of DGCs for each marker decreased as fixation times increased,
though, a recovery in the densities for both markers was reached by
pre-unmasking samples. Also, we studied the influence of other fixative
solutions using samples fixed in 3.7% formalin, but DGCs densities for any
marker could be recovered by this novel method. Finally, we analysed
pre-unmasked samples from 13 neurologically healthy subjects correlating both
markers densities with post-mortem delay (PMD). Nevertheless, PMD showed not
to affect DCX+ or PSA-NCAM+ DGCs densities. Taken together, these
observations demonstrate the great importance of fixative solutions and
unmasking procedures used instead of PMD for the newborn DGCs analysis in
human samples. |
miguedel@ucm.es |
| 2 |
15 |
Mariela |
Trinchero |
Leloir
Institute |
A
critical period for experience-dependent plasticity in neurons born in the
aged hippocampus |
Mariela
F. Trinchero, Magalí Herrero, M.
Cristina Monzón-Salinas, and Alejandro F. Schinder
|
The
aging brain displays a generalized decline in cognitive capacity and circuit
plasticity, including a decline in the production of adult-born hippocampal
neurons. Morphological development of new dentate granule cells (GCs) is also
affected by age. However, their functional properties and integration to the
circuit along maturation remains unclear. We performed whole-cell recordings
in 8-month old (8M) Ascl1(CreERT2);CAG(floxStopTom) mice to assess intrinsic
properties, firing behavior and afferent excitatory connectivity in
adult-born GCs labeled with tdTomato. We found that functional properties and
connectivity of these neurons develop very slowly. Despite the delayed
maturation, new GCs in aging mice display a remarkable potential for
structural plasticity. Retrovirally labeled 3-week-old GCs in middle-aged
mice are small, underdeveloped and disconnected. Notably, we found that a
7-day exposure to an enriched environment (EE) induced substantial dendritic
growth, spine formation and increase in the number of filopodia of mossy
fiber boutons in CA3, indicating that experience boosts both input and output
connectivity. EE was particularly
effective in promoting integration during the second week of GCs development,
but not earlier or later. Moreover, EE accelerated maturation of intrinsic
membrane properties and functional integration of new GCs. This short period
of increased responsiveness to hippocampal activity induced by experience
unveils high levels of neuronal plasticity in the aging brain. |
mftrinchero@gmail.com |
| 2 |
16 |
Frédéric |
Cassé |
Center
for psychiatric neurosciences, Lausanne University Hospital, Switzerland |
An
astrocyte-secreted peptide that increase adult hippocampal neurogenesis |
Frédéric
Cassé, Charline Carron, Kevin Richetin, Thomas Larrieu and Nicolas Toni |
Adult
hippocampal neurogenesis is regulated by astrocytes, which provides a
structural and molecular support for adult neuronal stem cell (aNSCs)
proliferation and differentiation and for the functional integration of new
neurons.
In this study, we investigated the
effect of astrocytic-released molecules on mouse hippocampal adult
neurogenesis. By using the doxycyclin-dependent inducible expression of a
dominant-negative form of synaptobrevin-2 (dnSNARE) in astrocytes we blocked
astrocytic vesicular release. Interestingly, we found a decrease of aNSCs
proliferation in the dentage gyrus (DG) of the dnSNARE mice suggesting that
astrocytic molecules released by SNARE dependent process control adult
neurogenesis.
Using a combination of in vitro approaches, biochemistry and mass
spectrometry, we identified a peptide released by astrocytes that regulate
adult neurogenesis. The secreted peptide, that we named peptide P9, is
derived from the phospoprotein enriched in astrocyte protein (PEA15) which is
a cytoplasmic protein involved in intracellular signaling and can regulates
diverse cellular processes, such as proliferation and apoptosis.
Interestingly, P9 increased aNSCs proliferation both in vitro and in vivo and
increased the number of newborn hippocampal neuron. However, despite its
effect on adult hippocampal neurogenesis, P9 neither enhanced memory
performance nor affected basal anxiety-like behavior.
These results indicate that astrocytes release peptides that regulate
hippocampal neurogenesis in the adult brain. Understanding the mechanism of
action of the astrocyte-secreted peptide P9 on adult neurogenesis in the
hippocampus could be an interesting therapeutic strategy in order to control
neurogenesis in pathological conditions.
|
frederic.casse@unil.ch |
| 2 |
17 |
Vijay
S |
Adusumilli |
German
Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden, Germany |
Redox
potential defines functional states of adult hippocampal stem cells
|
Vijay
S Adusumilli*, Tara L Walker*, Rupert W Overall*, Gesa M Klatt , Salma A
Zeidan, Tim J Fischer, Sara Zocher, Alex M Sykes, Susanne Reinhardt, Andreas
Dahl, Dilyana G Kirova, Jörg Mansfeld, Annette E Rünker, and Gerd Kempermann |
Intracellular
redox states regulate the balance between stem cell maintenance and
activation. Increased levels of reactive oxygen species (ROS) are linked to
proliferation and lineage specification. In contrast to this general
principle, we show that in the hippocampus of adult mice it is the quiescent
neural stem cells (NSCs) that maintain the highest ROS levels (hiROS).
Classifying NSCs based on intracellular ROS content identified subpopulations
with distinct molecular profiles, corresponding to functional states. Shifts
in ROS content primed cells for a subsequent transition of cellular state,
with lower cellular ROS content marking activity and differentiation.
Physical activity, a known physiological activator of adult hippocampal
neurogenesis, recruited the quiescent hiROS NSCs into proliferation via a
transient Nox2-dependent ROS surge. In the absence of Nox2, baseline
neurogenesis was unaffected, but the activity-induced increase in
proliferation disappeared. These results describe a novel mechanism linking
the modulation of cellular ROS by behavioral cues to the maintenance and
activation of adult NSCs.
|
Vijay.Adusumilli@dzne.de |
| 2 |
18 |
Meredith |
Lodge |
Department
of Biomedicine, University of Basel, Switzerland |
Differential
Synaptic Activation of α5-containing GABAA Receptors in Adult-born Young and
Mature Hippocampal Granule Cells |
Lodge,
M.E., Schulz, J. M., Bischofberger, J. |
γ-Aminobutyric
acid (GABA), the main inhibitory transmitter in the adult brain, acts as a
trophic factor during the development of adult-born granule cells in the
dentate gyrus. GABAergic synaptic currents have been observed in young cells
from as early as 4 days post-mitosis, however the molecular composition of
GABAA receptors in somatic and dendritic synapses are largely unknown . Here
we investigated soma-targeting inhibition using either electrical stimulation
of the granule cell layer, or optogenetic stimulation of parvalbumin-positive
GABAergic interneurons. Dendritic inhibition was examined using either
electrical stimulation of the molecular layer, or optogenetic stimulation of
somatostatin-positive interneurons. We found that both forms of inhibition
were present from as early as 9 days post-mitosis. Furthermore, we
investigated the voltage dependence of synaptic GABAA receptors in young
granule cells and found that the inputs are highly non-linear, with strong
outward rectification. While both dendritic and somatic inputs onto young
cells showed rectifying properties,
mature granules cells only showed rectification in dendritic inputs,
suggesting that GABAA receptors present in peri-somatic synapses in young
granule cells are different from those in mature. Due to the slow kinetic
properties of IPSCs seen in young cells, we tested for the presence of
α5-containing GABAA receptors. We found that young granule cells have
α5-GABARs present in both dendritic and peri-somatic synapses, while in
mature neurons these are specifically
targeted into dendritic synapses.
Supported by Swiss National Science Foundation (SNSF 31003A-176321)
|
meredith.lodge@unibas.ch |
| 2 |
19 |
Samuel |
Domínguez
García |
Universidad
de Cádiz |
NEUROGENESIS,
LEARNING AND MEMORY FACILITATED BY CHRONICAL ADMINISTRATION OF A PROTEIN
KINASE C ACTIVATING COMPOUND |
Samuel
Dominguez-García, Carmen Hierro-Bujalance, Noelia Geribaldi-Doldán, A.J.
Macías-Sánchez , Rosario Hernández-Galán, Mónica García-Alloza and Carmen
Castro |
A
therapeutic option to achieve neuronal renewal in damaged adult brains, is
promoting endogenous neurogenesis. We have previously seen that
12-deoxyphorbols activate PKC promoting the proliferation of adult neural
progenitor cell (NPC) in vitro and in vivo, with the advantage that they lack
tumorogenic activity. Intracerebroventricular administration of
12-deoxyphorbols such as ER272, induces the proliferation of NPC within the
subventricular zone and the dentate gyrus of the hippocampus facilitating the
generation of new neurons. In order to find a non-invasive method to deliver
this compound in the adult brain overcoming the blood brain barrier, we have
tested whether intranasal administration of ER272 exerts a similar effect on
proliferation. We have analyzed in here the effect of intranasal
administration during 3, 7 and 28 days. After treatment, an increase in the
proliferation of NPCs was observed in both SVZ and DG compared with the
control. Chronical intranasal administration of ER272 for 28 days increased
the number of neuroblasts and neurons within the DG of the hippocampus. In
addition, intranasal administration of ER272 for 28 days improved performance
of mice in the Morris Water Maze and in new object discrimination tasks
indicating it improved memory and learning tasks. These results suggest that
intranasal administration is a good non-invasive method of administration of
12-desoxyphorbols, which can be use to promote neuronal replacement for the
treatment of neurological disorder.
Funded by the Spanish Consejería de Innovación, Ciencia y Empleo, Junta de
Andalucía (P10CTS6639), and by Ministerio de Economía y Competitividad
(BFU2015-68652-R, and BFU2016-75038-R MINECO/FEDER)
|
samuel.dominguez@uca.es |
| 2 |
20 |
Ricardo |
Gomez
Oliva |
Universidad
de Cadiz |
CLASSICAL
PKC ACTIVATION FACILITATES TGF-alpha RELEASE PROMOTING UNDIFFERENTIATED
PROGENITOR CELL PROLIFERATION IN THE SUBVENTRICULAR ZONE |
Ricardo
Gómez-Oliva, Pedro A. Nunez-Abades, Noelia Geribaldi-Doldán, Samuel
Domínguez-García, Livia Carrascal, Félix A. Ruiz and Carmen Castro |
Neurogenic
niches such as the subventricular zone (SVZ) harbor neural stem cells (NSC),
which generate new neurons and glial cells throughout a lifetime. Upon
activation NSC give rise to transit amplifying undifferentiated progenitors,
which generate neuroblasts that migrate to the olfactory bulb. Activated NSC
and undifferentiated progenitors are colony forming cells when isolated and
cultured in vitro. Both types of cells express the epidermal growth factor
receptor (EGFR) and proliferate in response to the epidermal growth factor
(EGF). Activation of protein kinase C (PKC) by non-tumorigenic diterpenes
such as 12-deoxyphorbols promotes proliferation of SVZ-isolated cells in
vitro in a PKC-dependent manner and in vivo when infused into the SVZ. Here,
we have elucidated the cellular and molecular mechanisms underlying the
proliferative effect of 12-deoxyphorbols. We show herein that SVZ isolated
cells cultured as neurospheres in the presence of 12-deoxyphorbols maintain a
proliferation rate similar to cultures treated with the epidermal growth
factor and this effect is dependent on PKC-alpha activation. Moreover,
12-deoxyphorbols specifically promote proliferation of EGFR+ undifferentiated
progenitors when infused in the SVZ. Using cells transfected with a construct
expressing TGF-alpha fused to Cherry and green fluorescent protein in
opposite ends, we show that 12-deoxyphorbols facilitate the release of the
EGFR ligand transforming growth factor alpha (TGF-alpha) upon activation of a
PKC of the classical subfamily. These results highlight the role of
12-deoxyphorbols as potential drugs to induce neurogenesis for the treatment
of neurological disorders.
Funded by Spanish Ministerio de Ciencia, Innovación y Universidades
(BFU2015-68652-R). |
ricardo.gomez@uca.es |
| 2 |
21 |
Chiara |
La
Rosa |
Neuroscience
Institute Cavalieri Ottolenghi |
Cell proliferation and amount of
doublecortin-positive neurons in the dentate gyrus of different mammalian
species |
Chiara
La Rosa, Chiara Olmeo, Marco Ghibaudi, Irmgard Amrein, Luca Bonfanti |
Adult
neurogenesis extension, rate, time course and functions can be quite
heterogeneous among mammals. No systematic, fully comparable analyses are
available on a wide range of animal species. Knowledge is restricted to the
“extremes”: high rate of neurogenesis in small-brained rodents versus
reduced/vestigial in large-brained humans and dolphins. A debate is ongoing
due to reports with different conclusions about the rate and temporal
extension of adult human hippocampal neurogenesis (e.g., Sorrells et al.
2018; Moreno-Jiménez et al. 2019); in all cases, doublecortin-positive (DCX+)
“immature” neurons were observed during adulthood, while no substantial cell
proliferation was detectable.
Here, the optical Fractionator with StereoInvestigator software was used to
estimate the number of granule cells, DCX+ and Ki-67+ cells in three adjacent
sections (of corresponding levels) of the dentate gyrus (DG) of young-adult
rabbits, cats, and sheep. Preliminary data indicate that in brain sheep, the
largest/most gyrencephalic considered, the number of DCX+ cells is 80-fold
higher with respect to proliferating cells, while in rabbit, the
smallest/most lissencephalic brain, the ratio is about 9.
These data suggest that in gyrencephalic brains hippocampal immature
neurons might persist for a long time in a state of protracted maturation.
Previous studies carried out in the hippocampus of sheep and monkeys showed
that newly born neurons mature far slower than in rodents (3 to 6 months:
Brus et al. 2013). This trend is reminiscent of what has been described in
adult humans, and might be shared by newly generated and non-newly generated
immature neurons in large-brained mammals. |
chiara.larosa@unito.it |
| 2 |
22 |
Joana |
Mateus |
1-Instituto
de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de
Lisboa, Lisboa, Portugal; 2-Instituto de Medicina Molecular João Lobo Antunes
(iMM), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal. |
Adenosine
A2AR as modulators of adult oligodendrogenesis: a potential target for MS
therapy |
Joana
Moura Mateus1,2, Marta Alonso Gomes1,2, Rita Soares1,2, Sara L Paulo1,2,
Ângelo F Chora2, Ana M Sebastião1,2, Sara Xapelli1,2 |
Under
Multiple Sclerosis (MS) pathological conditions, there is a depletion of
oligodendrocytes (OLs), but oligodendrocyte precursor cells (OPCs) present in
the brain parenchyma or derived from subventricular zone (SVZ) neural stem
cells (NSCs) can differentiate, migrate and partially remyelinate the
lesioned areas. Previous data from our group demonstrated that activation of
adenosine A2A receptors (A2AR) promoted SVZ-NSCs oligodendroglial
differentiation, both in vitro and in vivo. Hence, we aimed at understanding
the role of A2AR in adult oligodendrogenesis derived from SVZ-NSCs in an in
vivo mouse model of MS. For this, the EAE mouse model was developed, and
behavioural tests (open field, rotarod, pole test) were performed to evaluate
motor function. Cellular differentiation was assessed by immunohistochemistry
assays for bromodeoxyuridine (BrdU) colocalization with oligodendrocytic
markers in brain regions of interest. Western blot and ELISA assays were used
for myelin protein levels and inflammatory cytokine quantification. Our
results for EAE model characterization suggested that motor impairment was
proportional to the score of the disease and cellular and molecular data
showed an increase in the levels of the pro-inflammatory cytokine TNFα (n=5,
p<0.01). A significant increase in NG2+BrdU+ cells in the corpus callosum
(CC) of EAE mice was observed (n=3, p<0.05), hinting at the migration of
precursor cells from the SVZ to the CC.
Ongoing studies encompass the administration of A2AR agonist CGS21680
in the lateral ventricle for 28 days and assessing its effect on EAE
phenotype and adult oligodendrogenesis, ultimately unveiling the modulation
of adult oligodendrogenesis as a putative therapy for MS. |
joanammateus95@gmail.com |
| 2 |
23 |
Muriel
D. |
Mardones |
1Institute
of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences,
Universidad Andres Bello; 2McGovern Institute for Brain Research, MIT,
Cambridge, MA, United States; 3Instituto de Ciencias Biomédicas, Facultad de
Ciencias de la Salud, Universidad Autónoma de Chile; 4Centro de
Envejecimiento y Regeneración (CARE), P. Universidad Católica de Chile. |
PSD95
regulates maturation of adult-born neurons in the mouse hippocampus |
Muriel
D. Mardones1, Patricia V. Jorquera1, Andrea Herrera-Soto1, Fernando J.
Bustos1,2, Estibaliz Ampuero3, Brigitte van Zundert1,4 and Lorena
Varela-Nallar1. |
The
generation of new neurons in the dentate gyrus of the adult mouse hippocampus
involves proliferation of neural stem cells, differentiation, neuronal
maturation and integration of new neurons into the hippocampal network. The
scaffold postsynaptic density protein 95 (PSD95) regulates dendritogenesis,
synaptic formation, and spine morphogenesis of hippocampal neurons during
embryonic development. Here we evaluated the role of PSD95 in adult
hippocampal neurogenesis. Retroviruses expressing a control shRNA or an shRNA
targeting PSD95 (shPSD95), and the ZsGreen reporter protein were
stereotaxically injected into the dentate gyrus of 2-month-old mice. Animals
were sacrificed 2 or 4 weeks post injection (wpi). PSD95 knockdown did not
affect differentiation of newborn cells into neurons as assessed 2 wpi by
double immunostaining for ZsGreen and the immature neuronal marker DCX. At 4
wpi, PSD95-deficient neurons expressing the mature neuronal marker NeuN
showed an increase in total dendritic length, and in the number of high-order
dendrites. Moreover, dendrites from shPSD95-expressing newborn granule
neurons showed a reduction in the density of dendritic spines. Our results
indicate that PSD95 is required for the final stages of morphological
maturation of adult-born granule neurons.
Supported by: FONDECYT N°1190461 (LVN); FONDECYT Nº1181645 and CARE-UC AFB
170005 (BvZ); Nucleo UNAB DI-4-17/N (LVN, BvZ); FONDECYT Nº 11180540 (FJB).
FONDECYT N°11180777 (EA) |
muriel.mardones.diaz@gmail.com |
| 2 |
24 |
Carmen |
Vivar |
Laboratory
of Neurogenesis and Neuroplasticity. Department of Physiology, Biophysics,
and Neuroscience, Center for Research and Advanced Studies of the National
Polytechnic Institute, Mexico City |
Long-term
exercise modifies the neuronal network of adult-born granule cells |
Carmen
Vivar |
The
adult mammalian brain continuously generates new neurons in the hippocampus.
The integration of newborn neurons into the existing hippocampal neuronal
network is physiologically important for learning and memory. Adult
neurogenesis is upregulated by exercise and this increment correlates with
improved synaptic plasticity and memory functions. In addition, exercise
evokes robust effects on neural plasticity with a rapid onset that evolves
over time. We previously described that adult-born hippocampal neurons are
sequentially innervated by structures important for memory function forming a
unique neuronal circuit and that this circuit is remodeled by one month of
physical activity. To understand how exercise enhances learning and memory,
we evaluated the long-term modifications to the circuitry of adult-born
neurons. Using a combination of retrovirus to label dividing cells and rabies
virus as a retrograde tracer we identified the monosynaptic inputs to the
adult-born hippocampal neurons in young male C57Bl/6 mice (5-6 weeks old) in
sedentary control or exercise conditions. Stereotaxic surgeries were
performed to deliver the retrovirus into the right dentate gyrus (DG) of the
hippocampus, and 3 or 5 months thereafter rabies virus was injected into the
same DG location. Preliminary histological analysis shows transsynaptic
labeling of both subcortical and cortical afferents to the DG. These
projections were modified by voluntary wheel running in a time-dependent
manner suggesting that exercise induces long-lasting modifications to the
adult-born hippocampal circuit. |
cvivar@fisio.cinvestav.mx |
| 2 |
25 |
Hiyaa |
Ghosh |
National Center for Biological Science, Tata Institute of
Fundamental Research, Bangalore, India |
A novel regulator of adult neurogenesis and fate-decision in the
dentate gyrus |
|
|
hiyaa@ncbs |
| 2 |
26 |
Jana |
Heppt |
University
Erlangen-Nürnberg, Institute of Biochemistry |
The
role of canonical Wnt-signaling in maturation of adult hippocampal neurons |
Jana
Heppt1, Marie-Theres Wittmann2, Benjamin Häberle1, Nilima Prakash3, D.
Chichung Lie1
1Institute of Biochemistry, Friedrich-Alexander Universität
Erlangen-Nürnberg, Germany
2Institute of Human Genetics, Friedrich-Alexander Universität Erlangen-Nürnberg,
Germany
3Institute of Developmental Genetics, Helmholtz Zentrum München, Germany |
It
has been established that precise regulation of maturation and functional
integration of new-born neurons is essential for adult hippocampal
neurogenesis-dependent memory formation, however molecular regulation of this
key developmental step remains largely unknown.
Using reporter mouse lines for canonical Wnt-signaling activity, we could
show a drop of canonical Wnt-activity after fate specification and
re-activation at the timepoint of functional integration, which points
towards the importance of canonical Wnt-signaling for maturation.
To investigate the function of canonical Wnt-signaling in maturation we
generated a transgenic mouse line that allowed activation of canonical
Wnt-signaling via expression of stabilized β-catenin. While continuous
Wnt-signaling activity throughout development led to neurons with aberrant
morphology, timed activation of canonical Wnt-signaling in immature neurons
resulted in downregulation of DCX, enhanced expression of mature neuronal
markers, enhanced dendritic refinement and increase in spine density. This
indicates that premature canonical Wnt-signaling activity accelerated
maturation, however a transient downregulation is necessary for neuronal
patterning.
With increasing age mice exhibit impaired maturation of adult-born
hippocampal neurons. Intriguingly, adult-born neurons in the aging
hippocampus also display a decrease in canonical Wnt-signaling activity,
suggesting that impaired Wnt-signaling may contribute to the age-associated
maturation deficit. Indeed, expression of stabilized β-catenin in immature
neurons of aged mice promoted maturation of adult-born neurons.
In summary, the data emphasize that tight regulation of canonical
Wnt-activity plays a crucial role in maturation of adult-born neurons and
also suggest that the age-related deceleration of neurogenesis is partly
mediated by a decrease in Wnt-signaling activity. |
jana.semmler@fau.de |
| 2 |
27 |
Agathe
Athena |
Grandcolas |
Institute
of Molecular Biotechnology (IMBA) |
Potential
role of the ECM as a regulator of adult neurogenesis in the hippocampal
neurogenic niche |
Agathe
Grandcolas, Tatjana Kepcija, Rut Gabarró-Solanas, Debora de Azevedo Pires,
Iván Crespo and Noelia Urbán |
Adult
neural stem cells (aNSCs) give rise to new neurons and astrocytes in the
dentate gyrus (DG) of the hippocampus. The majority remain in a quiescent
state, not actively proliferating. Quiescent aNSCs are tightly regulated by
niche components like extracellular matrix (ECM) proteins. The regulation of
the transition between quiescence and proliferation is essential to balance
generation of new neurons with long-term preservation of the aNSC pool. We
have analysed RNAseq and Mass Spectrometry data from quiescent versus
proliferative aNSCs in vivo and in vitro and selected ECM components
differentially expressed between these conditions. One of such candidates is
the apolipoprotein Clusterin, strongly expressed in quiescence, that could
play a role in maintaining this state through regulation of proliferation and
apoptosis pathways. Another candidate expressed in quiescence is Tmem47, a
membrane protein of unknown function in the brain. To confirm expression
differences, we use quantitative PCR and compare proliferative versus
quiescent aNSCs using an in vitro system that can mimic these states in
aNSCs. We have already started to characterise several candidates using
immunostaining and WB for protein profiling, first in vitro then in vivo. In
the future, we will assess the functional role of these candidates in
controlling quiescence/activation transitions with loss and gain of function
experiments in vitro. Ultimately, we aim to unravel how ECM proteins modulate
the effects of systemic metabolism on aNSC quiescence and adult
neurogenesis. |
agathe.grandcolas@imba.oeaw.ac.at |
| 2 |
28 |
Marion |
Martin |
1
Jean‐Pierre Aubert Research Centre, UMR‐S 1172, Développement et plasticité
du cerveau neuroendocrine, Lille Cedex, France;
2 University of Lille, School of Medicine, Place de Verdun, 59045 Lille
Cedex, France |
Cell
neogenesis in the rat maternal brain |
Marion
Martin1,2, Giuliana Pellegrino1,2, Clémentine Maurice1, Vincent Prevot1,2,
Ariane Sharif1,2 |
The
success of pregnancy involves a high degree of brain plasticity, including
increased neurogenesis in the subventricular zone/olfactory bulb system that
promotes maternal behaviour. The hypothalamus has recently emerged as another
germinal niche producing new neurons and glial cells in the postnatal brain.
Given the central role of the hypothalamus in the control of reproduction and
physiological adaptations to pregnancy, we explored whether cell neogenesis
occurs in the rat maternal hypothalamus.
Analysis of cell proliferation using the thymidine analogue BrdU showed
that hypothalamic proliferation varies across the estrous cycle, with a peak
in diestrus 2, which precedes the pre-ovulatory surge leading to ovulation.
Cells born in diestrus 2 preferentially survived if females became pregnant.
This differential survival was selectively seen in the medial preoptic area
(mPOA), a hypothalamic region acting as a hub in the onset of maternal
behaviour. Co-immunofluorescent labelings showed that most BrdU+ cells in the
mPOA expressed the oligodendroglial marker Olig2 but were negative for the
astrocyte markers GFAP and S100b, and for the neuronal marker HuC/D. The
fraction of BrdU+ cells co-expressing Olig2 was higher in pregnant versus
non-pregnant rats. Moreover, BrdU+ newborn cells were frequently found
morphologically associated with neuron cell bodies, some of which expressed
parvalbumin and/or ERa.
Altogether, our data show that
pregnancy is associated with the production of oligodendroglial lineage cells
in the mPOA that associate with neurons, and raise the possibility that
gliogenesis may contribute to modulating the activity of neuronal networks
involved in the onset of maternal behaviour. |
marion.martin@inserm.fr |
| 2 |
29 |
Davide |
De
Pietri Tonelli |
Fondazione
Istituto Italiano di Tecnologia (IIT) |
miR-135a-5p
is critical for exercise-induced adult neurogenesis |
Meritxell
Pons-Espinal; Caterina Gasperini; Matteo J Marzi; Clarissa Braccia; Andrea
Armirotti; Alexandra Pötzsch; Tara L Walker; Klaus Fabel; Francesco Nicassio;
Gerd Kempermann
and Davide De Pietri Tonelli |
Physical
exercise stimulates adult hippocampal neurogenesis and is considered a
relevant strategy for preventing age-related cognitive decline in humans. The
underlying mechanisms remains controversial. Here, we show that exercise
increases proliferation of neural precursor cells (NPCs) of the mouse dentate
gyrus (DG) via downregulation of microRNA 135a-5p (miR-135a). MiR-135a
inhibition stimulates NPC proliferation leading to increased neurogenesis,
but not astrogliogenesis, in DG of resting mice and intriguingly it
re-activates NPC proliferation in aged mice. We identify 17 proteins (11
putative targets) modulated by miR-135 in NPCs. Of note, inositol
1,4,5-trisphosphate (IP3) receptor 1(ITPR1) and inositol
polyphosphate-4-phosphatase type I (INPP4A) are among the modulated proteins,
suggesting that IP3-signaling may act downstream miR-135.
miR-135 is the first noncoding RNA essential modulator of the brain’s
response to physical exercise. Prospectively, the miR-135-IP3-axis might
represent a novel target of therapeutic intervention to prevent pathological
brain ageing. |
davide.depietri@iit.it |
| 2 |
30 |
Marie |
Lods |
1
INSERM U1215, Neurocentre Magendie, “Neurogenesis and Pathophysiology” Group,
146 rue Leo Saignat 33077 Bordeaux-CEDEX, France
2 INSERM U1215, Neurocentre Magendie, “Endocannabinoïds and
neuroadaptation” Group, 146 rue Leo Saignat 33077 Bordeaux-CEDEX, France
3 INSERM U1215, Neurocentre Magendie, “Energy balance and obesity” Group,
146 rue Leo Saignat 33077 Bordeaux-CEDEX, France
|
Pharmacogenetic
stimulation of hippocampal adult-born neurons increases remote spatial memory
accuracy |
Marie Lods1 | Emilie Pacary1 | Geoffrey Terral2 | Wilfried Maziers3 | Fanny Farrugia1 | Vanessa Charrier1 | Federico Massa2 | Daniela Cota3 | Djoher Nora Abrous1 | Sophie Tronel1 |
Adult
neurogenesis refers to the creation of new neurons in the dentate gyrus of
the adult hippocampus. A decade of research has established the role of adult
neurogenesis in memory formation, in particular in spatial learning. However,
the role of newborn neurons in long-term processes remains unclear.
Here we investigate the role of neurons that were either immature (1 week
old) or more functionally mature (6 weeks old) at the time of learning during
long-term memory retrieval, in rats.
Using immediate early gene expression analysis, we first show that 6
weeks-old neurons are activated by learning, which is not the case of
immature neurons. In order to stimulate adult-born neurons during remote
memory retrieval, we used a retrovirus coupled with a DREADD Gs protein. When
injected into the dentate gyrus, this retrovirus allows the specific and
reversible activation of new neurons a long time after memory acquisition.
Our data show that activating adult-born neurons during retrieval improves
remote memory retention. This improvement is observed when both populations,
immature and mature, are stimulated. This effect is specific of adult-born
neurons because stimulating neurons born during the development had no effect
on remote memory retention. These results suggest that new neurons are
involved in spatial remote memory during retrieval. Furthermore, these
results underline the role of a population of new neurons that is not
activated by learning but becomes nevertheless involved in the long term fate
of this memory.
|
marie.lods@inserm.fr |
| 2 |
31 |
Rocio |
Foltran |
Inst.
de Biología Celular y Neurociencias (IBCN) CONICET-UBA. Buenos Aires,
Argentina |
Exploring the role of
serotonin depletion in the BDNF pathway and the ability for pattern
separation |
Rocío B Foltran,
Karen Stefani, Silvina L Diaz |
Modulation
of serotonergic neurotransmission has revealed as an exciting tool to study
the process of neurogenesis in the adult hippocampus (HC). Chronic inhibition
of tryptophan hydroxylase by para-chlorophenylalanine (PCPA), induces a
decrease of serotonin (5-HT) levels and promotes survival of newborn neurons
in the HC. We analyzed the molecular pathway of the Brain derived
neurotrophin factor (BDNF) in mice treated with PCPA. C57BL/6J male 6-week
old mice were treated during 8 weeks by giving aprox PCPA 250mg/kg/day inside
yeast and jelly cubes, an oral administration we set up. Control group
received cubes without PCPA. After treatments, proteins were extracted from
hippocampi and levels of BDNF, TrkB, p75, proBDNF, BCL2 were quantified by
Western Blot. P75 was found to be enhanced after PCPA treatment, and a
tendency for a decrease was found for TrkB and proBDNF. When animals were
administered a 5-HT1A receptor agonist for 1 week after 4 weeks of PCPA, a
protocol that reestablishes the neurogenical phenotype, an increase was
observed for proBDNF and p75. As we intend to study the role of the new
neurons in the HC, we also set up the Object Pattern Separation (OPS), a test
recently developed that allows finding subtle differences compared to classical
tests. Although no significance was achieved, hyposerotonergic mice showed a
tendency to a minor discrimination index. Our results show a clear
participation of the BDNF pathway in the regulation of neurogenesis induced
by PCPA, but the lack of improved performance in the OPS casts doubts about
the functional role of these newborn neurons. |
rbfoltran@conicet.gov.ar |
| 2 |
32 |
Edina |
Silajdžić |
1Department
of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology &
Neuroscience, King’s College London, London, UK.
2Department of Public Health Sciences, King’s College London, London,
UK.
3Department of Psychiatry, University of Oxford, UK.
4Department of Neurology, Akershus University Hospital, Lørenskog,
Norway.
5Institute of Clinical Medicine, University of Oslo, Campus Ahus, Oslo,
Norway.
6Center for Age‐Related Diseases, Stavanger University Hospital, Stavanger,
Norway.
7Department of Old Age Psychiatry, Institute of Psychiatry, Psychology
& Neuroscience, King’s College London, London, UK.
|
Validation
study of a prognostic biomarker for Alzheimer's disease |
Edina Silajdžić1a, Aleksandra Maruszak1, Tytus Murphy1a, Benjamine Liu3, Chiara de Lucia1, Dr Abdel Douiri2, Alejo J Nevado3, Jack Price1, Simon Lovestone3, Tormod Fladby4,5, Dag Aarsland,4, 6,7, Sandrine Thuret1a |
Efficacy
trials for Alzheimer’s Disease (AD) will be more successful if conducted in
prodromal or preclinical stages necessitating the use of biomarkers that
reflect and detect the early disease process. Hippocampal neurogenesis, which
is important for learning and memory, is altered early in AD. We have previously developed a prognostic
biomarker for AD that predicts conversion from Mild Cognitive Impairment
(MCI) to AD by using an in vitro assay capable of measuring the neurogenic
process. In this assay, HPC0A07/03C
human hippocampal progenitor cells are treated with 1 % serum from a
prospective cohort including: cognitively healthy individuals, and
individuals that were diagnosed with mild cognitive impairment (MCI), some of
whom will not develop any disease (MCI-stable) and some will subsequently
convert to AD (MCI-converters). Serum
of individuals with MCI differentially alters human hippocampal progenitor
cell fate to predict conversion to AD.
The in vitro neurogenesis assay predicted the conversion of MCI
patients to AD up to 3.5 years before the AD clinical diagnosis with 92 %
sensitivity, 94 % specificity, 97 % positive predictive value, and 84 %
negative predictive value. We are currently validating the initial predictive
power of the neurogenesis assay, in a blinded fashion using a larger,
independent cohort of baseline samples from elderly cognitively healthy,
MCI-stable and MCI-progressive individuals.
Once validated in a larger independent cohort, this assay has the
potential to be further automated using cell-culture robots to qualify as an
affordable and minimally invasive biomarker test to identify individuals at
an earlier stage of AD for trial enrichment for disease-modifying therapy
interventions. |
edina.silajdzic@kcl.ac.uk |
| 3 |
1 |
Kunimasa |
Ohta |
Kumamoto
University |
DISRUPTION
OF TSUKUSHI FUNCTION LEADS TO HYDROCEPHALUS BY ABERRANT NEUROGENESIS IN THE
BRAIN |
K Ohta, SAI Ahmad, MB
Anam, and N Ito |
We
have been studying the molecular function of Tsukushi (TSK), which is a
soluble molecule belonging to the Small Leucine-Rich Proteoglycan family
(Ahmad et al., 2018). TSK is expressed in pericytes on the blood vessels and
ependymal cells in the subventricular zone (SVZ) of the lateral ventricle
(LV) of the mouse brain. We analyzed brain morphology and expression of
marker genes in TSK knockout mice (TSK-/-) brain. TSK-/- mice developed
hydrocephalus after birth and this phenotype became even more severe at later
stages. We found aberrant cell proliferation and cell death at SVZ in TSK-/-.
Both overexpression of TSK protein using transgenic mice in TSK-/- background
and direct injection of TSK protein into the LV of TSK-/- brain rescued the
LV expansion in TSK-/-. We performed sequencing of peripheral blood DNA from
13 hydrocephalus patients with unknown reason and found 3 heterozygous
nucleotides changes within TSK coding region, which introduce missense
mutations that are predicted to cause amino acid changes in TSK protein
sequence.
Our results suggest that TSK is involved in the pathogenesis of
hydrocephalus in human patients. We would like to discuss the developmental
mechanism of hydrocephalus in the absence of TSK, therapeutic potential of
TSK to rescue hydrocephalus and determine the percentage of patients carrying
mutated TSK gene to establish TSK as a marker for hydrocephalus
diagnosis. |
ohta9203@gpo.kumamoto-u.ac.jp |
| 3 |
2 |
Rui |
Rodrigues |
Instituto
de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade
de Lisboa, Lisboa, Portugal |
Cannabinoids
and Adenosine A2A receptors: impact on postnatal neurogenesis |
R.S.
Rodrigues 1,2, A. Armada-Moreira 1,2, F.F Ribeiro 1,2, A.M Sebastião 1,2, S.
Xapelli 1,2
1 - Instituto de Farmacologia e Neurociências, Faculdade de Medicina,
Universidade de Lisboa, Lisboa, Portugal;
2 - Instituto de Medicina Molecular João Lobo Antunes, Faculdade de
Medicina, Universidade de Lisboa, Lisboa, Portugal |
Postnatal
neurogenesis operates in specialized niches of the mammalian brain in a
process modulated by cannabinoid type 1 and 2 receptors (CB1Rs and CB2Rs).
Recent evidence sheds light on the interaction of adenosine A2A receptors
(A2ARs) with cannabinoid receptors. Herein, we aimed at understanding the
putative role of A2ARs on cannabinoid-mediated cell fate, cell proliferation
and neuronal differentiation of rat subventricular zone (SVZ) and dentate
gyrus (DG) neural stem/progenitor cell cultures. CB2R or A2AR activation was
found to promote self-renewing divisions of DG cells. Importantly, A2AR
antagonist blocked the effect mediated by CB2R activation, while CB1R or CB2R
antagonists blocked A2AR-mediated effect. SVZ cell proliferation was only
affected by CB1R activation, an effect blocked in the presence of an A2AR
antagonist. Although CB1R, CB2R or A2AR activation alone did not alter DG
cell proliferation, CB1R or CB2R co-activation with A2ARs promoted a
significant increase in DG cell proliferation. Lastly, CB1R and/or CB2R
activation promoted SVZ and DG neuronal differentiation, while A2AR
activation only promoted DG neuronal differentiation. In both cases, the
proneurogenic effect mediated by CB1R or CB2R agonists was blocked by an A2AR
antagonist, while in DG the A2AR-mediated actions on neuronal differentiation
were blocked by CB1R or CB2R antagonists. Preliminary in vivo evidence
suggests that blockage of A2ARs may be implicated in cannabinoid-mediated
regulation of hippocampal neurogenesis, affecting cognitive
performance.
Taken together, our findings suggest an interaction between the
adenosinergic and cannabinergic systems, cross-antagonism being evident,
responsible for controlling early stages of postnatal neurogenesis. |
rmsrodrigues@medicina.ulisboa.pt |
| 3 |
3 |
Julia |
Terreros
Roncal |
Centro
de Biología Molecular Severo Ochoa (CBMSO) |
ADULT
HIPPOCAMPAL NEUROGENESIS IS DRAMATICALLY IMPAIRED IN ALZHEIMER´S DISEASE
PATIENTS |
J.
Terreros-Roncal, E. P. Moreno-Jiménez, M. Flor-García, and M.
Llorens-Martín |
Alzheimer´s
disease (AD) is a devastating disease which is considered to be the most
common type of dementia in industrialized countries. One of the brain areas
primarily affected by disease progression, namely the hippocampus, hosts one
of the most unique phenomena that occurs in the adult mammalian brain. This
phenomenon, named adult hippocampal neurogenesis (AHN) encompasses the
addition of new neurons throughout life. This process is crucial for
hippocampal-dependent learning and confers an unparalleled degree of
plasticity to the entire hippocampal circuitry.
By using a collection of hippocampal samples obtained from 58 control
subjects and AD patients distributed among the 6 neuropathological Braak and
Braak stages of the disease, we have studied the survival and maturation of
immature neurons in the dentate gyrus of these individuals. Strikingly, our
data reveal a progressive reduction in the number immature neurons as the
disease progresses. Furthermore, the maturation of these cells is blocked at
multiple levels. Importantly, these alterations are observed at early stages
of the disease, although a progressive worsening is observed as the disease
advances.
Therefore, the putative detection of AHN impairments by non-invasive techniques
might turn this phenomenon into a relevant biomarker for AD progression.
Moreover, given that AHN can be regulated extrinsically (at least in
rodents), increasing AHN in humans emerges as a potential therapeutic target
for AD or other neurodegenerative diseases. |
julia.terrerosr@gmail.com |
| 3 |
4 |
Soraya |
Martín
Suárez |
Achucarro
Basque Center for Neuroscience.
University of the Basque Country (UPV/EHU). |
ATP
links the Induction of Reactive Neural Stem Cells by Neuronal Hyperexcitation |
Soraya
Martín-Suárez; Oier Pastor-Alonso José R Pineda; Juan M Encinas. |
Besides
generating neurons, the NSCs dwelling in the adult hippocampus generate
astrocytes, more copies of themselves and even olygodendrocytes after genetic
manipulation. The balance between excitatory and inhibitory input regulates
the behavior and fate of hippocampal NSCs. Thus, in normal conditions NSCs
generate mostly neurons and astrocytes and symmetric self-renewing division
cannot compensate for the natural decline of the population. As we
demonstrated using a model of temporal lobe epilepsy, when neuronal
hyperexcitation is high enough to trigger seizures NSCs become reactive
(React-NSCs): they lose their broccoli-like apical arborization, become
multibranched and hypertrophic, also entering massively into mitosis and
overexpressing proinflammatory cytokines. React-NSCs divide symmetrically
generating more copies of themselves that will ultimately differentiate into
reactive astrocytes. Therefore NSCs are able to contribute to the
neuroinflammatory response at the expense of abandoning their neurogenic
potential. We show here how the induction of React-NSCs requires neuronal
hyperexcitation and is cannot be only a consequence of inflammation. Thus our
hypothesis is that NSCs could become React-NSCs in parallel to the astroglial
and microglial reactive response, but is independent of it. Also our work
suggests that ATP is a direct link between hyperactive/excitotoxic neurons
and NSCs and mediates the induction of React-NSCs. Purinergic P2X receptors, specific for ATP,
are present in NSCs in vivo and in vitro and in both cases administrating ATP
triggers the conversion of NSCs into React-NSCs by increasing the
intracelullar concentration of calcium. This mechanism for NSC regulation in
pathological conditions could represent a potential therapeutic target to
preserve NSCs and adult neurogenesis in epilepsy. |
soraya_martin@hotmail.com |
| 3 |
5 |
Barbara |
Planchez |
Inserm
U1253 iBrain, Tours, France. |
Neurogenesis and resilience to Post-Traumatic Stress Disorder
|
Barbara
Planchez, Mohamed-Lyes Kaci, Bruno Brizard, Anne-Marie Le Guisquet, René Hen,
Catherine Belzung |
Post-Traumatic
Stress Disorder (PTSD) is a neuropsychiatric illness which can occur after
being exposed to a traumatic event, inducing typical symptom clusters in
patients such as intrusive revival memories, constant avoiding of stimuli
associated with the trauma and an overdrive of the autonomous nervous system.
This traumatic event also triggers morphological and functional alterations
in brain regions mediating emotions and stress-related situations. Thus, the
pathophysiology of PTSD is characterized by decreased volume and activity in
the medial prefrontal cortex and the hippocampus, a hyper-activity of the
amygdala and an alteration of the neuroendocrinian system (Hypothalamus
Pituitary Adrenal axis overdrive). Studies showed that the alteration of the
hippocampus, and more precisely the dentate gyrus, where adult neurogenesis
stem from, could produce abnormalities in stress regulation, fear response
extinction and contextual memorization. This knowledge made ground for an
hypothesis, that is, integrity of new neurons could be an important factor
for developing a PTSD. To answer this very question, we worked on mice having
an increase in adult-generated neurogenesis (Ibax mice) and confronted, at
different time-points after induction of neurogenesis, to acute traumatic
stress (an electric footshock). We show a decrease in anxiety-related
behaviors after an increase of newborn neurons, suggesting that it is
sufficient to reverse the trauma-related phenotype. Moreover, neurobiological
modifications in brain regions implicated in fear response along with these
behavioural changes were found. Thus, adult hippocampal neurogenesis could
impact the activity of extra-hippocampal brain areas. |
barbaraplanchez@gmail.com |
| 3 |
6 |
Hoda |
Eliwa |
PhD
student |
Estimation
of Adult Hippocampal Neurogenesis (AHN) sufficiency for anti-depressive like
effects |
Hoda
Eliwa, Anne-Marie Le Guisquet, René Hen, Catherine Belzung, Alexandre Surget |
Major
depressive disorders (MDDs) are the most up-growing diseases among millions
of people globally. However, the treatment options and approaches required
for drug development are still restricted. Deteriorated adult hippocampal
neurogenesis (AHN) has been identified as a putative contributor to the
evolution of MDDs. In addition, it has been revealed that AHN is crucial for
several behavioral effects of antidepressants (ADs). In our study, we investigate whether
increasing AHN during 8 weeks of unpredictable chronic mild stress (UCMS), a
mouse model of depression, could be sufficient to produce antidepressant-like
effects in a transgenic mouse line (iBax mice). In this mouse model, the
pro-apoptotic gene Bax can be inducibly ablated in the neural stem cells by
tamoxifen (Tam) intraperitoneal injection, in turn, this is assumed to
ameliorate the survival of adult born neurons whose 60% cells undergo
apoptosis naturally. Depressive-like behaviors (changes in coat state,
despair, anhedonia, and anxiety) have been evaluated within this study in
addition to neuro-histological evaluations including BrdU immunohistochemical
staining within the hippocampal dentate gyrus. UCMS induced several
behavioral effects that are related to depression-like state. These effects
were partly reversed by tamoxifen treatment. In addition, AHN alterations may
be related to some of these behavioral changes. Finally, our results are
discussed in relation to the adult neurogenesis hypothesis of depression and
antidepressant effects. |
hoda.elsayedeliwaalikasem@etu.univ-tours.fr |
| 3 |
7 |
Ruth |
Beckervordersandforth |
1
Institute of Biochemistry, Friedrich-Alexander-University of
Erlangen-Nuremberg, Germany
2 Department of Physiology, University of Lausanne, Switzerland |
Adult
astrogenesis and functional astrocyte heterogeneity in the adult mouse
hippocampus |
Julia
Schneider1, Julian Karpf1, Marlen Knobloch2, and Ruth Beckervordersandforth1 |
The
brain works as a functional co-operation unit between neurons and glial
cells. This unit differs in its physiological properties in distinct brain
regions and developmental stages. Neuronal diversity has been extensively
investigated in the last decades. Recent works now suggests that also
astrocytes are molecularly and functionally distinct, yet still little is
known about astrocyte heterogeneity. We found that the adult hippocampal
dentate gyrus is populated by morphologically distinct astrocytes that are
localized to specific compartments. In order to assess structural astrocyte
heterogeneity we carried out a detailed morphological analysis of distinct
astrocyte subtypes and assessed their “connectome”, i.e. which other niche
cells and structures are in direct contact to the astrocytes. As structural
heterogeneity of astrocytes may be a reflection of their functional
properties, we performed single-cell sequencing of astrocyte subtypes to
analyze distinct molecular properties of astrocytes and to identify new
markers for targeting astrocyte subtypes.
In contrast to the prevailing assumption that astrocytes are postmitotic in
the non-injured adult brain, our work revealed proliferation of non-radial
astrocytes in the adult dentate gyrus. Even more surprising was the finding
that morphologically distinct astrocytes show a differential proliferation
response in the context of specific stimuli (voluntary exercise and ageing).
These observations led to the hypothesis that the dentate gyrus is composed
of molecularly and functionally distinct astrocytes whose dynamics are
critical modulators for hippocampal adaption to changing conditions.
Collectively, our study provides the first description of adult astrogenesis,
structural heterogeneity and subtype-specific dynamics of astrocytes in the
hippocampus.
|
ruth.beckervordersandforth@fau.de |
| 3 |
8 |
CHIH-WEI |
WU |
INSTITUTE
FOR TRANSLATIONAL RESEARCH IN BIOMEDICINE |
Maternal
high fructose intake suppressed cell proliferation and neuronal
differentiation in dentate
gyrus of female offspring via histone deacetylase 4-mediated
neuroinflammation |
Chih-Wei
Wu§, Wen-Chung Liu§, Pi-Lien Hung, You-Lin Tain Lee-Wei Chen, Mu-Hui Fu,
Chih-Kuang Liang, Chun-Ying Hung
, Chou-Hwei Lee, and Kay L.H. Wu |
Histone
deacetylase 4 (HDAC4) mediates maternal high fructose diet (HFD)-impaired
learning and memory capacity of adult female offspring. However, the
underlying mechanism is largely unknown. Hippocampal adult neurogenesis is
important for supporting the cognition. Peroxisome proliferatoractivated
receptors γ (PPAR γ) enhances cell proliferation and differentiation while
nuclear factor-κB (NF-κB)-mediated neuroinflammation possess opposite
effects. In this study, we investigated the role of HDAC4 in PPAR γ, NF-κB
and the hippocampal neural stem cells (NSCs) proliferation and neuronal
differentiation of adult female offspring of maternal HFD during gestation
and lactation. The protein expressions and cell count of Ki67 and
doublecortin (DCX) signals indicated that maternal HFD suppressed hippocampal
NSCs proliferation and neuronal differentiation. Hippocampal ionized calcium
binding adaptor molecule 1 (Iba-1) and IL-1β were increased. Moreover, the
nuclear expression of PPAR γ was downregulated concurrent with increased
HDAC4 and NF-κB in the HFD group. Intracerebroventricular infusion with HDAC4
inhibitor (Mc1568, 4 weeks) upregulated the PPARγ, Ki67 and DCX alongside
with the downregulation of NF-κB and neuroinflammation. Further, PPARγ
activator (pioglitazone, 4 weeks) effectively decreased neuroinflammation and
reversed NSCs proliferation and neuronal differentiation. Together, these
results demonstrated that HDAC4-suppressed PPARγ to initiate
neuroinflammation resulting in decreased hippocampal NSCs proliferation and
neuronal differentiation of HFD female offspring. |
wuchihwei@hotmail.com |
| 3 |
9 |
Romain |
Troubat |
Inserm
U1253 « Imaging and Brain » (iBrain)
Team Neuro-functional Psychiatry |
“Impact
of P2X7 receptor Knock out mice on Neuroinflammation and Neurogenesis in
animal model of depression: research for new potential therapeutic targets.” |
Troubat
Romain, Brizard Bruno, Pinchaud Katleen, Roger Sébastien, Leman Samuel, Camus
Vincent |
Major
depressive disorder (MDD) is one of the most complex and frequent
neuropsychiatric condition with 300 million affected patients worldwide.
Despite its obvious importance to global disease burden, the last decades
have seen a persistent lack of progress in therapeutic research relating to
MDD. Actual standard treatments use antidepressants (ADs), efficient by
targeting monoamines neurotransmission and exhibit strong link with
hippocampal neurogenesis. Even if ADs display a good efficacy, it appears
that 40% of MDD’s patient develop a resistance to this treatment.
Comprehensive investigation of inflammatory pathways in depressed people have
characterized neuroinflammation (NI) as a potential pathophysiological
mechanism of MDD. Furthermore, converging data have already associated the
purinergic receptor P2X7 (P2X7R) with mood disorder due to its important
involvements in maturation and release of interleukin-1 β, a main actor in
NI. In our study, we investigate the P2X7 receptor gene deletion in mice
model of MDD to improve our understanding of NI’s mechanism in the depressive
pathophysiology and its potential interactions with hippocampal neurogenesis.
Unpredictable chronic mild stress (UCMS) protocol has been used as animal
model for depression follow by behavioral tests to evaluate depressive like
behavior (anxiety, anhedonia, resignation). In addition, we performed
immunostaining to study NI processes and neurogenesis on mice brain. As
expected P2X7R deletion elicit antidepressant effect in behavioral component
potentially explain by reduced NI and elevated neurogenesis observed by
immunohistochemical study. Our findings suggest that P2X7R can be used as
putative therapeutic strategies for MDD. |
romaintroubat@gmail.com |
| 3 |
10 |
Anthony |
Carrard |
Center
for Psychiatric Neurosciences |
Role
of adult hippocampal neurogenesis in the antidepressant effects of Lactate |
Anthony
Carrard, Frédéric Cassé, Sophie Burlet-Godino, Nicolas Toni, Pierre J.
Magistretti and Jean-Luc Martin |
Growing
evidence indicates that astrocytes are involved in the pathophysiology and
treatment of depression. For instance, SSRIs stimulate lactate release from
cortical astrocytes. Recently, we showed that acute lactate administration
increased lactate concentration in the hippocampus and reduced immobility in
the forced swim test (Carrard et al, Mol Psychiatry 2018). We further
investigated the antidepressant effects of lactate in the corticosterone
model of depression and the open-space forced swim model of depression, two
animal models that respond to chronic antidepressant treatment. Chronic
administration of lactate improved depressive-like behavior. In particular,
chronic lactate injection reversed the corticosterone-induced anhedonia and
partially restored mobility in the open-space forced swim model of
depression. The antidepressant effects of lactate are associated with changes
in the expression of Hes5, a transcription factor involved in adult
hippocampal neurogenesis. These findings led us to investigate the role of
adult hippocampal neurogenesis in the antidepressant effects of
lactate.
The involvement of hippocampal neurogenesis in the antidepressant effects
of lactate was assessed in the corticosterone model of depression. Chronic
peripheral injections of lactate counteracted the decreased neural progenitor
proliferation and survival induced by corticosterone treatment. In contrast,
chronic administration of pyruvate did not produce antidepressant effects and
did not prevent the inhibition of neural progenitor proliferation and
survival induced by corticosterone. Importantly, depletion of hippocampal
neurogenesis by the antimitotic drug temozolomide suppressed the
antidepressant effects of lactate in the chronic corticosterone paradigm.
Collectively, these data emphasize the importance of adult hippocampal
neurogenesis in the antidepressant effects of lactate.
|
anthony.carrard@chuv.ch |
| 3 |
11 |
Pascal |
Bielefeld |
University
of Amsterdam |
Single
cell RNA sequencing of hippocampal neural stem and progenitor cell
populations after Cortical Traumatic Brain Injury |
P.
Bielefeld1, A. Martirosyan2, E. Toledo1, J.M. Encinas2, M.G. Holt3,
Fitzsimons C.P1 |
Traumatic
brain injury (TBI) is associated with long-term cognitive deficits that are
often dependent on hippocampal functioning. Even when not directly
mechanically affected by the trauma, the hippocampus undergoes atrophy and
synaptic alterations after TBI. Furthermore, neural stem/progenitor cells
(NSPCs) in the hippocampus, which are crucial for adult hippocampal
neurogenesis, are also affected.
Here we aim to identify the effect of cortical TBI on different
subpopulations of NSPCs. To this aim we make use of the controlled cortical
impact (CCI) model of TBI, in combination with the Nestin-GFP NSPC reporter
mouse strain. We use single cell RNA sequencing to further identify
alterations within hippocampal NSPC populations isolated from the dentate
gyrus using FACS.
Initial immunohistochemistry data indicates that cortical TBI quickly
affects the NSPCs. Severe astrogliosis can be seen in the hippocampus 3 days
post TBI, as well as an increase in two astrogenic NSC populations, the Type
B NSCs and the reactive NSCs.
Ongoing single cell RNA sequencing analysis will help describe changes in
specific NSPC populations after TBI, and possibly identify potential genetic
mechanisms underlying changes in NSC fate.
This work is financed by the Horizon 2020 cofund initiative ERA-NET NEURON,
Hersenstichting Nederland and The Netherlands Organization for Scientific
Research (NWO) grants to C.P.F.
|
p.bielefeld@uva.nl |
| 3 |
12 |
Valentine |
Golzné |
CHUV/
Center of psychiatric Neurosciences |
Bugs
and the brain: Is adult neurogenesis sensitive to changes in gut microbiota
? |
Valentine
Golzné1, Frédéric Cassé1, , Manuel Oliveira2, Amy Pooler2, Chloé Picq3,
Sebastien Sultan2, Gabriela Bergonzelli3, Pascal Steiner2 and Nicolas Toni1 |
The
gut microbiota is involved in general health and an increasing number of
studies suggest that its impairment may participate to the development of
psychiatric diseases such as depression. Modulating the gut microbiota with
probiotics may therefore offer a novel therapeutic target for mood and
anxiety disorders.
In the present study, we tested the possibility that adult neurogenesis may
be sensitive to changes in the gut microbiota.
To this aim, cell proliferation using BrdU administration after
Bifidobacterium feeding was assess firstly. Secondly, survival,
differentiation and differentiation of newborn hippocampal neurons using
confocal microscopy were examined. Different administration protocols and
durations were tested to assess effect duration and stability.
|
valentine.golzne@chuv.ch |
| 3 |
13 |
Vanessa |
Oliveira
Moreira |
Collège
de France |
OTX2
signals from the choroid plexus to regulate adult neurogenesis |
Anabelle
Planques*, Vanessa Oliveira Moreira*, Chantal Dubreuil, Alain Prochiantz and
Ariel A. Di Nardo |
Proliferation
and migration during adult neurogenesis are regulated by a microenvironment
of signaling molecules originating from local vasculature, from cerebrospinal
fluid produced by the choroid plexus, and from local supporting cells
including astrocytes. Here, we focus on the function of OTX2 homeoprotein
transcription factor in the mouse adult ventricular-subventricular zone
(V-SVZ) which generates olfactory bulb neurons. We find that OTX2 secreted by
choroid plexus is transferred to supporting cells of the V-SVZ and rostral
migratory stream. Deletion of Otx2in choroid plexus affects neuroblast
migration and reduces the number of olfactory bulb newborn neurons. Adult
neurogenesis was also decreased by expressing secreted single-chain antibodies
to sequester OTX2 in the cerebrospinal fluid, demonstrating the importance of
non-cell autonomous OTX2. We show that OTX2 activity modifies extracellular
matrix components and signaling molecules produced by supporting astrocytes.
Thus, we reveal a multi-level and non-cell autonomous role of a homeoprotein
and reinforce the choroid plexus and astrocytes as key niche compartments
affecting adult neurogenesis.
|
vanessa.oliveira-moreira@college-de-france.fr |
| 3 |
14 |
Farah |
Chamaa |
American
University of Beirut |
Modulation
of Hippocampal Neurogenesis in Awake Rats by Electrical and Chemical Thalamic
Stimulation |
Farah
Chamaa, Batoul Darwish, Elie Al-Chaer, Ziad Nahas, Nayef Saade, and Wassim
Abou-Kheir |
Deep
brain stimulation (DBS) provides clinical benefit for a variety of
neurological disorders, but the underlying mechanism of how it alters neural
activity remains ill-understood. Our group showed that DBS to the
anteromedial thalamic nucleus (AMN) in awake rats modulates adult hippocampal
neurogenesis. As DBS might induce off-targets effects, we sought to
specifically stimulate the cell bodies of AMN by chemical stimulation using
low doses of Kainic acid (KA). (KA). This study included two groups of adult
male sprague-dawley rats: Group 1 received 6-sessions of unilateral DBS in
the right AMN and group 2 received implants of mini-osmotic pumps in same
region releasing KA (500pM) at a rate of 1ml/injection/hr/7days. Sham animals
were included for both groups. All rats received BrdU injections during
stimulation and were followed for 4 weeks. Novel arm exploration was examined
using the Y-maze, and co-labeling of BrdU/NeuN cells was counted in the
dentate gyrus. Four weeks after DBS, BrdU+/NeuN+ mature neurons were 3-folds
higher than sham. Continuous micro-perfusion of KA increased the number of
mature neurons to 4-folds higher than vehicle. The Y-maze test showed that
both electrical and chemical stimulation to the AMN enhanced novel arm
exploration at 4-weeks after stimulation. The current study presents
hippocampal neurogenic responses to electrical and chemical stimulation and
reveals a translational behavioral enhancement of hippocampal-related skills
following stimulation. It highlights the importance of glutamic kainate
receptor activation in the AMN nucleus in modulating hippocampal
neurogenesis. |
fs36@aub.edu.lb |
| 3 |
15 |
Nuria |
Masachs |
Neurocentre
Magendie INSERM U1215 |
Influence
of ontogenetic age of dentate granule neurons in spatial memory |
Masachs
N, Charrier V, Farrugia F, Mazier W, Blin N, Tronel S, Montaron MF, Cota D,
Deroche-Gamonet V, Herry C, Abrous DN |
The
mammalian dentate gyrus presents the peculiarity to generate granule neurons
throughout the life. Although the contribution of neurons born during
adulthood to spatial navigation has been demonstrated, the implication of
developmentally born ones’ is unknown. Here, we analyzed the implication of
embryonic and, neonatal, early postnatal and juvenile neurogenesis in spatial
leaning. We have shown that meanwhile embryonic and postnatal do not play a
role in spatial navigation, granule cells born during adolescence play a
transient role in spatial navigation. |
nuria.masachs@inserm.fr |
| 3 |
16 |
Louis |
Foucault |
Univ
Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research
Institute U1208, 69500 Bron, France. |
Pharmacological Wnt/β-catenin activation promotes cellular
regeneration within the neonatal cortex while preserving stem cell
maintenance |
Louis
Foucault, Diane Angonin, Vanessa Donega, Guillaume Marcy, Olivier
Raineteau
|
Germinal
activity persists throughout life within the subventricular zone (SVZ) of the
postnatal forebrain, due to the presence of quiescent neural stem cells
(NSCs) that gradually reactivate throughout life. Accumulating evidences
point at a role for these cells during tissue repair following premature
brain injuries (Fagel et al., 2006; Salmaso et al., 2014), and suggest their
amenability to pharmacological manipulations (Azim et al., 2017 Scafidi et
al., 2014). The extent of this repair and its long-term consequences on
forebrain germinal activity however remain to be explored.
We used chronic neonatal hypoxia as a rodent model of premature brain
injury, to investigate the contribution of SVZ NSCs to cellular regeneration
within the cortex. Our results reveal an increased proliferation and
production of TBR2+ & OLIG2+ progenitors within the dorsal SVZ, which was
paralleled by an activation of the Wnt canonical pathway. Fate mapping of SVZ
NSCs demonstrates their contribution to de novo oligodendrogenesis and
cortical neurogenesis following hypoxia, while confirming a delay of
oligodendrocytes maturation. Remarkably, a pharmacological activation of the
Wnt/β-catenin pathway by intranasal administration of a Gsk3β inhibitor
following hypoxia, promotes neurogenesis and oligodendrogenesis as well as
their specification and maturation. Importantly, labeling of NSCs in
different states of activation, demonstrates that neither hypoxia nor
pharmacological NSCs activation have adverse effects on the reservoir of SVZ
NSCs and on their long-term germinal activity.
Altogether, our work highlights the potential of pharmacological approaches
to promote cellular regeneration within the neonatal forebrain, while
demonstrating no detrimental long-term effect on forebrain germinal activity.
|
louis.foucault@inserm.fr |
| 3 |
17 |
Joanna |
Danielewicz |
Achucarro
Basque Center for Neuroscience |
TRAUMATIC
BRAIN INJURY-INDUCED CHANGES IN ELECTROPHYSIOLOGICAL PROPERTIES OF GRANULE
CELLS AND ADULT HIPPOCAMPAL NEUROGENESIS |
J.
Danielewicz1; I. Durá 1,2; J.M. Encinas. 1,2,3
1 Achucarro Basque Center for Neuroscience, Leioa, Bizkaia,Spain.
2 University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain.
3 Ikerbasque, The Basque Science Foundation, Bilbao, Bizkaia, Spain. |
Functional
plasticity of synaptic networks in the hippocampus has been implicated in the
development of posttraumatic epilepsy after traumatic brain injury (TBI).
Within the hippocampus Dentate Gyrus (DG) acts as “gatekeeper” and “filter”
of aberrant or excessive input information. DG function is directly
determined by a delicate balance between neuronal excitation and inhibition
and TBI can cause changes of this state of equilibrium. Moreover TBI can
affect adult hippocampal neurogenesis (AHN) and induce long-term changes in
both neural stem cells (NSCs) and newborn neurons and those alterations can
contribute to hippocampal dysfunction.
We aim to understand what particular changes TBI induces at the cellular,
molecular and electrophysiological level in existing granule cells (GCs),
NSCs and newborn neurons by using a model of controlled cortical impact.
We have observed an increase in neurogenesis up to two months after the
injury. These newborn neurons however present altered morphology and
migration. In addition, we have found that NSCs get activated in higher
numbers and acquire a reactive-like phenotype that is most likely caused by
hiperexcitation. Observed changes in spontaneous excitatory currents (sEPSCs)
frequency indicate remodeling of excitatory input likely expressed as an
increase in the number of excitatory synapses. Those changes are accompanied
by a decrease in spontaneous inhibitory currents (sIPSCs) frequency
indicating a loss of GABAergic neurons.
This project has received founding from the European Union's Horizon 2020
research and innovation program under the Marie Skłodowska – Curie grant
agreement No. 799384. |
joanna.danielewicz@achucarro.org |
| 3 |
18 |
Rut |
Gabarró
Solanas |
Institute
of Molecular Biotechnology (IMBA) |
Diet
as a regulator of adult neurogenesis |
Rut
Gabarró Solanas, Tatjana Kepcija, Agathe Grandcolas, Débora Pires, Rebecca
McDonald, Iván Crespo, Noelia Urbán |
Adult
neural stem cells (aNSCs) generate new neurons throughout life that regulate
memory and emotions in the hippocampus. This process is subjected to strict
intrinsic regulation and responds to extrinsic signals such as diet. For
instance, high-fat diet (HFD) decreases neurogenesis, while intermittent
fasting (IF) has the opposite effect. The lifelong potential to produce
newly-born neurons is determined by the long-term maintenance of aNSCs, which
switch between a quiescent or proliferating state to preserve the pool. This
transition is, in fact, the most important regulatory step for aNSCs,
however, very little is known about its systemic regulation. Combining
lineage tracing and DNA label retention experiments, I showed that one month
of IF does not affect neuronal production. On the other hand, I have observed
changes in behaviour of NSCs upon IF that I am currently characterizing. My
next step will be to look at the long-term consequences IF has on the aNSC
pool and neurogenesis. I have also investigated the effects of HFD and have
not found differences in neurogenesis with its control. However, both the HFD
and the control diet reduced neurogenesis compared to a regular chow diet,
highlighting the importance of using nutrient matched control diets.
Moreover, I want to identify the circulating factors that bridge diet and
adult neurogenesis and dissect the molecular mechanism by which they modulate
aNSCs. Lessons learned from aNSCs could be applied to other adult stem cell
systems and provide new therapeutic approaches for regenerative medicine. |
rut.gabarro.solanas@imba.oeaw.ac.at |
| 3 |
19 |
Marco |
Fogli |
1
Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Italy
2 Department of Life Sciences and System Biology, University of Turin,
Italy
3 Mathematical Sciences, University of Southampton, United Kingdom
4 Department of Neurosciences “Rita Levi Montalcini”, University of Turin,
Italy
* These authors contributed equally to the study
|
Transient
neurogenic niches are generated by the sparse and asynchronous activation of
striatal astrocytes after excitotoxic lesion |
Marco
Fogli 1,2, Nato Giulia 1,2, Philip Greulich 3, Paolo Peretto 1,2, Annalisa
Buffo 1,4,* & Federico Luzzati 1,2,* |
In
the adult brain, subsets of astrocytes act as neural stem cells in two
anatomically defined neurogenic niches: the sub-ventricular zone and
hippocampal dentate gyrus. Surprisingly, after excitotoxic lesion striatal
astrocytes acquire stem cell properties and generate a large amount of
neuroblasts for at least six months. Yet the presence and organization of
striatal neurogenic niches and the spatio-temporal dynamics of striatal
astrocytes activation and lineage progression remain by large unclear.
Here, through genetic lineage-tracing experiments and 3D reconstructions
coupled with mathematical modelling and computer simulations we dissected the
transition of striatal astrocytes toward neurogenesis. In the striatum,
neurogenic astrocytes are scattered throughout the parenchyma and expand
locally, generating clusters of clonally related cells, that we define as
striatal niches. These structures are initially composed only of activated
astrocytes and transient amplifying progenitors. These latter cells
subsequently expand and generate proliferating neuroblasts following a
stochastic mode of division and differentiation. Post-mitotic neuroblasts
accumulate in the cluster before dispersing as individual cells.
Interestingly, striatal astrocytes become activated at a constant rate,
resulting in the continuous addition of new striatal niches with time.
Nevertheless, the total number of niches does not increase with time
indicating that these structures have a transient existence. Thus, continuous
striatal neurogenesis occurs through the asynchronous transition of scattered
neurogenic astrocytes from quiescence to an active state.
Overall, these data suggest that the neurogenic potential is widespread
among striatal astrocytes, and that the striatal parenchyma is largely
permissive for de-novo establishment of neurogenic niches. |
marco.fogli@edu.unito.it |
| 3 |
20 |
Giulia |
Nato |
1
Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Orbassano,
Italy
2 Department of Life Sciences and Systems Biology, University of Turin,
Italy.
3 Institute of Physiological Chemistry, University Medical Center of the
Johannes Gutenberg University, Mainz, Germany; and Focus Program
Translational Neuroscience, Johannes Gutenberg University Mainz,
Germany.
4 Centre for Developmental Neurobiology, King's College London, United
Kingdom.
5 Department of Neuroscience Rita Levi-Montalcini, University of Turin,
Italy.
‡These authors contributed equally to this work |
Astrocyte-generated
neurons functionally integrate into the lesioned striatum |
Giulia
Nato 1,2, Marco Fogli 1,2, Nicolás Marichal 3,4, Ilaria Ghia 1, Paolo Peretto
1,2, Benedikt Berninger 3,4, Annalisa Buffo 1,5,‡ and Federico Luzzati1,2,‡ |
After
excitotoxic lesion, subsets of striatal astrocytes undergo a spontaneous
neurogenic activation leading to the local generation of a large amount of
neuroblasts for at least six months post-lesion. Yet, the identity of the
lesion induced neurons and their functional integration remain unclear. Fate
mapping and 3D reconstruction analyses show that striatal neuroblasts undergo
a maturation process in which initially they organize in clusters,
subsequently disperse as individual cells, and gradually attain complex
morphologies often showing dendritic spines. These neurons fail to express
typical markers of striatal neurons and live transiently, similar to other
models of physiological and pathological striatal neurogenesis. Surprisingly,
rabies virus-based monosynaptic tracing indicated that despite their
transient life, striatal neuroblasts receive local inputs from striatal
projection neurons and interneurons as well as long-range connections from
different cortical and thalamic areas. Electrophysiological recordings in
acute brain slices showed that many of these local-generated cells acquired
membrane properties similar to immature neurons, displaying transient inward
currents and generating single action potentials in response to depolarizing current
steps. Further, some individual neuroblasts received spontaneous excitatory
synaptic inputs while others, likely consistent with a more mature status,
generated action potentials repetitively and exhibited inhibitory
postsynaptic currents. These results indicate that striatal neuroblasts
functionally interact with pre-existing circuits, thus potentially taking
part in post-lesion network plasticity supporting functional recovery after
damage.
|
giulia.nato@unito.it |
| 3 |
21 |
Roberta |
Gioia |
Department
of Biology and Biotechnology “Charles Darwin”, Sapienza University, Rome,
Italy. |
Neural
stem cell properties and adult hippocampal neurogenesis in a knock-in mice
model, expressing an autism-associated mutation.
|
Roberta
Gioia, Raimondo Sollazzo, Marina Vitale, Laura Trobiani, Miriam Di Mattia,
Stefano Biagioni, Antonella De Jaco and Emanuele Cacci. |
The
alteration of adult neurogenesis has been associated with neuropsychiatric
disorders, including autism spectrum disorders (ASDs). Particularly, in the
hippocampus of few ASD mice models, the properties of adult neural
stem/progenitor cells (aNSPC) pool and the formation of new neurons have been
found altered, suggesting a link between deregulated neurogenesis and some of
the behavioural deficits found in these mice.
In order to investigate neurogenesis in association to ASDs, we have been
using the R451C Neuroligin3 (NLG3) knock-in mice, a model of a monogenic form
of ASDs carrying the R451C substitution found in autistic patients. NLG3 is a
postsynaptic protein involved in maturation, specification and plasticity of
neural networks and the R451C knock-in mice display excitatory/inhibitory
balance alterations in different brain regions, behavioural deficits, and
structural brain abnormalities.
We focused our study on the subgranular zone of the hippocampal dentate
gyrus (DG), a neurogenic niche of the adult brain. Specifically, we compared
proliferation and differentiation of new neurons between knock-in and
wild-type mice, both in vivo and in vitro.
In vitro data demonstrate that NSPC cultures derived from the DG of two-month-old
knock-in mice contained a higher number of cells compared to the wild-type.
However, BrdU cell number in the DGs was unchanged between KI and WT mice. In
vivo data also show a decrease in the number of newly formed differentiated
mature neurons (BrdU+/NeuN+ cells) in the hippocampus of the knock-in
compared to wild-type mice.
The mechanisms underlying the neurogenesis reduction in the knock-in mice
are currently under investigation. |
roberta.gioia@uniroma1.it |
| 3 |
22 |
Julia |
Leschik |
University
Medical Center Mainz, Institute of Physiological Chemistry |
BDNF
overexpression in serotonergic neurons increases adult stem cell
proliferation and confers protection against chronic stress by acting in an
antidepressive-like manner |
Julia
Leschik, Antonietta Gentile, Cigdem Cicek, Beat Lutz |
The
neurotrophin brain-derived neurotrophic factor (BDNF) influences structural
plasticity and function of serotonergic neurons. Both, the serotonergic
system and BDNF/TrkB signaling modulate behavioral responses to stress and
can lead to pathological states when dysregulated. Both system have been
shown to mediate the therapeutic efficacy of antidepressant drugs. Herein,
one mechanism could be the upregulation of adult neurogenesis in the
hippocampus, which is suggested to play a role in stress resilience.
Furthermore, BDNF and serotonin individually upregulate neurogenesis in the
subgranular zone (SGZ) of the dentate gyrus. The details on how both systems
work together and influence each other on the cellular and behavioral level
still remain elusive. Therefore, we have generated a transgenic mouse line
which overexpresses BDNF in serotonergic neurons in an inducible manner. In
these mice, we observe increased neural stem/progenitor cell proliferation in
the SGZ and an enhanced hippocampus-dependent context fear learning, whereas
cued fear learning is unchanged. Furthermore, transgenic mice are less
affected by chronic social defeat stress (CSD) compared to wild-type animals,
likely through upregulated neurogenesis specifically in the ventral part of
the hippocampus. In the forced swim test (FST), BDNF-overexpressing mice
behave similarly as wild-type mice treated with the antidepressant
fluoxetine. Our data indicate an antidepressant role for serotonergic BDNF by
enhancing adult neurogenesis.
|
leschik@uni-mainz.de |
| 3 |
23 |
Monika |
Małż |
German
Center for Neurodegenerative Diseases (DZNE) |
Effect
of ALS/FTD-related mutation in FUS protein on the adult hippocampal
neurogenesis |
Monika
Małż, Vijay Adusumilli, Annette Rünker, Zeina Nicola,
Gerd Kempermann
|
In
the adult brain new neurons are continuously generated from neural stem cells
(NSCs) in the dentate gyrus of the hippocampus, providing structural
plasticity and playing role in learning and memory. This process of adult
neurogenesis is altered in the neurodegenerative diseases but still, there is
a lack of knowledge pertaining to adult neurogenesis in Amyotrophic Lateral
Sclerosis (ALS)/ Frontotemporal Dementia (FTD) spectrum. Therefore, we aim to
characterize how the ALS/FTD-related mutation in the Fus gene affects adult
hippocampal neurogenesis during aging and how that may contribute to brain
function.
We use a mouse model of ALS/FTD in which one copy of FUS harbors complete
nuclear localization signal deletion and their wild type littermates as a
control. In vivo results indicate that the baseline adult neurogenesis stays
on a similar level in mice of both genotypes. However, in vitro proliferation
level of cells containing mutated FUS is significantly higher than control’s
cells during early passages and this difference declines later on. Moreover,
our results indicate that the mutation of FUS protein alters the ability of
NSCs to respond to external stimuli such as hypoxia or physical activity,
which are known as strong, positive regulators of neurogenesis. Now, our
research focuses on investigation what is the underlying mechanism of change
in activation ability of NSCs and to test multiple phenotypic aspects,
including differentiation potential and response to stress conditions.
Understanding the pathomechanisms of ALS/FTD-FUS in relation to adult
hippocampal neurogenesis may provide fundamental bases to consider new
therapy based on NSCs.
|
monika.malz@dzne.de |
| 3 |
24 |
Mahmoud |
Dahab |
Hans-Berger-Department
of Neurology, Jena University Hospital, Jena, Germany |
Deletion
of the chloride transporter NKCC1 increases radial glia-like stem cell pool
in the hippocampus and impairs learning and memory performance in adult mice |
M.
Dahab, E. Göller, K. Reiche, M. Günther, L. Wohlsperger, I. Schaeffner, CW.
Schmeer, CA. Hübner, OW. Witte, K. Holthoff, DC. Lie, S. Keiner |
Aging
is the most important contributing factor for decreasing number of radial
glia-like stem cells (RGLs) and impaired neurogenesis in the healthy brain.
The underlying determinants of this age-dependent decline are not fully
understood but may comprise an increase in RGL quiescence or a reduction of
RGL self-renewal. One important intrinsic regulator of adult neurogenesis is
the inhibitory neurotransmitter GABA. The mode of GABA action depends on
intracellular chloride levels, which are determined the differential
expression of chloride transporters NKCC1 and KCC2. NKCC1 is predominantly
expressed in neural precursor cells and drives cellular Cl- influx. The role
of these transporters in RGLs activity in the dentate gyrus remains unknown.
In our study we used a transgenic mouse model
(NestinCreERT2/NKCC1fl/fl/tdtomato mice) to specifically delete the NKCC1
transporter in nestin+ RGLs. Our data show that NKCC1 knockout strongly
promotes the expansion of the RGL neural stem cell population in the hippocampal
dentate gyrus during aging. Detailed morphometric analyses of branched and
unbranched RGLs indicated an increased cellular complexity in adult and aged
mice. Learning and memory performance were assessed with a modified version
of the Morris water maze including the re-learning paradigm, as well as
hippocampus-dependent and -independent search strategies. KO mice showed
higher latency to find the platform. This impairment in flexible learning was
also reflected by reduced use of hippocampus-dependent strategies. Our study
shows for the first time that the self-renewal capacity of RGLs in the adult
and aged hippocampal dentate gyrus is strongly dependent on the chloride
importer NKCC1. |
Mahmoud.Mohamed@med.uni-jena.de |
| 3 |
25 |
Jeff |
Davies |
Swansea
University Medical School |
Circulating
unacylated-ghrelin impairs hippocampal neurogenesis and memory in mice and is
altered in human Parkinson's disease dementia |
Amanda
K. E. Hornsby1, Luke Buntwal1, Vanessa V. Santos2, Fionnuala Johnston3, Luke
D. Roberts1, Romana Stark2, Alex Reichenbach2, Mario Siervo3, Timothy Wells4,
Zane B. Andrews2, David J. Burn3, Jeffrey S. Davies1*. |
New
neurones are formed from neural stem/progenitor cells (NSPCs) in the adult
dentate gyrus (DG) throughout life and contribute to spatial pattern
separation memory. Factors that promote neurogenesis may attenuate
age-related cognitive decline.
Calorie restriction (CR) has been shown to modulate the DG and improve
cognitive function, albeit via unknown mechanisms. Previously, we showed that
the stomach hormone, acyl-ghrelin (AG), which is elevated during CR,
increases neurogenesis in the DG and enhances pattern-separation memory (Kent
et al.2015). The ghrelin-receptor (GHSR) is expressed in mature DG neurones
in close proximity to DG NSPCs of adult mice, suggesting a non-cell
autonomous mechanism of action. We also show that CR enhances neurogenesis in
WT but not in GHSR-null mice, demonstrating that CR induces AHN in a
GHSR-dependent manner (Hornsby et al.2016).
Here, to determine whether unacylated-ghrelin (UAG), the so-called inactive
form of ghrelin, regulates neurogenesis, WT and ghrelin-O-acyl transferase
null mice (GOAT-ko) - that lack circulating acyl-ghrelin - were treated with
vehicle or UAG for 7-days. Surprisingly, UAG-treated WT mice had reduced
proliferating (Ki67+) cells, (DCX+) neurones and newborn (BrdU+/DCX+) neurones.
GOAT-ko mice had similar reductions in neurogenic markers and impairments in
hippocampal-dependent memory that were restored by acyl-ghrelin
treatment.
Finally, we show that circulating AG:UAG in Parkinson's disease dementia
was significantly reduced compared to both age-matched healthy controls and a
cognitively normal PD group.
These data identify a novel role for UAG in regulating hippocampal
plasticity and memory, and suggest that AG:UAG may be a biomarker of dementia
in humans.
|
jeff.s.davies@swansea.ac.uk |
| 3 |
26 |
Friederike |
Klempin |
Max
Delbrueck Center Berlin |
Novel
genetic tool to manipulate brain serotonin levels: a new window on the
neurobiology of affective disorders |
Maria
Sidorova, Susann Matthes, Natalia Alenina, Golo Kronenberg, and Friederike
Klempin |
Serotonin
is a crucial signal in the neurogenic niche microenvironment, and involved in
antidepressant action. Studies of modified animal models constitutively
depleted of brain serotonin support the importance of the neurotransmitter in
adult neurogenesis. However, one cannot discriminate between phenotypes
induced by serotonin per se and compensatory processes provoked by its
life-long depletion. Here, we employ a new transgenic rat model
(TetO-shTph2), where brain serotonin levels can be acutely depleted, or
repeatedly stimulated, which recapitulate the human condition more
adequately. Based on doxycycline-inducible shRNA-expression, we measure
serotonin levels, and its metabolite, in various brain areas, and
specifically examine precursor cell proliferation and survival in the dentate
gyrus. Surprisingly, we found that decreased serotonin levels in the raphe
and prefrontal cortex of TetO-shTph2 rats at 14 days (Tph2 knockdown) are
associated with increased numbers of BrdU-labeled cells in the hippocampus. A
result that remains, for the moment, counterintuitive, considering that the
mechanism of antidepressants targeting the serotonin system is believed to be
increased neurogenesis. Furthermore, reduced brain serotonin in TetO-shTph2
rats leads to a more anxious phenotype in the Open field test. At 5 weeks
after serotonin replenishment, the anxious phenotype remains; yet, no
differences on cell proliferation and survival were observed compared with
control groups using the CldU/IdU treatment paradigm. This study will yield
insights into the role of serotonin in the etiology and pathogenesis of
affective syndromes. We speculate that decreased serotonin concentrations
might represent a compensatory mechanism. Further research will be required
to address the new questions raised by these findings. |
friederike.klempin@mdc-berlin.de |
| 3 |
27 |
Magdalena |
Zaniewska |
1Department
of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy
of Sciences, Kraków, Poland
2Laboratory of Pharmacology and Brain Biostructure, Department of
Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences,
Kraków, Poland
|
Effects
of the long-term physical activity on depression-like symptoms, drug-seeking
behavior and changes in hippocampal neurogenesis during nicotine cessation |
Magdalena
Zaniewska1,2,*, Sabina Brygider1,2, Dawid Gawliński1, Głowacka Urszula2,
Glińska Sława3, Balcerzak Łucja3, Mateusz Wątroba1, Krzysztof Wędzony2,
Marzena Maćkowiak2
1Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology,
Polish Academy of Sciences, Kraków, Poland
2Laboratory of Pharmacology and Brain Biostructure, Department of
Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences,
Kraków, Poland
3Laboratory of Microscopic Imaging and Specialized Biological Techniques,
Faculty of Biology and Environmental Protection, University of Lodz, Lodz,
Poland. |
Literature
data indicate that chronic exposure to nicotine impairs the adult hippocampal
neurogenesis in rats, while the long-term exercise may enhance this process.
Since the abnormal hippocampal neurogenesis seems to contribute to
depression, it can therefore be assumed that disturbances in this process
observed in animals self-administering nicotine may be associated with mood
disorders occurring during nicotine withdrawal, and that their modification
could prevent relapses.
The present study aimed at investigating the effect of running on nicotine
withdrawal symptoms and hippocampal neurogenesis. Rats were subjected to
nicotine (0.03 mg/kg/inf) self-administration under an increasing schedule of
reinforcement. After 21 self-administration sessions, animals were subjected
to a withdrawal phase during which they were kept in cages equipped with
running wheels (for 14 days).
We reported that exposure to the running wheels during nicotine withdrawal
attenuated depression (day 14), but was devoid of the effect on nicotine
craving (day 15). We found that on day 14 of nicotine withdrawal there was a
significant attenuation of neuronal maturation and decrease in the number of
DCX-positive cells, but no change in the number of BrdU- or Ki-67-positive
cells. The long-term physical activity during nicotine withdrawal ameliorated
the attenuated number of DCX-positive cells.
In summary, the long-term exposure to the running wheels reduced
depression-like behavior in nicotine-weaned rats. One possible mechanism
underlying the positive effect of running on the affective state during
nicotine withdrawal may be the attenuation of deficits in DCX-positive cells
in the hippocampus. Research supported by grant HARMONIA 2014/14/M/N24/00561. |
zaniew@if-pan.krakow.pl |
| 3 |
28 |
Filippo |
Calzolari |
Institute
of Physiological Chemistry, University Medical Center, Mainz |
Increased
quiescence and NSC division asymmetry during ageing, in the adult
subependymal zone |
Filippo
Calzolari* , Lisa Bast*, Michael Strasser, Jan Hasenauer, Fabian Theis,
Jovica Ninkovic and Carsten Marr |
Neural
stem cells in the adult murine brain have only a limited capacity to
self-renew, and the number of neurons they generate drastically declines with
age. How cellular dynamics sustain neurogenesis and how alterations with age
may result in this decline, are both unresolved issues. Therefore, we
clonally traced neural stem cell lineages using confetti reporters in young
and middle-aged adult mice. To understand the underlying mechanisms, we
derived mathematical population models of adult
neurogenesis that explain observed clonal cell type abundances. Models
fitting the data best, consistently show self renewal of transit amplifying
progenitors and rapid neuroblast cell cycle exit. Most importantly, we
identified an increased probability of asymmetric stem cell divisions at the
expense of symmetric differentiation, accompanied by an extended persistence
into quiescence between activation phases,
with age. Our model explains existing longitudinal population data and
identifies particular cellular strategies underlying adult neural stem cell
homeostasis and the aging of this stem cell compartment. Moreover, we provide
a quantitative framework to facilitate the interpretation of reported and
novel neurogenesis-related phenotypes. |
fcalzola@uni-mainz.de |
| 3 |
29 |
Evgenia |
Salta |
VIB-KULEUVEN |
MicroRNA-132
restores adult hippocampal neurogenesis and memory deficits in Alzheimer's
disease |
Evgenia
Salta, Hannah Walgrave, Katleen Craessaerts, Nicky Thrupp, Sriram Balusu,
Edina Silajdzic, Henrik Zetterberg, Sandrine Thuret, Mark Fiers, Bart De
Strooper |
Adult
hippocampal neurogenesis (AHN) is functionally linked to mnemonic and
cognitive plasticity in humans and rodents. In Alzheimer’s disease (AD), the
process of generating new neurons at the hippocampal neurogenic niche is
altered, but the mechanisms involved are unknown. Here we identify miR-132,
one of the most consistently downregulated microRNAs in AD, as a potent
regulator of AHN, exerting complex proneurogenic effects in several resident
niche cell populations in vivo. Using distinct AD mouse models, cultured
human primary and established neural stem cells, and human patient material,
we demonstrate that AHN is directly impacted by AD pathology. MiR-132
replacement in adult mouse AD hippocampus restores AHN and relevant memory
deficits. Our findings corroborate the significance of AHN in AD and reveal
the possible therapeutic significance of targeting miR-132 in
neurodegeneration. |
Evgenia.Salta@cme.vib-kuleuven.be |
| 3 |
30 |
Angelica |
Zepeda |
Universidad
Nacional Autónoma de México |
Neurogenesis
as a correlate of functional reorganization in the damaged dentate gyrus |
Andrea
Aguilar-Arredondo; Laura Ramos Languren; Martha Escobar; Clorinda Arias and
Angélica Zepeda |
The
dentate gyrus (DG) displays enhanced neurogenesis along functional recovery
after damage. It is unknown whether new cells become functional with time and
if its activation correlates with recovery. To evaluate this, we induced a
focal lesion in the DG of young adult rats and analyzed long-term
potentiation in the mossy fiber pathway as well as memory function and
activation of new neurons in response either to contextual fear memory (CFM)
or to a control spatial exploratory task. We analyzed the number of BrdU+
cells that co-localized with doublecortin (DCX) or with NeuN within the
damaged DG and evaluated the number of cells in each population that
co-labeled with the activity marker c-fos after either task.
At 10 days post-lesion (dpl), a region of the granular cell layer was
devoid of cells, evidencing the damaged area, whereas at 30 dpl this region
was significantly smaller. At 10 dpl, LTP could not be elicited and CFM was
impaired while the number of BrdU+/DCX+/c-fos+ cells had increased compared
to the sham-lesion group. At 30 dpl, a significantly greater number of
BrdU+/NeuN+/cfos+ cells was observed compared to 10 dpl and LTP could be
induced. Activation of BrdU+/NeuN+ cells correlated with CFM recovery, while
performance in the spatial exploratory task induced marginal c-fos
immunoreactivity in this cell population. Our results show that neurons born
after DG damage, survive and become activated in a time- and task-dependent
manner, while activation of new neurons occurs along functional
recovery.
Funding: CONACyT 282470, PAPIIT IN208518
|
azepeda@biomedicas.unam.mx |
| 3 |
31 |
Thomas |
Berger |
1Institute
of Psychiatry, Psychology and Neuroscience, King’s College London, The
Maurice Wohl Clinical Neuroscience Institute,125 Coldharbour Lane, SE5 9NU
London, United Kingdom 2Social, Genetic & Developmental Psychiatry
Centre, King’s College London, 16 De Crespigny Park, SE5 9NU London, United
Kingdom |
Adult
hippocampal neurogenesis – A potential converging mechanism for Major
Depressive Disorder & Alzheimer’s Disease |
Thomas
Berger1, Hyunah Lee1, Marc-David Ruepp1, Timothy R. Powell2, Sandrine
Thuret1 |
Mental
health disorders are widespread throughout society. Two of the most common
neurological or psychiatric disorders are dementia and depression. About 50
million people suffer from dementia (70 % Alzheimer’s Disease) worldwide.
Clinical studies report correlations between Alzheimer’s Disease (AD) and
Major Depressive Disorder (MDD). AD patients are significantly more likely to
develop depressive symptoms and impaired cognition is a common symptom of
both disorders. One brain region where the production of new neurons
continues throughout life and which plays an important role in memory and
cognitive function is the hippocampus. The generation of those new neurons
and their integration is crucial for the manifestation of novel memories and
cognitive performance and the regulation of mood. Previous studies have
already suggested that hippocampal neurogenesis is altered in MDD and AD.
However, no cellular mechanism has been proposed yet to connect these two
disorders. Therefore, this project aims to investigate the role of
hippocampal neurogenesis in MDD and AD as a shared mechanism and as a
potential therapeutic target. Therefore, using Clustered Regularly
Interspaced Short Palindromic Repeats (CRISPR) we will generate isogenic
induced pluripotent stem cell (iPSC) lines with mutations that are most
likely to have an impact on neurogenesis based on significance levels in
genome-wide association studies (GWAS) and bioinformatic predictions. |
thomas.berger@kcl.ac.uk |
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 Updating... Ċ eurogenesis Bordeaux, Jun 6, 2019, 2:37 AM
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