Publications by authors named "Muriel Koehl"

32 Publications

A Baldwin interpretation of adult hippocampal neurogenesis: from functional relevance to physiopathology.

Mol Psychiatry 2021 Jun 8. Epub 2021 Jun 8.

University Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France.

Hippocampal adult neurogenesis has been associated to many cognitive, emotional, and behavioral functions and dysfunctions, and its status as a selected effect or an "appendix of the brain" has been debated. In this review, we propose to understand hippocampal neurogenesis as the process underlying the "Baldwin effect", a particular situation in evolution where fitness does not rely on the natural selection of genetic traits, but on "ontogenetic adaptation" to a changing environment. This supports the view that a strong distinction between developmental and adult hippocampal neurogenesis is made. We propose that their functions are the constitution and the lifelong adaptation, respectively, of a basic repertoire of cognitive and emotional behaviors. This lifelong adaptation occurs through new forms of binding, i.e., association or dissociation of more basic elements. This distinction further suggests that a difference is made between developmental vulnerability (or resilience), stemming from dysfunctional (or highly functional) developmental hippocampal neurogenesis, and adult vulnerability (or resilience), stemming from dysfunctional (or highly functional) adult hippocampal neurogenesis. According to this hypothesis, developmental and adult vulnerability are distinct risk factors for various mental disorders in adults. This framework suggests new avenues for research on hippocampal neurogenesis and its implication in mental disorders.
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http://dx.doi.org/10.1038/s41380-021-01172-4DOI Listing
June 2021

Inhibition of mTOR signaling by genetic removal of p70 S6 kinase 1 increases anxiety-like behavior in mice.

Transl Psychiatry 2021 03 15;11(1):165. Epub 2021 Mar 15.

Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, Neurogenesis and Pathophysiology Group, F-3300, Bordeaux, France.

The mechanistic target of rapamycin (mTOR) is a ubiquitously expressed kinase that acts through two complexes, mTORC1 and mTORC2, to regulate protein homeostasis, as well as long lasting forms of synaptic and behavioral plasticity. Alteration of the mTOR pathway is classically involved in neurodegenerative disorders, and it has been linked to dysregulation of cognitive functions and affective states. However, information concerning the specific involvement of the p70 S6 kinase 1 (S6K1), a downstream target of the mTORC1 pathway, in learning and memory processes and in the regulation of affective states remains scant. To fill this gap, we exposed adult male mice lacking S6K1 to a battery of behavioral tests aimed at measuring their learning and memory capabilities by evaluating reference memory and flexibility with the Morris water maze, and associative memory using the contextual fear conditioning task. We also studied their anxiety-like and depression-like behaviors by, respectively, performing elevated plus maze, open field, light-dark emergence tests, and sucrose preference and forced swim tests. We found that deleting S6K1 leads to a robust anxious phenotype concomitant with associative learning deficits; these symptoms are associated with a reduction of adult neurogenesis and neuronal atrophy in the hippocampus. Collectively, these results provide grounds for the understanding of anxiety reports after treatments with mTOR inhibitors and will be critical for developing novel compounds targeting anxiety.
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http://dx.doi.org/10.1038/s41398-020-01187-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960700PMC
March 2021

Cord Serum Cytokines at Birth and Children's Anxiety-Depression Trajectories From 3 to 8 Years: The EDEN Mother-Child Cohort.

Biol Psychiatry 2021 03 24;89(6):541-549. Epub 2020 Oct 24.

Université Côte d'Azur, Nice, France; Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.

Background: Recent research suggests that immune dysregulation in pregnancy could be a risk factor for anxiety and depression symptoms in offspring. Whereas animal studies have demonstrated the importance of the link between perinatal cytokines and abnormal behaviors in offspring, human epidemiological studies in this area remain limited. The objectives of the study were to describe the network of cord serum cytokines at birth and test whether they are associated with subsequent anxiety and depression symptom trajectories in offspring.

Methods: We used data and biological samples from 871 mother-child pairs followed up from pregnancy to 8 years of age and participating in the French mother-child cohort EDEN (a study on the pre- and early postnatal determinants of child health and development). Cord serum cytokines were measured at birth. Children's symptoms of anxiety and depression were assessed with the emotional difficulties subscore of the Strength and Difficulties Questionnaire at ages 3, 5, and 8 years, from which trajectories of anxiety-depression symptoms were derived.

Results: Results showed a significant association between cord serum interleukin-7 at birth and the trajectories of children's anxiety-depression symptoms between ages 3 to 8 years (adjusted odds ratio, 0.73; 95% confidence interval, 0.57-0.93). The associations considered relevant confounders, including prenatal maternal depressive symptoms.

Conclusions: Early immune changes may contribute to subsequent anxiety and depression symptoms in childhood. Beyond the understanding of mechanisms underlying the occurrence of emotional difficulties in children, our findings open avenues for future research in human and animals.
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http://dx.doi.org/10.1016/j.biopsych.2020.10.009DOI Listing
March 2021

Sox11 is an Activity-Regulated Gene with Dentate-Gyrus-Specific Expression Upon General Neural Activation.

Cereb Cortex 2020 05;30(6):3731-3743

Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.

Neuronal activity initiates transcriptional programs that shape long-term changes in plasticity. Although neuron subtypes differ in their plasticity response, most activity-dependent transcription factors (TFs) are broadly expressed across neuron subtypes and brain regions. Thus, how region- and neuronal subtype-specific plasticity are established on the transcriptional level remains poorly understood. We report that in young adult (i.e., 6-8 weeks old) mice, the developmental TF SOX11 is induced in neurons within 6 h either by electroconvulsive stimulation or by exploration of a novel environment. Strikingly, SOX11 induction was restricted to the dentate gyrus (DG) of the hippocampus. In the novel environment paradigm, SOX11 was observed in a subset of c-FOS expressing neurons (ca. 15%); whereas around 75% of SOX11+ DG granule neurons were c-FOS+, indicating that SOX11 was induced in an activity-dependent fashion in a subset of neurons. Environmental enrichment or virus-mediated overexpression of SOX11 enhanced the excitability of DG granule cells and downregulated the expression of different potassium channel subunits, whereas conditional Sox11/4 knock-out mice presented the opposite phenotype. We propose that Sox11 is regulated in an activity-dependent fashion, which is specific to the DG, and speculate that activity-dependent Sox11 expression may participate in the modulation of DG neuron plasticity.
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http://dx.doi.org/10.1093/cercor/bhz338DOI Listing
May 2020

Juvenile mild traumatic brain injury elicits distinct spatiotemporal astrocyte responses.

Glia 2020 03 31;68(3):528-542. Epub 2019 Oct 31.

CNRS UMR5287, University of Bordeaux, Bordeaux, France.

Mild-traumatic brain injury (mTBI) represents ~80% of all emergency room visits and increases the probability of developing long-term cognitive disorders in children. To date, molecular and cellular mechanisms underlying post-mTBI cognitive dysfunction are unknown. Astrogliosis has been shown to significantly alter astrocytes' properties following brain injury, potentially leading to significant brain dysfunction. However, such alterations have never been investigated in the context of juvenile mTBI (jmTBI). A closed-head injury model was used to study jmTBI on postnatal-day 17 mice. Astrogliosis was evaluated using glial fibrillary acidic protein (GFAP), vimentin, and nestin immunolabeling in somatosensory cortex (SSC), dentate gyrus (DG), amygdala (AMY), and infralimbic area (ILA) of prefrontal cortex in both hemispheres from 1 to 30 days postinjury (dpi). In vivo T2-weighted-imaging (T2WI) and diffusion tensor imaging (DTI) were performed at 7 and 30 dpi to examine tissue level structural alterations. Increased GFAP-labeling was observed up to 30 dpi in the ipsilateral SSC, the initial site of the impact. However, vimentin and nestin expression was not perturbed by jmTBI. The morphology of GFAP positive cells was significantly altered in the SSC, DG, AMY, and ILA up to 7 dpi that some correlated with magnetic resonance imaging changes. T2WI and DTI values were significantly altered at 30 dpi within these brain regions most prominently in regions distant from the impact site. Our data show that jmTBI triggers changes in astrocytic phenotype with a distinct spatiotemporal pattern. We speculate that the presence and time course of astrogliosis may contribute to pathophysiological processes and long-term structural alterations following jmTBI.
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http://dx.doi.org/10.1002/glia.23736DOI Listing
March 2020

Transcriptional Dysregulation in Postnatal Glutamatergic Progenitors Contributes to Closure of the Cortical Neurogenic Period.

Cell Rep 2018 03;22(10):2567-2574

Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France; Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland. Electronic address:

Progenitors of cortical glutamatergic neurons (Glu progenitors) are usually thought to switch fate before birth to produce astrocytes. We used fate-mapping approaches to show that a large fraction of Glu progenitors persist in the postnatal forebrain after closure of the cortical neurogenesis period. Postnatal Glu progenitors do not accumulate during embryonal development but are produced by embryonal radial glial cells that persist after birth in the dorsal subventricular zone and continue to give rise to cortical neurons, although with low efficiency. Single-cell RNA sequencing reveals a dysregulation of transcriptional programs, which parallels changes in mA methylation and correlates with the gradual decline in cortical neurogenesis observed in vivo. Rescuing experiments show that postnatal progenitors are partially permissive to genetic and pharmacological manipulations. Our study provides an in-depth characterization of postnatal Glu progenitors and identifies potential therapeutic targets for promoting brain repair.
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http://dx.doi.org/10.1016/j.celrep.2018.02.030DOI Listing
March 2018

Depleting adult dentate gyrus neurogenesis increases cocaine-seeking behavior.

Mol Psychiatry 2019 02 5;24(2):312-320. Epub 2018 Mar 5.

Neurocentre Magendie, Physiopathology of addiction and traumatic memories group, INSERM U1215, 33077, Bordeaux, France.

The hippocampus is the main locus for adult dentate gyrus (DG) neurogenesis. A number of studies have shown that aberrant DG neurogenesis correlates with many neuropsychiatric disorders, including drug addiction. Although clear causal relationships have been established between DG neurogenesis and memory dysfunction or mood-related disorders, evidence of the causal role of DG neurogenesis in drug-seeking behaviors has not been established. Here we assessed the role of new DG neurons in cocaine self-administration using an inducible transgenic approach that selectively depletes adult DG neurogenesis. Our results show that transgenic mice with decreased adult DG neurogenesis exhibit increased motivation to self-administer cocaine and a higher seeking response to cocaine-related cues. These results identify adult hippocampal neurogenesis as a key factor in vulnerability to cocaine addiction.
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http://dx.doi.org/10.1038/s41380-018-0038-0DOI Listing
February 2019

Plasticity in the olfactory bulb of the maternal mouse is prevented by gestational stress.

Sci Rep 2016 11 25;6:37615. Epub 2016 Nov 25.

INSERM U1215, Magendie Neurocenter, Neurogenesis and Pathophysiology group, 146 rue Léo Saignat, Bordeaux-33077, France.

Maternal stress is associated with an altered mother-infant relationship that endangers offspring development, leading to emotional/behavioral problems. However, little research has investigated the stress-induced alterations of the maternal brain that could underlie such a disruption of mother-infant bonding. Olfactory cues play an extensive role in the coordination of mother-infant interactions, suggesting that motherhood may be associated to enhanced olfactory performances, and that this effect may be abolished by maternal stress. To test this hypothesis, we analyzed the impact of motherhood under normal conditions or after gestational stress on olfactory functions in C57BL/6 J mice. We report that gestational stress alters maternal behavior and prevents both mothers' ability to discriminate pup odors and motherhood-induced enhancement in odor memory. We investigated adult bulbar neurogenesis as a potential mechanism of the enhanced olfactory function in mothers and found that motherhood was associated with an increased complexity of the dendritic tree of newborn neurons. This motherhood-evoked remodeling was totally prevented by gestational stress. Altogether, our results may thus provide insight into the neural changes that could contribute to altered maternal behavior in stressed mothers.
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http://dx.doi.org/10.1038/srep37615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122868PMC
November 2016

LAMP5 Fine-Tunes GABAergic Synaptic Transmission in Defined Circuits of the Mouse Brain.

PLoS One 2016 7;11(6):e0157052. Epub 2016 Jun 7.

Aix-Marseille University, Centre National pour la Recherche Scientifique, IBDM, Developmental Biology Institute of Marseille, UMR 7288, 13009, Marseille, France.

LAMP5 is member of the LAMP family of membrane proteins. In contrast to the canonical members of this protein family, LAMP1 and LAMP2, which show widespread expression in many tissues, LAMP 5 is brain specific in mice. In C. elegans, the LAMP5 ortholog UNC-46 has been suggested to act a trafficking chaperone, essential for the correct targeting of the nematode vesicular GABA-transporter UNC-47. We show here that in the mouse brain LAMP5 is expressed in subpopulations of GABAergic forebrain neurons in the striato-nigral system and the olfactory bulb. The protein was present at synaptic terminals, overlapping with the mammalian vesicular GABA-transporter VGAT. In LAMP5-deficient mice localization of the transporter was unaffected arguing against a conserved role in VGAT trafficking. Electrophysiological analyses in mutants showed alterations in short term synaptic plasticity suggesting that LAMP5 is involved in controlling the dynamics of evoked GABAergic transmission. At the behavioral level, LAMP5 mutant mice showed decreased anxiety and deficits in olfactory discrimination. Altogether, this work implicates LAMP5 function in GABAergic neurotransmission in defined neuronal subpopulations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157052PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896627PMC
July 2017

[Early life stressful experiences and neuropsychiatric vulnerability: evidences from human and animal models].

Med Sci (Paris) 2016 Jan 5;32(1):93-9. Epub 2016 Feb 5.

Université de Bordeaux, Nutrition et neurobiologie intégrée (NUTRINEURO), UMR 1286, 146, rue Léo Saignat, 33076 Bordeaux Cedex, France - Inra, Nutrition et neurobiologie intégrée (NUTRINEURO), UMR 1286, F-33076 Bordeaux, France.

The human newborn is highly dependent on parental care for its survival but also for the healthy development of its brain. A large body of literature demonstrates the impact of early life adversity, even during the prenatal period, on the adult's health. The susceptibility to neuropsychiatric diseases is often potentiated by early stress. If there is an agreement that a critical developmental period exists, the mechanisms underlying the long term effects of early life adversity are still poorly understood. Recent studies in animals highlight the involvement of epigenetic processes in the transmission of such vulnerabilities, notably via modifications in germ cells, which can be transmitted in the next generations.
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http://dx.doi.org/10.1051/medsci/20163201015DOI Listing
January 2016

Running per se stimulates the dendritic arbor of newborn dentate granule cells in mouse hippocampus in a duration-dependent manner.

Hippocampus 2016 Mar 8;26(3):282-8. Epub 2015 Dec 8.

Neurogenesis and Physiopathology Group, NeuroCentre Magendie, Bordeaux, France.

Laboratory rodents provided chronic unlimited access to running wheels display increased neurogenesis in the hippocampal dentate gyrus. In addition, recent studies indicate that such an access to wheels stimulates dendritic arborization in newly formed neurons. However, (i) the presence of the running wheel in the housing environment might also bear intrinsic influences on the number and shape of new neurons and (ii) the dendritic arborization of new neurons might be insensitive to moderate daily running activity (i.e., several hours). In keeping with these uncertainties, we have examined neurogenesis and dendritic arborization in newly formed granular cells in adult C57Bl/6N male mice housed for 3 weeks under standard conditions, with a locked wheel, with a running wheel set free 3 h/day, or with a running wheel set permanently free. The results indicate that the presence of a blocked wheel in the home cage increased cell proliferation, but not the number of new neurons while running increased in a duration-dependent manner the number of newborn neurons, as assessed by DCX labeling. Morphological analyses of the dendritic tree of newborn neurons, as identified by BrdU-DCX co-staining, revealed that although the presence of the wheel stimulated their dendritic architecture, the amplitude of this effect was lower than that elicited by running activity, and was found to be running duration-dependent.
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http://dx.doi.org/10.1002/hipo.22551DOI Listing
March 2016

Gene-environment interaction in programming hippocampal plasticity: focus on adult neurogenesis.

Authors:
Muriel Koehl

Front Mol Neurosci 2015 4;8:41. Epub 2015 Aug 4.

INSERM U862, Magendie Neurocenter, Neurogenesis and Pathophysiology Group, Institut F. Magendie Bordeaux Cedex, France ; Université de Bordeaux Bordeaux, France.

Interactions between genes and environment are a critical feature of development and both contribute to shape individuality. They are at the core of vulnerability resiliency for mental illnesses. During the early postnatal period, several brain structures involved in cognitive and emotional processing, such as the hippocampus, still develop and it is likely that interferences with this neuronal development, which is genetically determined, might lead to long-lasting structural and functional consequences and increase the risk of developing psychopathology. One particular target is adult neurogenesis, which is involved in the regulation of cognitive and emotional processes. Insights into the dynamic interplay between genes and environmental factors in setting up individual rates of neurogenesis have come from laboratory studies exploring experience-dependent changes in adult neurogenesis as a function of individual's genetic makeup. These studies have implications for our understanding of the mechanisms regulating adult neurogenesis, which could constitute a link between environmental challenges and psychopathology.
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http://dx.doi.org/10.3389/fnmol.2015.00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523721PMC
August 2015

Effects of spaced learning in the water maze on development of dentate granule cells generated in adult mice.

Hippocampus 2015 Nov 2;25(11):1314-26. Epub 2015 Apr 2.

Inserm U862, Bordeaux, France.

New dentate granule cells (GCs) are generated in the hippocampus throughout life. These adult-born neurons are required for spatial learning in the Morris water maze (MWM). In rats, spatial learning shapes the network by regulating their number and dendritic development. Here, we explored whether such modulatory effects exist in mice. New GCs were tagged using thymidine analogs or a GFP-expressing retrovirus. Animals were exposed to a reference memory protocol for 10-14 days (spaced training) at different times after newborn cells labeling. Cell proliferation, cell survival, cell death, neuronal phenotype, and dendritic and spine development were examined using immunohistochemistry. Surprisingly, spatial learning did not modify any of the parameters under scrutiny including cell number and dendritic morphology. These results suggest that although new GCs are required in mice for spatial learning in the MWM, they are, at least for the developmental intervals analyzed here, refractory to behavioral stimuli generated in the course of learning in the MWM.
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http://dx.doi.org/10.1002/hipo.22438DOI Listing
November 2015

Prenatal stress inhibits hippocampal neurogenesis but spares olfactory bulb neurogenesis.

PLoS One 2013 29;8(8):e72972. Epub 2013 Aug 29.

Inserm U862, Bordeaux, France.

The dentate gyrus (DG) and the olfactory bulb (OB) are two regions of the adult brain in which new neurons are integrated daily in the existing networks. It is clearly established that these newborn neurons are implicated in specific functions sustained by these regions and that different factors can influence neurogenesis in both structures. Among these, life events, particularly occurring during early life, were shown to profoundly affect adult hippocampal neurogenesis and its associated functions like spatial learning, but data regarding their impact on adult bulbar neurogenesis are lacking. We hypothesized that prenatal stress could interfere with the development of the olfactory system, which takes place during the prenatal period, leading to alterations in adult bulbar neurogenesis and in olfactory capacities. To test this hypothesis we exposed pregnant C57Bl/6J mice to gestational restraint stress and evaluated behavioral and anatomic consequences in adult male offspring. We report that prenatal stress has no impact on adult bulbar neurogenesis, and does not alter olfactory functions in adult male mice. However, it decreases cell proliferation and neurogenesis in the DG of the hippocampus, thus confirming previous reports on rats. Altogether our data support a selective and cross-species long-term impact of prenatal stress on neurogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072972PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756947PMC
April 2014

Interplay of maternal care and genetic influences in programming adult hippocampal neurogenesis.

Biol Psychiatry 2012 Aug 5;72(4):282-9. Epub 2012 Apr 5.

Institut National de la Santé et de la Recherche Médicale, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, 146 rue Leo Saignat, Bordeaux, France.

Background: Adult hippocampal neurogenesis, which is involved in the physiopathology of hippocampal functions, is genetically determined and influenced by early life events. However, studies on the interaction of these determining forces are lacking. This prompted us to investigate whether adult hippocampal neurogenesis can be modulated by maternal care and whether this influence depends upon the genetic background of the individual.

Methods: We used a model of fostering that allows singling out the influence of the genetic make-up of the pups on the outcome of maternal behavior. Mice from two different inbred strains (C57BL/6J and DBA/2J) known to differ in their baseline neurogenesis as well as in their sensitivity to the influence of environmental experiences were raised by nonrelated mothers from the AKR/Ola (AKR) and C3H/He (C3H) strains exhibiting low- and high-pup-oriented behavior, respectively. Neurogenesis was then assessed in the dentate gyrus of the adult adopted C57BL/6J and DBA/2J mice.

Results: We show that both the number and the morphological features of newborn granule cells in the dentate gyrus are determined by the maternal environment to which mice were exposed as pups and that this sensitivity to maternal environment is observed only in genetically vulnerable subjects.

Conclusions: Altogether, our data indicate interplay between early environment and the genetic envelop of an individual in determining adult hippocampal neurogenesis. Our experimental approach could thus contribute to the identification of factors determining the neurogenic potential of the adult hippocampus.
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http://dx.doi.org/10.1016/j.biopsych.2012.03.001DOI Listing
August 2012

Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD.

Cell 2012 Mar;148(5):1039-50

College of Life Sciences and Key Laboratory of Modern Teaching Technology, Shaanxi Normal University, Xian, China.

Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo.
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http://dx.doi.org/10.1016/j.cell.2012.01.037DOI Listing
March 2012

Conditional reduction of adult neurogenesis impairs bidirectional hippocampal synaptic plasticity.

Proc Natl Acad Sci U S A 2011 Apr 4;108(16):6644-9. Epub 2011 Apr 4.

Institut National de la Santé et de la Recherche Médicale U862, Neurocentre Magendie, Glia-Neuron Interactions Group, F33077 Bordeaux, France.

Adult neurogenesis is a process by which the brain produces new neurons once development has ceased. Adult hippocampal neurogenesis has been linked to the relational processing of spatial information, a role attributed to the contribution of newborn neurons to long-term potentiation (LTP). However, whether newborn neurons also influence long-term depression (LTD), and how synaptic transmission and plasticity are affected as they incorporate their network, remain to be determined. To address these issues, we took advantage of a genetic model in which a majority of adult-born neurons can be selectively ablated in the dentate gyrus (DG) and, most importantly, in which neurogenesis can be restored on demand. Using electrophysiological recordings, we show that selective reduction of adult-born neurons impairs synaptic transmission at medial perforant pathway synapses onto DG granule cells. Furthermore, LTP and LTD are largely compromised at these synapses, probably as a result of an increased induction threshold. Whereas the deficits in synaptic transmission and plasticity are completely rescued by restoring neurogenesis, these synapses regain their ability to express LTP much faster than their ability to express LTD. These results demonstrate that both LTP and LTD are influenced by adult neurogenesis. They also indicate that as newborn neurons integrate their network, the ability to express bidirectional synaptic plasticity is largely improved at these synapses. These findings establish that adult neurogenesis is an important process for synaptic transmission and bidirectional plasticity in the DG, accounting for its role in efficiently integrating novel incoming information and in forming new memories.
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http://dx.doi.org/10.1073/pnas.1016928108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081011PMC
April 2011

A new chapter in the field of memory: adult hippocampal neurogenesis.

Eur J Neurosci 2011 Mar;33(6):1101-14

Neurogenesis and Pathophysiology Laboratory, INSERM 862, Bordeaux, France.

Understanding the cellular mechanisms underlying learning and memory is a major challenge in neurobiology. Structural and functional changes occurring in the hippocampus such as synaptic remodeling and long-term potentiation are key signatures of long-term memory processes. The discovery of a de novo hippocampal production of neurons in the adult brain has been a breakthrough in the field of plasticity and memory, introducing a new actor that could sustain memory processes. Here we will review our current knowledge on the role of these adult new neurons in memory. In particular we will provide evidence showing that they are required for learning and memory and that an alteration in their production rate or maturation leads to memory impairments. Through a thorough survey of the literature, we will also acknowledge that there are many controversies regarding the specific role played by newborn neurons. The emerging picture is that they are involved in the establishment of spatiotemporal relationships among multiple environmental cues for the flexible use of the acquired information. Indeed, newborn neurons have been found to be required for separating events based on their spatial and temporal characteristics, a process that preserves the uniqueness of a memory representation. Thus, adult-born neurons are required for allocentric space representation, for long-term memory retention and for flexible inferential memory expression. Finally, we will conclude by highlighting directions for future research, emphasizing that the exact participation of newborn neurons in memory processes will not be approached without considering the hippocampal network in general.
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http://dx.doi.org/10.1111/j.1460-9568.2011.07609.xDOI Listing
March 2011

A critical time window for the recruitment of bulbar newborn neurons by olfactory discrimination learning.

J Neurosci 2011 Jan;31(3):1010-6

INSERM U862, Magendie Neurocenter, Neurogenesis and Pathophysiology Group, Bordeaux F-33077, France.

In the mammalian brain, the dentate gyrus and the olfactory bulb are regions where new neurons are continuously added. While the functional consequences of continuous hippocampal neurogenesis have been extensively studied, the role of olfactory adult-born neurons remains elusive. In particular, the involvement of these newborn neurons in odor processing is still a matter of debate. We demonstrate a critical impact of both the age of new neurons and the memory processes involved (learning vs recall) in the recruitment of newborn cells. Thus, odor stimulation preferentially recruited immature neurons over more mature ones (2 weeks old vs 5 and 9 weeks old), whereas associative learning based on odor discrimination preferentially recruited mature neurons (5-9 weeks old). Furthermore, while mature neurons were activated by this associative learning, they were not activated by long-term memory recall, indicating that the contribution of newborn neurons in olfactory functions depends also on the memory process involved. Our data thus show that newborn neurons are indeed involved in odor processing and that their recruitment is age- and memory process-dependent.
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http://dx.doi.org/10.1523/JNEUROSCI.3941-10.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632920PMC
January 2011

Adult-born neurons are necessary for extended contextual discrimination.

Hippocampus 2012 Feb 3;22(2):292-8. Epub 2010 Nov 3.

Inserm U862, Bordeaux-F33077, France.

New neurons are continuously produced in the adult dentate gyrus of the hippocampus. It has been shown that one of the functions of adult neurogenesis is to support spatial pattern separation, a process that transforms similar memories into nonoverlapping representations. This prompted us to investigate whether adult-born neurons are required for discriminating two contexts, i.e., for identifying a familiar environment and detect any changes introduced in it. We show that depleting adult-born neurons impairs the animal's ability to disambiguate two contexts after extensive training. These data suggest that the continuous production of new dentate neurons plays a crucial role in extracting and separating efficiently contextual representation in order to discriminate features within events.
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http://dx.doi.org/10.1002/hipo.20895DOI Listing
February 2012

The planar polarity protein Scribble1 is essential for neuronal plasticity and brain function.

J Neurosci 2010 Jul;30(29):9738-52

Molecular and Cellular Neurobiology Group, INSERM, Neurocentre Magendie, Laboratory of Pathophysiology of Neural Plasticity, U862, 33077 Bordeaux, France, University of Bordeaux, 33077 Bordeaux Cedex, France.

Scribble (Scrib) is a key regulator of apicobasal polarity, presynaptic architecture, and short-term synaptic plasticity in Drosophila. In mammals, its homolog Scrib1 has been implicated in cancer, neural tube closure, and planar cell polarity (PCP), but its specific role in the developing and adult nervous system is unclear. Here, we used the circletail mutant, a mouse model for PCP defects, to show that Scrib1 is located in spines where it influences actin cytoskeleton and spine morphing. In the hippocampus of these mutants, we observed an increased synapse pruning associated with an increased number of enlarged spines and postsynaptic density, and a decreased number of perforated synapses. This phenotype was associated with a mislocalization of the signaling pathway downstream of Scrib1, leading to an overall activation of Rac1 and defects in actin dynamic reorganization. Finally, Scrib1-deficient mice exhibit enhanced learning and memory abilities and impaired social behavior, two features relevant to autistic spectrum disorders. Our data identify Scrib1 as a crucial regulator of brain development and spine morphology, and suggest that Scrib1(crc/+) mice might be a model for studying synaptic dysfunction and human psychiatric disorders.
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http://dx.doi.org/10.1523/JNEUROSCI.6007-09.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632828PMC
July 2010

CB1 receptor deficiency decreases wheel-running activity: consequences on emotional behaviours and hippocampal neurogenesis.

Exp Neurol 2010 Jul 4;224(1):106-13. Epub 2010 Feb 4.

AVENIR Team Endocannabinoids and NeuroAdaptation, NeuroCentre INSERM U862, 33077 Bordeaux, France.

Chronic voluntary wheel-running activity has been reported to hypersensitise central CB1 receptors in mice. On the other hand, pharmacological findings suggest that the CB1 receptor could be involved in wheel-running behaviour and in running-induced neurogenesis in the hippocampus. We analysed wheel-running behaviour for 6 weeks and measured its consequences on hippocampal neurogenesis in CB1 knockout (CB1(-/-)) animals, compared to wild-type (CB1(+/+)) littermates. Because wheel running has been shown to affect locomotor reactivity in novel environments, memory for aversive events and depression-like behaviours, we also assessed these behaviours in control and running CB1(+/+) and CB1(-/-) mice. When compared with running CB1(+/+) mice, the distance covered weekly by CB1(-/-) mice was decreased by 30-40%, an observation accounted for by decreased time spent and maximal velocity on the wheels. Analyses of running distances with respect to the light/dark cycle revealed that mutant covered less distance throughout both the inactive and the active phases of that cycle. Locomotion in an activity cage, exploration in an open field, and immobility time in the forced swim test proved insensitive to chronic wheel running in either genotype. Wheel running, per se, did not influence the expression and extinction of cued fear memory but counteracted in a time-dependent manner the deficiency of extinction measured in CB1(-/-) mice. Hippocampal neurogenesis, assessed by doublecortin labelling of immature neurons in the dentate gyrus, was lowered by 40% in control CB1(-/-) mice, compared to control CB1(+/+) mice. Although CB1(-/-) mice ran less than their wild-type littermates, the 6-week running protocol increased neurogenesis to similar extents (37-39%) in both genotypes. This study suggests that mouse CB1 receptors control wheel running but not its neurogenic consequences in the hippocampus.
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http://dx.doi.org/10.1016/j.expneurol.2010.01.017DOI Listing
July 2010

Age-dependent effect of prenatal stress on hippocampal cell proliferation in female rats.

Eur J Neurosci 2009 Feb;29(3):635-40

INSERM U862, Neurocentre Magendie, Neurogenesis and Physiopathology Group, Bordeaux, France.

Stressors occurring during pregnancy can alter the developmental trajectory of offspring and lead to, among other deleterious effects, cognitive deficits and hyperactivity of the hypothalamo-pituitary-adrenal axis. A recent feature of the prenatal stress (PS) model is its reported influence on structural plasticity in hippocampal formation, which sustains both cognitive functions and stress responsiveness. Indeed, we and others have previously reported that males exposed to stress in utero are characterized by a decrease in hippocampal cell proliferation, and consequently neurogenesis, from adolescence to senescence. Recent studies in females submitted to PS have reported conflicting results, ranging from no effect to a decrease in cell proliferation. We hypothesized that changes in cell proliferation in PS female rats are age dependent. To address this issue, we examined the impact of PS on hippocampal cell proliferation in juvenile, young, middle-aged and old females. As hypothesized, we found an age-dependent effect of PS in female rats as cell proliferation was significantly decreased only when animals reached senescence, a time when adrenal gland weight also increased. These data suggest that the deleterious effects of PS on hippocampal cell proliferation in females are either specific to senescence or masked during adulthood by protective factors.
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http://dx.doi.org/10.1111/j.1460-9568.2009.06608.xDOI Listing
February 2009

Spatial relational memory requires hippocampal adult neurogenesis.

PLoS One 2008 Apr 9;3(4):e1959. Epub 2008 Apr 9.

INSERM U862, Institut F. Magendie, Bordeaux, France.

The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001959PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2396793PMC
April 2008

Maternal environment influences cocaine intake in adulthood in a genotype-dependent manner.

PLoS One 2008 May 21;3(5):e2245. Epub 2008 May 21.

U862, Institut National de la Santé Et de la Recherche Médicale, Bordeaux, France.

Background: Accumulating epidemiological evidence points to the role of genetic background as a modulator of the capacity of adverse early experiences to give rise to mental illness. However, direct evidence of such gene-environment interaction in the context of substance abuse is scarce. In the present study we investigated whether the impact of early life experiences on cocaine intake in adulthood depends on genetic background. In addition, we studied other behavioral dimensions associated with drug abuse, i.e. anxiety- and depression-related behaviors.

Methodology/principal Findings: For this purpose, we manipulated the maternal environment of two inbred mouse strains, the C57BL/6J and DBA/2J by fostering them with non-related mothers, i.e. the C3H/HeN and AKR strains. These mother strains show respectively high and low pup-oriented behavior. As adults, C57BL/6J and DBA/2J were tested either for cocaine intravenous self-administration or in the elevated plus-maze and forced swim test (FST). We found that the impact of maternal environment on cocaine use and a depression-related behavior depends upon genotype, as cocaine self-administration and behavior in the FST were influenced by maternal environment in DBA/2J, but not in C57BL/6J mice. Anxiety was not influenced by maternal environment in either strain.

Conclusions/significance: Our experimental approach could contribute to the identification of the psychobiological factors determining the susceptibility or the resilience of certain individuals to develop psychopathologies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0002245PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373927PMC
May 2008

Sex differences in sleep: the response to sleep deprivation and restraint stress in mice.

Sleep 2006 Sep;29(9):1224-31

Institute F Magendie, INSERM U588, University of Bordeaux 2, Bordeaux, France.

Study Objectives: Numerous clinical studies and sleep surveys have shown pronounced sex differences in the occurrence of insomnia and other sleep pathologies. It has been suggested that sex differences in sleep, while subtle under baseline conditions, may increase in magnitude under biological or environmental challenges. However, controlled and experimental studies on sleep under challenged conditions rarely include female subjects. In this context, we examined sex differences in sleep in the mouse, not only under baseline conditions, but also after sleep deprivation and restraint stress.

Design: Adult male and female C57BL/6J mice were implanted with electrodes to record sleep-wake architecture and sleep electroencephalogram under baseline conditions and after 6 hours of sleep deprivation or 1 hour of restraint stress at the beginning of the daily light phase.

Results: Although baseline sleep patterns slightly differed between the sexes, the homeostatic recovery response to sleep deprivation was similar. In contrast, the changes in sleep after restraint stress were markedly different between male and female mice, with males displaying a stronger initial suppression of sleep and a stronger rebound of rapid-eye-movement sleep later in the recovery phase.

Conclusions: In mice, the fundamental homeostatic properties of sleep regulation may not differ between the sexes, but the way sleep is affected and disrupted by environmental influences may be sex dependent. The latter may reflect sex differences in stress sensitivity.
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http://dx.doi.org/10.1093/sleep/29.9.1224DOI Listing
September 2006

Adult neurogenesis: from precursors to network and physiology.

Physiol Rev 2005 Apr;85(2):523-69

Laboratoire de Physiopathologie des Comportements, Institut National de la Sané et de la Recherche Médicale, U588, Université de Bordeaux, France.

The discovery that the adult mammalian brain creates new neurons from pools of stemlike cells was a breakthrough in neuroscience. Interestingly, this particular new form of structural brain plasticity seems specific to discrete brain regions, and most investigations concern the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampal formation (HF). Overall, two main lines of research have emerged over the last two decades: the first aims to understand the fundamental biological properties of neural stemlike cells (and their progeny) and the integration of the newly born neurons into preexisting networks, while the second focuses on understanding its relevance in brain functioning, which has been more extensively approached in the DG. Here, we propose an overview of the current knowledge on adult neurogenesis and its functional relevance for the adult brain. We first present an analysis of the methodological issues that have hampered progress in this field and describe the main neurogenic sites with their specificities. We will see that despite considerable progress, the levels of anatomic and functional integration of the newly born neurons within the host circuitry have yet to be elucidated. Then the intracellular mechanisms controlling neuronal fate are presented briefly, along with the extrinsic factors that regulate adult neurogenesis. We will see that a growing list of epigenetic factors that display a specificity of action depending on the neurogenic site under consideration has been identified. Finally, we review the progress accomplished in implicating neurogenesis in hippocampal functioning under physiological conditions and in the development of hippocampal-related pathologies such as epilepsy, mood disorders, and addiction. This constitutes a necessary step in promoting the development of therapeutic strategies.
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http://dx.doi.org/10.1152/physrev.00055.2003DOI Listing
April 2005

Effects of gamma-hydroxybutyrate (GHB) on vigilance states and EEG in mice.

Sleep 2004 Aug;27(5):899-904

Center for Sleep and Circadian Biology, Department of Neurobiology & Physiology, Northwestern University, Evanston, IL, USA.

Study Objectives: Gamma-hydroxybutyrate (GHB) is an endogenous neuromodulator that appears to have wide-ranging effects on vigilance and behavior. In the present study, we examined the effects of GHB on sleep-wake behavior and EEG in mice. In addition, we measured effects of GHB on body temperature and arousal or stress hormones.

Design: Adult male BALB/c mice were implanted with electroencephalographic and electromyographic electrodes to record vigilance states and an intraperitoneal transmitter to record body temperature. After recovery from surgery and habituation to the recording procedure, the mice were intraperitoneally injected with saline or GHB (50, 150 or 250 mg/kg) half an hour after light onset. Blood samples to measure effects of GHB on corticosterone and prolactin levels were collected in a separate group of mice.

Setting: N/A PATIENTS: N/A INTERVENTIONS: N/A RESULTS: At the lowest dose, GHB had no conspicuous effects on behavioral vigilance and electroencephalogram, nor on body temperature and endocrine measures. At the 2 higher doses, GHB induced a short period of electroencephalographic hypersynchrony in parallel to complete behavioral inactivity, an unnatural flat body posture, and nonresponsiveness to stimulation. After the highest dose of GHB, this state of reduced vigilance was associated with a decrease in body temperature, while prolactin and corticosterone levels were strongly increased.

Conclusions: The results do not indicate a clear sleep-promoting effect of GHB in mice, but, at higher doses, it caused electroencephalographic hypersynchronization together with a coma-like state.
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http://dx.doi.org/10.1093/sleep/27.5.899DOI Listing
August 2004

Early and later adoptions differently modify mother-pup interactions.

Behav Neurosci 2004 Jun;118(3):590-6

Laboratory of Perinatal Stress, Unite Propre de Recherche l'Enseignement Superieur-Jeune Equipe 2365, University of Lille 1, Bâtiment Sn4.1, 59655 Villeneuve d'Ascq, France.

Life events occurring during the perinatal period have strong long-term effects. In rats, prenatal stress, postnatal maternal separations, or adoptions at different periods are known to affect behavior and reactivity to stress in offspring. To determine the role of maternal factors on differential outcome adoptions, the authors investigated interactions between pups and the adopting mothers by assessing both pups' ultrasound emissions and maternal behavior. Early and late adoptions increased mother care at the moment of adoption and during mother-infant reunion after a separation procedure. However, although early adoption induced a decrease in pups' ultrasound emissions in response to a stressful separation, later adoptions enhanced it. Results suggest a sensitive period during which fostering may change pups' and dams' behavior.
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http://dx.doi.org/10.1037/0735-7044.118.3.590DOI Listing
June 2004

Individual vulnerability to substance abuse and affective disorders: role of early environmental influences.

Neurotox Res 2002 Jun;4(4):281-96

Laboratoire de Psychobiologie des Comportements Adaptatifs - INSERM U.259, Université Victor Ségalen Bordeaux 2, Institut François Magendie, Rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France.

One of the most important questions raised by modern psychiatry and experimental psychopathology is the origin of mental diseases. More concisely, clinical and experimental neurosciences are increasingly concerned with the factors that render one individual more vulnerable than another to a given pathological outcome. Animal models are now available to understand the sources of individual differences for specific phenotypes prone to behavioral disadaptations. Over the last 10 years we have explored the consequences of environmental perinatal manipulations in the rat. We have shown that prenatal stress is at the origin of a wide range of physiological and behavioral aberrances such as alterations in the activity of the hormonal stress axis, increased vulnerability to drug of abuse, emotional liability, cognitive impairments and predisposition to pathological aging. Taken together, these abnormalities define a bio-behavioral syndrome. Furthermore, the cognitive disabilities observed in prenatally-stressed rats were recently related to an alteration of neurogenesis in the dentate gyrus, thus confirming the impact of early life events on brain morphology. A second model (handling model) has also been developed in which pups are briefly separated from their mothers during early postnatal life. In contrast with prenatally-stressed animals, handled rats exhibited a reduced emotion response when confronted with novel situations and were protected against age-induced impairments of both the hormonal stress axis and cognitive functions. Taken together, the results of these investigations show that the bio-behavioral phenotype that characterizes each individual is strongly linked to the nature and timing of perinatal experience. Furthermore, data collected in prenatally-stressed animals indicate that this model could be used profitably to understand the etiology and pathophysiology of affective disorders.
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http://dx.doi.org/10.1080/1029842021000010866DOI Listing
June 2002
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