Publications by authors named "Djoher Nora Abrous"

42 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

Adult-born neurons immature during learning are necessary for remote memory reconsolidation in rats.

Nat Commun 2021 03 19;12(1):1778. Epub 2021 Mar 19.

University of Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux, France.

Memory reconsolidation, the process by which memories are again stabilized after being reactivated, has strengthened the idea that memory stabilization is a highly plastic process. To date, the molecular and cellular bases of reconsolidation have been extensively investigated particularly within the hippocampus. However, the role of adult neurogenesis in memory reconsolidation is unclear. Here, we combined functional imaging, retroviral and chemogenetic approaches in rats to tag and manipulate different populations of rat adult-born neurons. We find that both mature and immature adult-born neurons are activated by remote memory retrieval. However, only specific silencing of the adult-born neurons immature during learning impairs remote memory retrieval-induced reconsolidation. Hence, our findings show that adult-born neurons immature during learning are required for the maintenance and update of remote memory reconsolidation.
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http://dx.doi.org/10.1038/s41467-021-22069-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979763PMC
March 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

Responsiveness of dentate neurons generated throughout adult life is associated with resilience to cognitive aging.

Aging Cell 2020 08 29;19(8):e13161. Epub 2020 Jun 29.

INSERM UMR 1215, Magendie Neurocenter, Neurogenesis and Pathophysiology Group, Bordeaux, France.

During aging, some individuals are resilient to the decline of cognitive functions whereas others are vulnerable. These inter-individual differences in memory abilities have been associated with differences in the rate of hippocampal neurogenesis measured in elderlies. Whether the maintenance of the functionality of neurons generated throughout adult life is linked to resilience to cognitive aging remains completely unexplored. Using the immediate early gene Zif268, we analyzed the activation of dentate granule neurons born in adult (3-month-old), middle-aged (12-month-old), or senescent (18-month-old) rats (n = 96) in response to learning when animals reached 21 months of age. The activation of neurons born during the developmental period was also examined. We show that adult-born neurons can survive up to 19 months and that neurons generated 4, 10, or 19 months before learning, but not developmentally born neurons, are activated in senescent rats with good learning abilities. In contrast, aged rats with bad learning abilities do not exhibit activity-dependent regulation of newborn cells, whatever their birthdate. In conclusion, we propose that resilience to cognitive aging is associated with responsiveness of neurons born during adult life. These data add to our current knowledge by showing that the aging of memory abilities stems not only from the number but also from the responsiveness of adult-born neurons.
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http://dx.doi.org/10.1111/acel.13161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431828PMC
August 2020

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

Dentate Granule Neurons Generated During Perinatal Life Display Distinct Morphological Features Compared With Later-Born Neurons in the Mouse Hippocampus.

Cereb Cortex 2019 07;29(8):3527-3539

INSERM U1215, Neurocentre Magendie, Bordeaux, France.

In nonhuman mammals and in particular in rodents, most granule neurons of the dentate gyrus (DG) are generated during development and yet little is known about their properties compared with adult-born neurons. Although it is generally admitted that these populations are morphologically indistinguishable once mature, a detailed analysis of developmentally born neurons is lacking. Here, we used in vivo electroporation to label dentate granule cells (DGCs) generated in mouse embryos (E14.5) or in neonates (P0) and followed their morphological development up to 6 months after birth. By comparison with mature retrovirus-labeled DGCs born at weaning (P21) or young adult (P84) stages, we provide the evidence that perinatally born neurons, especially embryonically born cells, are morphologically distinct from later-born neurons and are thus easily distinguishable. In addition, our data indicate that semilunar and hilar GCs, 2 populations in ectopic location, are generated during the embryonic and the neonatal periods, respectively. Thus, our findings provide new insights into the development of the different populations of GCs in the DG and open new questions regarding their function in the brain.
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http://dx.doi.org/10.1093/cercor/bhy224DOI Listing
July 2019

mTORC1 pathway disruption abrogates the effects of the ciliary neurotrophic factor on energy balance and hypothalamic neuroinflammation.

Brain Behav Immun 2018 05 13;70:325-334. Epub 2018 Mar 13.

INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France. Electronic address:

Ciliary neurotrophic factor (CNTF) potently decreases food intake and body weight in diet-induced obese mice by acting through neuronal circuits and pathways located in the arcuate nucleus (ARC) of the hypothalamus. CNTF also exerts pro-inflammatory actions within the brain. Here we tested whether CNTF modifies energy balance by inducing inflammatory responses in the ARC and whether these effects depend upon the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which regulates both energy metabolism and inflammation. To this purpose, chow- and high fat diet (HFD)- fed mice lacking the S6 kinase 1 (S6K1), a downstream target of mTORC1, and their wild-type (WT) littermates received 12 days continuous intracerebroventricular (icv) infusion of the CNTF analogue axokine (CNTF). Behavioral, metabolic and molecular effects were evaluated. Central chronic administration of CNTF decreased body weight and feed efficiency in WT mice only, when fed HFD, but not chow. These metabolic effects correlated with increased number of iba-1 positive microglia specifically in the ARC and were accompanied by significant increases of IL-1β and TNF-α mRNA expression in the hypothalamus. Hypothalamic iNOS and SOCS3 mRNA, molecular markers of pro-inflammatory response, were also increased by CNTF. All these changes were absent in S6K1 mice. This study reveals that CNTF requires a functional S6K1 to modulate energy balance and hypothalamic inflammation in a diet-dependent fashion. Further investigations should determine whether S6K1 is a suitable target for the treatment of pathologies characterized by a high neuroinflammatory state.
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http://dx.doi.org/10.1016/j.bbi.2018.03.014DOI Listing
May 2018

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

Inhibiting Microglia Expansion Prevents Diet-Induced Hypothalamic and Peripheral Inflammation.

Diabetes 2017 04 30;66(4):908-919. Epub 2016 Nov 30.

INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, Bordeaux, France

Cell proliferation and neuroinflammation in the adult hypothalamus may contribute to the pathogenesis of obesity. We tested whether the intertwining of these two processes plays a role in the metabolic changes caused by 3 weeks of a high-saturated fat diet (HFD) consumption. Compared with chow-fed mice, HFD-fed mice had a rapid increase in body weight and fat mass and specifically showed an increased number of microglia in the arcuate nucleus (ARC) of the hypothalamus. Microglia expansion required the adequate presence of fats and carbohydrates in the diet because feeding mice a very high-fat, very low-carbohydrate diet did not affect cell proliferation. Blocking HFD-induced cell proliferation by central delivery of the antimitotic drug arabinofuranosyl cytidine (AraC) blunted food intake, body weight gain, and adiposity. AraC treatment completely prevented the increase in number of activated microglia in the ARC, the expression of the proinflammatory cytokine tumor necrosis factor-α in microglia, and the recruitment of the nuclear factor-κB pathway while restoring hypothalamic leptin sensitivity. Central blockade of cell proliferation also normalized circulating levels of the cytokines leptin and interleukin 1β and decreased peritoneal proinflammatory CD86 immunoreactive macrophage number. These findings suggest that inhibition of diet-dependent microglia expansion hinders body weight gain while preventing central and peripheral inflammatory responses due to caloric overload.
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http://dx.doi.org/10.2337/db16-0586DOI Listing
April 2017

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

Interaction between Neurogenesis and Hippocampal Memory System: New Vistas.

Cold Spring Harb Perspect Biol 2015 Jun 1;7(6). Epub 2015 Jun 1.

Department of Physiology, University of Toronto, Medical Sciences Building, Toronto, Ontario M5S 1A8, Canada.

During the last decade, the questions on the functionality of adult neurogenesis have changed their emphasis from if to how the adult-born neurons participate in a variety of memory processes. The emerging answers are complex because we are overwhelmed by a variety of behavioral tasks that apparently require new neurons to be performed optimally. With few exceptions, the hippocampal memory system seems to use the newly generated neurons for multiple roles. Adult neurogenesis has given the dentate gyrus new capabilities not previously thought possible within the scope of traditional synaptic plasticity. Looking at these new developments from the perspective of past discoveries, the science of adult neurogenesis has emerged from its initial phase of being, first, a surprising oddity and, later, exciting possibility, to the present state of being an integral part of mainstream neuroscience. The answers to many remaining questions regarding adult neurogenesis will come along only with our growing understanding of the functionality of the brain as a whole. This, in turn, will require integration of multiple levels of organization from molecules and cells to circuits and systems, ultimately resulting in comprehension of behavioral outcomes.
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http://dx.doi.org/10.1101/cshperspect.a018952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448601PMC
June 2015

Serotonin2C receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow.

Neuropharmacology 2015 Feb;89:375-81

Inserm, U862, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux F-33000, France.

The serotonin(2C) receptor (5-HT(2C)R) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT(2C)Rs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT(2C)R agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT(2C)R antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT(2C)Rs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum.
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http://dx.doi.org/10.1016/j.neuropharm.2014.10.016DOI Listing
February 2015

Serotonin2C receptors modulate dopamine transmission in the nucleus accumbens independently of dopamine release: behavioral, neurochemical and molecular studies with cocaine.

Addict Biol 2015 May 24;20(3):445-57. Epub 2014 Mar 24.

Neurocentre Magendie, Physiopathology of Addiction Group, Inserm U862, France; Université de Bordeaux, France.

In keeping with its ability to control the mesoaccumbens dopamine (DA) pathway, the serotonin2C receptor (5-HT2C R) plays a key role in mediating the behavioral and neurochemical effects of drugs of abuse. Studies assessing the influence of 5-HT2C R agonists on cocaine-induced responses have suggested that 5-HT2C Rs can modulate mesoaccumbens DA pathway activity independently of accumbal DA release, thereby controlling DA transmission in the nucleus accumbens (NAc). In the present study, we assessed this hypothesis by studying the influence of the 5-HT2C R agonist Ro 60-0175 on cocaine-induced behavioral, neurochemical and molecular responses. The i.p. administration of 1 mg/kg Ro 60-0175 inhibited hyperlocomotion induced by cocaine (15 mg/kg, i.p.), had no effect on cocaine-induced DA outflow in the shell, and increased it in the core subregion of the NAc. Furthermore, Ro 60-0175 inhibited the late-onset locomotion induced by the subcutaneous administration of the DA-D2 R agonist quinpirole (0.5 mg/kg), as well as cocaine-induced increase in c-Fos immunoreactivity in NAc subregions. Finally, Ro 60-0175 inhibited cocaine-induced phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine residues in the NAc core, this effect being reversed by the selective 5-HT2C R antagonist SB 242084 (0.5 mg/kg, i.p.). Altogether, these findings demonstrate that 5-HT2C Rs are capable of modulating mesoaccumbens DA pathway activity at post-synaptic level by specifically controlling DA signaling in the NAc core subregion. In keeping with the tight relationship between locomotor activity and NAc DA function, this interaction could participate in the inhibitory control of cocaine-induced locomotor activity.
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http://dx.doi.org/10.1111/adb.12137DOI Listing
May 2015

Influence of ontogenetic age on the role of dentate granule neurons.

Brain Struct Funct 2015 Mar 9;220(2):645-61. Epub 2014 Feb 9.

Inserm U862, 33077, Bordeaux, France,

New neurons are continuously produced in the adult dentate gyrus of the hippocampus, a key structure in learning and memory. It has been shown that adult neurogenesis is crucial for normal memory processing. However, it is not known whether neurons born during the developmental period and during adulthood support the same functions. Here, we demonstrate that neurons born in neonates (first postnatal week) are activated in different memory processes when they are mature compared to neurons born in adults. By imaging the activation of these two different neuron generations in the same rat and using the IEG Zif268 and Fos, we show that these neurons are involved in discriminating dissimilar contexts and spatial problem solving, respectively. These findings demonstrate that the ontogenetic stage during which neurons are generated is crucial for their function within the memory network.
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http://dx.doi.org/10.1007/s00429-014-0715-yDOI Listing
March 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

Partial loss in septo-hippocampal cholinergic neurons alters memory-dependent measures of brain connectivity without overt memory deficits.

Neurobiol Dis 2013 Jun 31;54:372-81. Epub 2013 Jan 31.

INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.

The functional relevance of septo-hippocampal cholinergic (SHC) degeneration to the degradation of hippocampus-dependent declarative memory (DM) in aging and Alzheimer's disease (AD) remains ill-defined. Specifically, selective SHC lesions often fail to induce overt memory impairments in animal models. In spite of apparent normal performance, however, neuronal activity within relevant brain structures might be altered by SHC disruption. We hypothesized that partial SHC degeneration may contribute to functional alterations within memory circuits occurring in aging before DM decline. In young adult mice, we studied the effects of behaviorally ineffective (saporin-induced) SHC lesions - similar in extent to that seen in aged animals - on activity patterns and functional connectivity between three main neural memory systems: the septo-hippocampal system, the striatum and the amygdala that sustain declarative, procedural and emotional memory, respectively. Animals were trained in a radial maze procedure dissociating the human equivalents of relational/DM and non-R/DM expressions in animals. Test-induced Fos activation pattern revealed that the partial SHC lesion significantly altered the brain's functional activities and connectivity (co-activation pattern) despite the absence of overt behavioral deficit. Specifically, hippocampal CA3 hyperactivity and abnormal septo-hippocampo-amygdalar inter-connectivity resemble those observed in aging and prodromal AD. Hence, SHC neurons critically coordinate hippocampal function in concert with extra-hippocampal structures in accordance with specific mnemonic demand. Although partial SHC degeneration is not sufficient to impact DM performance by itself, the connectivity change might predispose the emergence of subsequent DM loss when, due to additional age-related insults, the brain can no longer compensate the holistic imbalance caused by cholinergic loss.
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http://dx.doi.org/10.1016/j.nbd.2013.01.010DOI Listing
June 2013

Visualization and genetic manipulation of dendrites and spines in the mouse cerebral cortex and hippocampus using in utero electroporation.

J Vis Exp 2012 Jul 26(65). Epub 2012 Jul 26.

Division of Molecular Neurobiology, MRC National Institute for Medical Research.

In utero electroporation (IUE) has become a powerful technique to study the development of different regions of the embryonic nervous system (1-5). To date this tool has been widely used to study the regulation of cellular proliferation, differentiation and neuronal migration especially in the developing cerebral cortex (6-8). Here we detail our protocol to electroporate in utero the cerebral cortex and the hippocampus and provide evidence that this approach can be used to study dendrites and spines in these two cerebral regions. Visualization and manipulation of neurons in primary cultures have contributed to a better understanding of the processes involved in dendrite, spine and synapse development. However neurons growing in vitro are not exposed to all the physiological cues that can affect dendrite and/or spine formation and maintenance during normal development. Our knowledge of dendrite and spine structures in vivo in wild-type or mutant mice comes mostly from observations using the Golgi-Cox method( 9). However, Golgi staining is considered to be unpredictable. Indeed, groups of nerve cells and fiber tracts are labeled randomly, with particular areas often appearing completely stained while adjacent areas are devoid of staining. Recent studies have shown that IUE of fluorescent constructs represents an attractive alternative method to study dendrites, spines as well as synapses in mutant / wild-type mice (10-11) (Figure 1A). Moreover in comparison to the generation of mouse knockouts, IUE represents a rapid approach to perform gain and loss of function studies in specific population of cells during a specific time window. In addition, IUE has been successfully used with inducible gene expression or inducible RNAi approaches to refine the temporal control over the expression of a gene or shRNA (12). These advantages of IUE have thus opened new dimensions to study the effect of gene expression/suppression on dendrites and spines not only in specific cerebral structures (Figure 1B) but also at a specific time point of development (Figure 1C). Finally, IUE provides a useful tool to identify functional interactions between genes involved in dendrite, spine and/or synapse development. Indeed, in contrast to other gene transfer methods such as virus, it is straightforward to combine multiple RNAi or transgenes in the same population of cells. In summary, IUE is a powerful method that has already contributed to the characterization of molecular mechanisms underlying brain function and disease and it should also be useful in the study of dendrites and spines.
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http://dx.doi.org/10.3791/4163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3476406PMC
July 2012

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

Long-lasting plasticity of hippocampal adult-born neurons.

J Neurosci 2012 Feb;32(9):3101-8

Institut National de la Santé et de la Recherche Médicale and Université Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, Unité 862, F-33000 Bordeaux, France.

Adult neurogenesis occurs in the dentate gyrus of the hippocampus, which is a key structure in learning and memory. It is believed that adult-born neurons exert their unique role in information processing due to their high plasticity during immature stage that renders them malleable in response to environmental demands. Here, we demonstrate that, in rats, there is no critical time window for experience-induced dendritic plasticity of adult-born neurons as spatial learning in the water maze sculpts the dendritic arbor of adult-born neurons even when they are several months of age. By ablating neurogenesis within a specific period of time, we found that learning was disrupted when the delay between ablation and learning was extended to several months. Together, these results show that mature adult-born neurons are still plastic when they are functionally integrated into dentate network. Our results suggest a new perspective with regard to the role of neo-neurons by highlighting that even mature ones can provide an additional source of plasticity to the brain to process memory information.
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http://dx.doi.org/10.1523/JNEUROSCI.4731-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622037PMC
February 2012

The antidepressant hyperforin increases the phosphorylation of CREB and the expression of TrkB in a tissue-specific manner.

Int J Neuropsychopharmacol 2013 Feb 9;16(1):189-98. Epub 2012 Jan 9.

UMR CNRS 5249, Grenoble, France.

Hyperforin is one of the main bioactive compounds that underlie the antidepressant actions of the medicinal plant Hypericum perforatum (St. John's wort). However, the effects of a chronic hyperforin treatment on brain cells remains to be fully addressed. The following study was undertaken to further advance our understanding of the biological effects of this plant extract on neurons. Special attention was given to its impact on the brain-derived neurotrophic factor (BDNF) receptor TrkB and on adult hippocampal neurogenesis since they appear central to the mechanisms of action of antidepressants. The consequences of a chronic hyperforin treatment were investigated on cortical neurons in culture and on the brain of adult mice treated for 4 wk with a daily injection (i.p.) of hyperforin (4 mg/kg). Its effects on the expression of the cyclic adenosine monophosphate response element-binding protein (CREB), phospho-CREB (p-CREB), TrkB and phospho-TrkB (p-TrkB) were analysed by Western blot experiments and its impact on adult hippocampal neurogenesis was also investigated. Hyperforin stimulated the expression of TRPC6 channels and TrkB via SKF-96365-sensitive channels controlling a downstream signalling cascade involving Ca(2+), protein kinase A, CREB and p-CREB. In vivo, hyperforin augmented the expression of TrkB in the cortex but not in the hippocampus where hippocampal neurogenesis remained unchanged. In conclusion, this plant extract acts on the cortical BDNF/TrkB pathway leaving adult hippocampal neurogenesis unaffected. This study provides new insights on the neuronal responses controlled by hyperforin. We propose that the cortex is an important brain structure targeted by hyperforin.
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http://dx.doi.org/10.1017/S146114571100188XDOI Listing
February 2013

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 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

[A new chapter in the field of memory: hippocampal neo-neurogenesis].

Biol Aujourdhui 2010 21;204(2):113-29. Epub 2010 Jun 21.

MRC Anatomical Neuropharmacology Unit, Oxford OX1 3TH, UK.

The dogma according to which "once the development of the central nervous system ended, generation of neurons was impossible" has been challenged by the discovery that new neurons are created in specific regions of the adult mammalian brain. This discovery has been one of the most controversial of modern neuroscience. One of these regions is the dentate gyrus of the hippocampal formation, a key structure in memory. Here we will review our current knowledge on the role of adult hippocampal neurogenesis in memory and in the pathophysiology of memory. In particular we will review evidence showing that adult-born neurons are required for learning and memory and that an alteration of their production rate leads to memory impairments. We also discuss how neurogenesis is finely shaped by learning for the purpose of mnemonic information processing.
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http://dx.doi.org/10.1051/jbio/2010004DOI Listing
November 2010

Spatial learning sculpts the dendritic arbor of adult-born hippocampal neurons.

Proc Natl Acad Sci U S A 2010 Apr 7;107(17):7963-8. Epub 2010 Apr 7.

Institut National de la santé et de la Recherche Médicale, Unité 862, Neurocentre Magendie, Neurogenesis and Pathophysiology Group, 33077 Bordeaux, France.

Neurogenesis in the hippocampus is characterized by the birth of thousand of cells that generate neurons throughout life. The fate of these adult newborn neurons depends on life experiences. In particular, spatial learning promotes the survival and death of new neurons. Whether learning influences the development of the dendritic tree of the surviving neurons (a key parameter for synaptic integration and signal processing) is unknown. Here we show that learning accelerates the maturation of their dendritic trees and their integration into the hippocampal network. We demonstrate that these learning effects on dendritic arbors are homeostatically regulated, persist for several months, and are specific to neurons born during adulthood. Finally, we show that this dendritic shaping depends on the cognitive demand and relies on the activation of NMDA receptors. In the search for the structural changes underlying long-term memory, these findings lead to the conclusion that shaping neo-networks is important in forming spatial memories.
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http://dx.doi.org/10.1073/pnas.0914613107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867872PMC
April 2010

Cellular and behavioral effects of cranial irradiation of the subventricular zone in adult mice.

PLoS One 2009 Sep 15;4(9):e7017. Epub 2009 Sep 15.

Institut Pasteur, Laboratory for Perception and Memory, Paris, France.

Background: In mammals, new neurons are added to the olfactory bulb (OB) throughout life. Most of these new neurons, granule and periglomerular cells originate from the subventricular zone (SVZ) lining the lateral ventricles and migrate via the rostral migratory stream toward the OB. Thousands of new neurons appear each day, but the function of this ongoing neurogenesis remains unclear.

Methodology/principal Findings: In this study, we irradiated adult mice to impair constitutive OB neurogenesis, and explored the functional impacts of this irradiation on the sense of smell. We found that focal irradiation of the SVZ greatly decreased the rate of production of new OB neurons, leaving other brain areas intact. This effect persisted for up to seven months after exposure to 15 Gray. Despite this robust impairment, the thresholds for detecting pure odorant molecules and short-term olfactory memory were not affected by irradiation. Similarly, the ability to distinguish between odorant molecules and the odorant-guided social behavior of irradiated mice were not affected by the decrease in the number of new neurons. Only long-term olfactory memory was found to be sensitive to SVZ irradiation.

Conclusion/significance: These findings suggest that the continuous production of adult-generated neurons is involved in consolidating or restituting long-lasting olfactory traces.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007017PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737283PMC
September 2009

Retinoic acid restores adult hippocampal neurogenesis and reverses spatial memory deficit in vitamin A deprived rats.

PLoS One 2008 22;3(10):e3487. Epub 2008 Oct 22.

Nutrition & Neurosciences laboratory, University of Bordeaux 1, Talence, France.

A dysfunction of retinoid hippocampal signaling pathway has been involved in the appearance of affective and cognitive disorders. However, the underlying neurobiological mechanisms remain unknown. Hippocampal granule neurons are generated throughout life and are involved in emotion and memory. Here, we investigated the effects of vitamin A deficiency (VAD) on neurogenesis and memory and the ability of retinoic acid (RA) treatment to prevent VAD-induced impairments. Adult retinoid-deficient rats were generated by a vitamin A-free diet from weaning in order to allow a normal development. The effects of VAD and/or RA administration were examined on hippocampal neurogenesis, retinoid target genes such as neurotrophin receptors and spatial reference memory measured in the water maze. Long-term VAD decreased neurogenesis and led to memory deficits. More importantly, these effects were reversed by 4 weeks of RA treatment. These beneficial effects may be in part related to an up-regulation of retinoid-mediated molecular events, such as the expression of the neurotrophin receptor TrkA. We have demonstrated for the first time that the effect of vitamin A deficient diet on the level of hippoccampal neurogenesis is reversible and that RA treatment is important for the maintenance of the hippocampal plasticity and function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0003487PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567033PMC
January 2009
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