Epigenetic regulation of BDNF-TRKB signaling in the pathophysiology and treatment of mood disorders

Les troubles de l humeur font partie des problèmes de santé majeurs dans le monde, du fait de leur forte incidence et récurrence dans la population générale, de la nuisance pour la qualité de vie des patients ainsi que la répercussion majeure sur les systèmes de santé. A ce jour, l étiologie ainsi que les mécanismes biologiques sous-jacents les troubles de l humeur sous encore très mal connus. Un nombre grandissant de preuves suggère qu une interaction complexe entre les gènes et l environnement serait a l origine de la mise en place et évolution des épisodes dépressifs majeurs un des troubles de l humeur les plus répandus. Par conséquent, des régulations épigénétiques complexes, qui consistent en des mécanismes clefs par lesquels l environnement induit des changements persistant sur l expression des gènes (sans modifier le code génétique), joueraient un rôle prépondérant dans la pathophysiologie de la dépression. De manière plus spécifique, la répression épigénétique du gène codant pour le brain-derived neurotrophic factor (BDNF) un facteur de croissance impliqué dans la plasticité neuronale et développement du système nerveux central serait un mécanisme clef dans la mise en place de la dépression et autres troubles de l humeur. Dans ce contexte, les travaux de recherche présentés dans cette thèse visent à explorer le rôle des régulations épigénétiques au niveau de la signalisation BDNF/TrkB dans la physiopathologie et traitement des troubles de l humeur. Les résultats montrent que les régulations épigénétiques au niveau de la signalisation BDNF/TrkB sont fortement impliquées dans la mise en place et maintenance de la plasticité neuronale. De plus, les variations environnementales, particulièrement au cours du développement, sont capables d induire une reprogrammation épigénétique stable et persistante au niveau du complexe BDNF/TrkB ainsi qu une altération de la neuroplasticité, conduisant à une augmentation de la vulnérabilité au stress et troubles de l humeur. De manière intéressante, la signalisation du récepteur TrkB est nécessaire pour les effets neurobiologiques et comportementaux des antidépresseurs. De ce fait, une approche pharmocologique ciblée sur le complexe BDNF/TrkB et ses régulations épigénétiques sous-jacentes apparaît comme stratégie thérapeutique prometteuse pour le traitement des troubles de l humeur tel que la dépression.Mood disorders are among the major health problems worldwide due to the high prevalence and recurrence in the general population, and the significant burden for individual life quality and the repercussion on healthcare systems and society. Up to date, the etiology and biological mechanisms underlying mood disorders are still poorly understood. Mounting evidences suggest that a complex interaction between genes and environment might account in the development and course of major depression i.e. one of the most prevalent affective disorders. Accordingly, complex epigenetic regulations - consisting of key mechanisms by which environmental factors induce enduring changes in gene expression without altering the DNA code - have been suspected to plays a pivotal role in the pathophysiology of depression. More specifically, epigenetic repression of the gene encoding for brain-derived neurotrophic factor (BDNF) - a small-secreted growth factor implicated in brain development and neuronal plasticity - may have a preponderant role in the onset of depression and other mood disorders. In this context, the research presented in this thesis aimed at exploring the role of BDNF signaling and its downstream epigenetic regulations in the pathophysiology and treatment of mood disorders. Our findings indicate that epigenetic regulation at BDNF/TrkB signaling is critically important in the establishment and maintenance of neuronal plasticity. Moreover, environmental variations, especially when occurring in development, are able to induce stable and enduring epigenetic reprogramming involving aberrant BDNF/TrkB signaling and impaired neuroplasticity, thereby increasing vulnerability to stress and mood disorders. Interestingly, antidepressants require TrkB to exert some of their neurochemical and behavioral effects. Hence, targeting the BDNF receptor TrkB to restore a normal epigenetic regulation and neuronal functioning appears to be a promising strategy for the treatment of mood disorders.PARIS5-Bibliotheque electronique (751069902) / SudocPARIS-BIUM-Bib. électronique (751069903) / SudocSudocFranceF

5-hydroxytryptamine (5-HT)1A autoreceptor adaptive changes in substance P (neurokinin 1) receptor knock-out mice mimic antidepressant-induced desensitization

Antagonists at substance P receptors of the neurokinin 1 (NK1) type have been shown to represent a novel class of antidepressant drugs, with comparable clinical efficacy to the selective serotonin (5-HT) reuptake inhibitors (SSRIs). Because 5-HT 1A receptors may be critically involved in the mechanisms of action of SSRIs, we examined whether these receptors could also be affected in a model of whole-life blockade of NK1 receptors, i.e. knock-out mice lacking the latter receptors (NK1Ϫ/Ϫ). 5-HT 1A receptor labeling by the selective antagonist radioligand receptor agonist ipsapirone to inhibit the discharge of serotoninergic neurons in the dorsal raphe nucleus within brainstem slices, and reduced hypothermic response to 8-OH-DPAT, were noted in NK1Ϫ/Ϫ versus NK1ϩ/ϩ mice. On the other hand, cortical 5-HT overflow caused by systemic injection of the SSRI paroxetine was four-to sixfold higher in freely moving NK1Ϫ/Ϫ mutants than in wild-type NK1ϩ/ϩ mice. Accordingly, the constitutive lack of NK1 receptors appears to be associated with a downregulation/functional desensitization of 5-HT 1A autoreceptors resembling that induced by chronic treatment with SSRI antidepressants. Double immunocytochemical labeling experiments suggest that such a heteroregulation of 5-HT 1A autoreceptors in NK1Ϫ/Ϫ mutants does not reflect the existence of direct NK1-5-HT 1A receptor interactions in normal mice

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington's Disease and Depression

Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT1A receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT2A receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice

Plasticite du systeme nerveux central au cours du developpement : effets de la lesion neonatale du locus coeruleus

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Conséquences comportementales et neurobiologiques d'une exposition précoce à l'alcool chez des souris consanguines

L objectif de ma thèse était d évaluer les conséquences comportementales et neurobiologiques d une alcoolisation pendant l adolescence chez les souris consanguines, de la lignée C57BL/6J (alcoolo-préférante) et DBA/2J (non alcoolo-préférante). L ingestion d une faible dose d éthanol (1g/kg/j x 5j) chez les souris C57BL/6J juvéniles diminue de façon transitoire leur consommation volontaire d alcool à l âge adulte, alors que l alcoolisation précoce des souris DBA/2J augmente significativement et de façon dosedépendante la quantité d alcool ingérée à l âge adulte. La prise d éthanol à l adolescence accentue également la perception des propriétés renforçantes de la cocaïne et de la morphine chez les souris DBA/2J, et reste sans conséquence chez les souris C57BL/6J. Ces effets sont accompagnés de modifications fonctionnelles des neurotransmissions sérotoninergique et cannabinoidergique et des voies de signalisation intracellulaire impliquant ERK (extracellular signal-regulated kinase). Nos données montrent que l exposition précoce à l alcool constitue un facteur de risque d addiction pour ce produit et/ou pour d autres composés à l âge adulte. De plus, elles mettent en lumière des interactions gène-environnement pendant la période critique du développement qu est l adolescence, dans l établissement des différences inter-individuelles pour les troubles addictifs à l âge adulte. Ces différences sont probablement sous le contrôle de mécanismes épigénétiques induits par l éthanol consommé pendant le développementThe aim of my thesis was to evaluate in two mouse strains, C57BL/6J and DBA/2J, with marked differences in native alcohol preference, whether alcohol consumption during the juvenile period could modify the preference for drugs of abuse when adult and to explore the long term consequences of early ethanol exposure on the neurotransmission systems known to be associated with vulnerability to addiction. In C57BL/6J mice, which present a high appetence for alcohol, early ethanol administration induced a transient decrease of alcohol consumption at adulthood. Conversely, DBA/2J mice, which have a low appetence for alcohol, significantly increased their spontaneous alcohol intake when they received ethanol during the juvenile period. In addition, early ethanol ingestion enhanced perception of rewarding reinforcement properties by cocaine and morphine at adult age in DBA/2J mice but had no effect in C57BL/6J. These changes were associated with a modulation of serotoninergic and cannabinoid neurotransmissions and ERK (extracellular signal-regulated kinase) intracellular signaling. These results show that an early ethanol exposure can exert a permissive control on further drug intake and/or perception. However, in addition to the observed genetic driven differences towards drugs of abuse, our results also unveiled regulations induced by early events that are probably under epigenetic controls. These data support the hypothesis that adolescence is a critical period of vulnerability. Exposition to ethanol at this period might induce long term consequences both on behavior towards drugs of abuse and on the neurobiological regulations of this behaviorPARIS-BIUP (751062107) / SudocSudocFranceF

Caractérisation des phénotypes sérotoninergique et corticotrope chez des lignées de souris mutantes considérées comme modèles pour l'étude de la physiopathologie de la dépression

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Implication du stress dans l'hypothèse neurogénique de la dépression et effets des antidépresseurs

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Neurogenèse, stress et dépression (étude chez la souris des conséquences plastiques et comportementales de modifications géniques ou épigéniques)

Cette thèse vise à préciser les interactions entre neuroplasticité, stress, et dépression à l aide de différents modèles: les souris transgéniques GR-i, déficientes en GR; les souris résignées helpless de Rouen; et un modèle épigénique basé sur l application d'un stress aigu ou chronique modéré. L'ensemble des résultats suggère que des vulnérabilités géniques à la dépression, liées à des altérations de l'axe corticotrope, sont associées à une altération de la neurogenèse hippocampique. Cependant, d'autres facteurs sont probablement impliqués puisque une activation chronique modérée de l'axe corticotrope favorise cette neurogenèse à l inverse d'une activation aiguë intense qui l inhibe. L altération de la neurogenèse peut être corrigée par l administration chronique d'antidépresseurs via l induction de BDNF et/ou des GR. Enfin, il semble que l effet comportemental des antidépresseurs ne soit pas systémiquement corrélé à une augmentation de la neurogenèse et réciproquement.The aim of this thesis was to elucidate the interactions between neuroplasticity, stress and depression using various animal models: GR-i transgenic mice deficient for GR, the Rouen helpless mice, and an epigenic model based on exposure to acute or chronic mild stress. Together, these results suggest that genic vulnerability to depression, linked to corticotropic axis alterations, are associated to hippocampal neurogenesis reduction. However, others factors are probably involved, since a chronic mild activation of the corticotropic axis stimulates neurogenesis in contrast to a severe acute activation which decreases it. Neurogenesis deficits can be prevented by a chronic administration of antidepressants presumably via BDNF and/or GR induction mechanisms. Finally, it seems that behavioural effects of antidepressants and increased neurogenesis is not systematically linked.PARIS-BIUP (751062107) / SudocSudocFranceF