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

International audienceHyperforin 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 Ca2+, 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

Spatial Relational Memory Requires Hippocampal Adult Neurogenesis

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

Inhibiting microglia expansion prevents diet-induced hypothalamic and peripheral inflammation

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-? in microglia, and the recruitment of the nuclear factor-?B pathway while restoring hypothalamic leptin sensitivity. Central blockade of cell proliferation also normalized circulating levels of the cytokines leptin and interleukin 1? 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.Dissection des mécanismes hypothalamiques impliqués dans la détection du statut nutritionnel et régulation de la prise alimentaire via les interactions entre mTORC1, les mélanocortines et les endocannabinoïdes

Spatial Learning Depends on Both the Addition and Removal of New Hippocampal Neurons

The role of adult hippocampal neurogenesis in spatial learning remains a matter of debate. Here, we show that spatial learning modifies neurogenesis by inducing a cascade of events that resembles the selective stabilization process characterizing development. Learning promotes survival of relatively mature neurons, apoptosis of more immature cells, and finally, proliferation of neural precursors. These are three interrelated events mediating learning. Thus, blocking apoptosis impairs memory and inhibits learning-induced cell survival and cell proliferation. In conclusion, during learning, similar to the selective stabilization process, neuronal networks are sculpted by a tightly regulated selection and suppression of different populations of newly born neurons

Retinoic Acid Restores Adult Hippocampal Neurogenesis and Reverses Spatial Memory Deficit in Vitamin A Deprived Rats

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

Cellular and Behavioral Effects of Cranial Irradiation of the Subventricular Zone in Adult Mice

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 i

Greffes intra-cerebrales de neurones dopaminergiques chez le rat nouveau-ne: etude anatomo-fonctionnelle

SIGLEINIST T 73226 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Les fausses mémoires: de la fiction à la réalité. De la crainte à l'espoir

International audienceMemory is essential for the adaptation and survival of the individual in his/her environment. We knew that memory is fragile and sometime failing, bur recently it has become more complex than we imagined. Thus our brain not only forgets but creates false memoires. This false memory syndrome can have catastrophic consequences in the field of justice but has opened new avenues in the treatment of certain mental disorders such as phobias and post-traumatic stress disorder.La mémoire est essentielle pour l’adaptation et la survie de l’individu dans son environnement. On savait la mémoire fragile, défaillante mais récemment elle est apparue plus complexe qu’on l’imaginait. Ainsi, notre cerveau non seulement oublie mais il crée des faux souvenirs. Ce syndrome de faux souvenir peut avoir des conséquences catastrophiques dans le domaine de la justice mais a ouvert de nouvelles pistes dans le traitement de certains troubles mentaux comme les phobies et les troubles de stress post-traumatiques

Etude des relations réciproques entre neurogénèse adulte et fonctions hippocampiques

Le gyrus dentelé (GD) de la formation hippocampique (FH) est l'une des régions cérébrales capables à l"âge adulte, de produire de nouveaux neurones. A ce jour, le rôle de cette "neurogénèse adulte" reste cependant méconnu. Le travail de cette thèse porte sur l'étude des relations réciproques entre cette neurogénèse et les fonctions dépendants de la FH. Les objectifs menés sont de : 1) déterminer s'il existe une relation de causalité entre les néo-neurones et les fonctions hippocampiques et, 2) disséquer l'influence de l'apprentissage spatial sur la neurogénèse. Tout d'abord, nous avons développé une approche de double transgénèse permettant de bloquer in vivo la neurogénèse. Cette approche a permis de montrer qu'une déplétion de néo-neurones provoque des déficits de mémoire spatiale relationnelle et augmente l'expression anormale des réponses de type anxiété. Ces résultats sont discutés dans le cadre d'une implication potentielle des néo-neurones dans le traitement des informations parvenant à la FH. Ensuite, nous avons montré que, réciproquement, l'apprentissage spatial sélectionne dans la population des neurones immatures ceux qui survivent et ceux qui périclitent par apoptose. Cette sélection bidirectionnelle des néo-neurones est un événement plastique de type régressif essentiel puisque le blocage de cette mort neuronale détériore les performances d'apprentissage. Ces résultats sont discutés dans le cadre du rôle possible de la stabilisation sélective des néo-neurones. Dans l'ensemble, ce travail de thèse monttre que la neurogénèse adulte est un exemple unique de plastcité structurale impliqué dans les comportements dépendants de la FH.The dentate gyrus (DG) of the hippocampal formation (HF) is one of the few regions where an ongoing neurogenesis persists throughout adulthood. So far, the functional implication of hippocampal newborn neurons remains misunderstood. My work aimed to examine the reciprocical relationship adult neurogenesis and hippocampal functions. In particular I examined : 1) the causal relationship between adult neurogenesis and both the physiology and pathophysiology of hippocampal functions and, 2) whether hippocampo-dependent spatial learning influences the different steps of neurogenesis. First, we developed an original transgenic approach allowing specific ablation of adult hippocampal precursors cells. We found that depleted adult neurogenesis impairs spatial relational memory and increases anxiety-like responses. We discussed the putative implication of hippocampal newborn neurons in information processing. Second, we found that adult neurogenesis is regulated by spatial learning. Indeed, learning in the water maze modulates the fate of new neurones by selecting them for either survival or death depending on their level of integration when performances are stabilized. More precisely, apoptotic removal of young newborn neurones is required for both the survival of older ones and the stabilization of spatial performances. Such a learning-dependent regulation of adult neurogenesis is discussed in the context of selective stabilisation. Overall, my work shows that adult neurogenesis is a unique example of structural plasticity involved in both the physiology and pathophysiology of hippocampal functions.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF