Postprandial hyperglycemia stimulates neuroglial plasticity in hypothalamic POMC neurons after a balanced meal

Mechanistic studies in rodents evidenced synaptic remodeling in neuronal circuits that control food intake. However, the physiological relevance of this process is not well defined. Here, we show that the firing activity of anorexigenic POMC neurons located in the hypothalamus is increased after a standard meal. Postprandial hyperactivity of POMC neurons relies on synaptic plasticity that engages pre-synaptic mechanisms, which does not involve structural remodeling of synapses but retraction of glial coverage. These functional and morphological neuroglial changes are triggered by postprandial hyperglycemia. Chemogenetically induced glial retraction on POMC neurons is sufficient to increase POMC activity and modify meal patterns. These findings indicate that synaptic plasticity within the melanocortin system happens at the timescale of meals and likely contributes to short-term control of food intake. Interestingly, these effects are lost with a high-fat meal, suggesting that neuroglial plasticity of POMC neurons is involved in the satietogenic properties of foods.Contrôle nerveux de la prise alimentaire et du métabolisme par une molécule neurale d'adhésion cellulaireISITE " BFCRéseau d'Innovation sur les Voies de Signalisation en Sciences de la Vi

Impact of chronic maternal separation on metabolism, food motivation and brain gene expression profiles in C57BL/6J and C3H/Hen mice

PosterEarly life adversity during infancy influences the development of child and exerts long-lasting effects on physiological functions and vulnerability to psychiatric disorders in particular depression and anxiety. Recent studies also suggest a higher prevalence of metabolic dysfunctions and obesity as well as risks of food addiction in adulthood in subjects exposed to childhood adversity. Maternal separation (MS) in rodents is a well-studied model of early life stress. Several studies demonstrate that chronic MS leads to an exaggerated hypothalamic-pituitary-adrenal axis response to stress and impairs emotional behavior in adult offspring. In contrast, the impact of MS on metabolism and food motivation remain poorly characterized. The aim of the present study was to explore in 2 mouse strains (C57BL/6J and C3H/HeN) differing by their initial maternal behavior, the impact of MS on motivation for palatable food in adult male and female offspring. MS lasted 3 h/day from postnatal day (PND) 2 to PND14 and was combined with a chronic unpredictable stress in dams. We found that MS reduced body weight growth in C3H pups at PDN 15 but had no effect in C57 mice. This effect persisted into adulthood in male C3H but not in females. To investigate MS impact on motivation for palatable food, we used operant conditioning chambers, in which mice, fed ad libitum, must press one (FR1) or several times (Variable Ratio 5, VR10 and VR20) on a lever to obtain a food reward (sweet milk). MS exacerbated the motivation to obtain the palatable reward in male and female C3H mice but not in C57. In conclusion, vulnerability to early stress strongly differs between strain mice. C3H strain seems more susceptible to the long lasting effects of MS on metabolism and on motivation for food reward. Finally, to better understand the brain changes associated with MS in C3H mice, we used microarray to examine gene expression in the hypothalamus, the nucleus accumbens and the medial prefrontal cortex, three regions related to stress and reward functions

Strain-specific changes in nucleus accumbens transcriptome and motivation for palatable food reward in mice exposed to maternal separation

International audienceIntroduction In humans, adversity in childhood exerts enduring effects on brain and increases the vulnerability to psychiatric diseases. It also leads to a higher risk of eating disorders and obesity. Maternal separation (MS) in mice has been used as a proxy of stress during infancy. We hypothesized that MS in mice affects motivation to obtain palatable food in adulthood and changes gene expression in reward system. Methods Male and female pups from C57Bl/6J and C3H/HeN mice strains were subjected to a daily MS protocol from postnatal day (PND) 2 to PND14. At adulthood, their motivation for palatable food reward was assessed in operant cages. Results Compared to control mice, male and female C3H/HeN mice exposed to MS increased their instrumental response for palatable food, especially when the effort required to obtain the reward was high. Importantly, this effect is shown in animals fed ad libitum . Transcriptional analysis revealed 375 genes differentially expressed in the nucleus accumbens of male MS C3H/HeN mice compared to the control group, some of these being associated with the regulation of the reward system (e.g., Gnas , Pnoc ). Interestingly, C57Bl/6J mice exposed to MS did not show alterations in their motivation to obtain a palatable reward, nor significant changes in gene expression in the nucleus accumbens. Conclusion MS produces long-lasting changes in motivation for palatable food in C3H/HeN mice, but has no impact in C57Bl/6J mice. These behavioral alterations are accompanied by drastic changes in gene expression in the nucleus accumbens, a key structure in the regulation of motivational processes

Attenuated levels of hippocampal connexin 43 and its phosphorylation correlate with antidepressant- and anxiolytic-like activities in mice

Clinical and preclinical studies have implicated glial anomalies in major depression. Conversely, evidence suggests that the activity of antidepressant drugs is based, at least in part, on their ability to stimulate density and/or activity of astrocytes, a major glial cell population. Despite this recent evidence, little is known about the mechanism(s) by which astrocytes regulate emotionality. Glial cells communicate with each other through gap junction channels (GJCs), while they can also directly interact with neurons by releasing gliotransmitters in the extracellular compartment via an hemichannels (HCs)-dependent process. Both GJCs and HCs are formed by two main protein subunits: connexins (Cx) 30 and 43 (Cx30 and Cx43). Here we investigate the role of hippocampal Cx43 in the regulation of depression-like symptoms using genetic and pharmacological approaches. The first aim of this study was to evaluate the impact of the constitutive knock down of Cx43 on a set of behaviors known to be affected in depression. Conversely, the expression of Cx43 was assessed in the hippocampus of mice subjected to prolonged corticosterone (CORT) exposure, given either alone or in combination with an antidepressant drug, the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that the constitutive deficiency of Cx43 resulted in the expression of some characteristic hallmarks of antidepressant-/anxiolytic-like behavioral activities along with an improvement of cognitive performances. Moreover, in a new cohort of wild-type mice, we showed that CORT exposure elicited anxiety and depression like abnormalities that were reversed by chronic administration of fluoxetine. Remarkably, CORI also increased hippocampal amounts of phosphorylated form of Cx43 whereas fluoxetine treatment normalized this parameter. From these results, we envision that antidepressant drugs may exert their therapeutic activity by decreasing the expression and/or activity of Cx43 resulting from a lower level of phosphorylation in the hippocampus