ABSTRACT
We found that increasing ghrelin levels, through subcutaneous injections or calorie restriction, produced anxiolytic- and antidepressant-like responses in the elevated plus maze and forced swim test. Moreover, chronic social defeat stress, a rodent model of depression, persistently increased ghrelin levels, whereas growth hormone secretagogue receptor (Ghsr) null mice showed increased deleterious effects of chronic defeat. Together, these findings demonstrate a previously unknown function for ghrelin in defending against depressive-like symptoms of chronic stress.
Subject(s)
Depression/prevention & control , Ghrelin/administration & dosage , Stress, Psychological/complications , Analysis of Variance , Animals , Behavior, Animal , Caloric Restriction/methods , Depression/etiology , Disease Models, Animal , Eating/drug effects , Eating/genetics , Enzyme-Linked Immunosorbent Assay , Freezing Reaction, Cataleptic/drug effects , Freezing Reaction, Cataleptic/physiology , Ghrelin/metabolism , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Motor Activity/genetics , Orexin Receptors , Reaction Time/physiology , Receptors, G-Protein-Coupled/deficiency , Receptors, Ghrelin/deficiency , Receptors, Neuropeptide/deficiency , Stress, Psychological/genetics , Swimming , Time FactorsABSTRACT
During periods of reduced food availability, animals must respond with behavioral adaptations that promote survival. Despite the fact that many psychiatric syndromes include disordered eating patterns as a component of the illness, little is known about the neurobiology underlying behavioral changes induced by short-term calorie restriction. Presently, we demonstrate that 10 d of calorie restriction, corresponding to a 20-25% weight loss, causes a marked antidepressant-like response in two rodent models of depression and that this response is dependent on the hypothalamic neuropeptide orexin (hypocretin). Wild-type mice, but not mice lacking orexin, show longer latency to immobility and less total immobility in the forced swim test after calorie restriction. In the social defeat model of chronic stress, calorie restriction reverses the behavioral deficits seen in wild-type mice but not in orexin knock-out mice. Additionally, chronic social defeat stress induces a prolonged reduction in the expression of prepro-orexin mRNA via epigenetic modification of the orexin gene promoter, whereas calorie restriction enhances the activation of orexin cells after social defeat. Together, these data indicate that orexin plays an essential role in mediating reduced depression-like symptoms induced by calorie restriction.
Subject(s)
Caloric Restriction , Depression/therapy , Intracellular Signaling Peptides and Proteins/physiology , Neuropeptides/physiology , Signal Transduction/physiology , Analysis of Variance , Animals , Behavior, Animal , Chromatin Immunoprecipitation/methods , Depression/etiology , Disease Models, Animal , Dominance-Subordination , Female , Gene Expression Regulation , Hypothalamus/pathology , Intracellular Signaling Peptides and Proteins/deficiency , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/genetics , Neurons/metabolism , Neuropeptides/deficiency , Orexins , Stress, Psychological/complications , Stress, Psychological/etiology , SwimmingABSTRACT
BACKGROUND: Calorie restriction (CR) induces long-term changes in motivation to eat highly palatable food and, in body weight regulation, through an unknown mechanism. METHODS: After a period of CR and refeeding, mice were assessed by behavioral and metabolic studies and for levels of the transcription factor ΔFosB. The ΔFosB levels were then increased specifically in nucleus accumbens (NAc) with viral-mediated gene transfer, and behavioral and metabolic studies were conducted. RESULTS: We show that accumulation of ΔFosB in the NAc shell after CR in mice corresponds to a period of increased motivation for high fat reward and reduced energy expenditure. Furthermore, ΔFosB overexpression in this region increases instrumental responding for a high fat reward via an orexin-dependent mechanism while also decreasing energy expenditure and promoting adiposity. CONCLUSIONS: These results suggest that ΔFosB signaling in NAc mediates adaptive responses to CR.