Orexin Signaling Mediates the Antidepressant-Like Effect of Calorie Restriction

Abstract

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.

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

“…Differential expression of orexin and dynorphin by the same population of hypothalamic neurons may be a mechanism by which the excitability of DA neurons in the VTA can be regulated by external stimuli, as well as by experience or disease. As one example, orexin mRNA levels are decreased following a type of chronic social stress that results in a depressive-like phenotype in mice (48) and rats (49). This depressive-like phenotype could be due, at least in part, to reductions in orexin expression that render the actions of dynorphin unopposed.…”

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

“…Furthermore, in patients, NAC was found to have antidepressant‐like effects in randomized clinical trials (Maes et al ., 2011). Interestingly, dietary restriction, a well‐established method to extend lifespan that also reduces oxidative damage, was found to have antidepressant effects in mice (Lutter et al ., 2008). This links lifespan, stress resistance, and antidepressant‐like effects (Lutter et al ., 2008), in a manner similar to what we have shown for Mianserin in our studies.…”

Epigenetics: Integrating Genetic Programs, Brain Development and Emergent Phenotypes

“…In mice, this social avoidance resulted in increased transcriptionally repressive H3K27me2 levels and decreased expression of hippo campal Bdnf splice variants (Bdnf III and Bdnf IV) important in mediating depressive responses [157]. Similarly, chronic social defeat stress was found to increase the repressive mark H3K9me3 in the hypothalamic orexin (hypocretin) gene promoter-a neuropeptide implicated in normal emotion processing [158]. Chronic administration of the widely used antidepressant imipramine increased markers of transcriptional activation H3K9/K14ac and H3K4me2 and reversed the repression of the BDNF transcripts induced by defeat stress [157,159].…”