Adaptive Control of Dorsal Raphe by 5-HT4 in the Prefrontal Cortex Prevents Persistent Hypophagia following Stress

Summary: Transient reduced food intake (hypophagia) following high stress could have beneficial effects on longevity, but paradoxically, hypophagia can persist and become anorexia-like behavior. The neural underpinnings of stress-induced hypophagia and the mechanisms by which the brain prevents the transition from transient to persistent hypophagia remain undetermined. In this study, we report the involvement of a network governing goal-directed behavior (decision). This network consists of the ascending serotonergic inputs from the dorsal raphe nucleus (DR) to the medial prefrontal cortex (mPFC). Specifically, adult restoration of serotonin 4 receptor (5-HT4R) expression in the mPFC rescues hypophagia and specific molecular changes related to depression resistance in the DR (5-HT release elevation, 5-HT1A receptor, and 5-HT transporter reductions) of stressed 5-HT4R knockout mice. The adult mPFC-5-HT4R knockdown mimics the null phenotypes. When mPFC-5-HT4Rs are overexpressed and DR-5-HT1ARs are blocked in the DR, hypophagia following stress persists, suggesting an antidepressant action of early anorexia. : Jean et al. report causal relationships between serotonin 4 receptors and stress-induced hypophagia, attributable to specific neural signals of depression resistance in the dorsal raphe nucleus, which protect from early anorexia. Keywords: food intake, brain, anorexia, serotonin, 5-HT4R, serotonin 4 receptors, 5-HT1A, 5-HT transporter, medial prefrontal cortex, nucleus accumbens, dorsal raphe nucleus, knockout, siRNA, stress, gene transfer, decision, eating, appetite, depression, hypophagi