Antidepressant action of early anorexia
Résumé
Adaptive decision making to eat is crucial for survival, but in anorexia nervosa, the brain persistently supports reduced food intake despite a growing need for energy. How the brain persists in reducing food intake, sometimes even to the point of death and despite the evolution of multiple mechanisms to ensure survival by governing adaptive eating behaviors, remains mysterious. Adaptive responses to stress include transient reduced food intake (hypophagia). 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 (viral gene transfer) 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-HT4 Rs are overexpressed and DR-5- HT1ARs are blocked in the DR, hypophagia following stress persists, suggesting an antidepressant action of early anorexia, supporting the view that persistent caloric restriction mimics some aspects of addiction to drugs of abuse.