Hypothalamic AgRP and POMC neurons modulate stress-induced depression-related behaviors

Abstract

Depression is a common and debilitating mental disease. Currently available antidepressants are not effective for many individuals with depression and our understanding of the underlying mechanisms remain limited. Evidence suggests that hypothalamic arcuate nucleus (ARC) is highly responsive to acute stress. The ARC contains two distinct subpopulations of neurons—expressing orexigenic agouti-related peptide (AgRP) and anorexigenic pro-opiomelanocortin (POMC). AgRP and POMC neurons regulate food intake and the food reward system. It is unknown whether AgRP and POMC neurons are recruited by chronic stress and if their dysfunction may contribute to the development of chronic stress-induced depression-related behaviors. To address this, we have developed a mouse model of chronic unpredictable stress (CUS), which can induce anhedonia and despair behavior that mimic symptoms in human depression. Using this animal model, I investigated the roles of AgRP and POMC neurons in stress responses and stress-induced depression-related behaviors. I demonstrated that CUS decreases activity of AgRP neurons but increases activity of POMC neurons. A chemogenetic approach was used to selectively manipulate the activity of POMC and AgRP neurons, leading to opposite effects of stress-induced depression-related behaviors. These results suggest that AgRP and POMC neurons are differentially involved in stress maladaptation and related behaviors. It provides insight into the mechanisms underlying the development of depression and novel strategies for the treatment of this mental illness.