Stress integration by an ascending adrenergic-melanocortin circuit

Stress is thought to be an important contributing factor for eating disorders; however, neural substrates underlying the complex relationship between stress and appetite are not fully understood. Using in vivo recordings from awake behaving mice, we show that various acute stressors activate catecholaminergic nucleus tractus solitarius (NTS^TH) projections in the paraventricular hypothalamus (PVH). Remarkably, the resulting adrenergic tone inhibits MC4R-expressing neurons (PVH^MC4R), which are known for their role in feeding suppression. We found that PVH^MC4R silencing encodes negative valence in sated mice and is required for avoidance induced by visceral malaise. Collectively, these findings establish PVH^MC4R neurons as an effector of stress-activated brainstem adrenergic input in addition to the well-established hypothalamic-pituitary-adrenal axis. Convergent modulation of stress and feeding by PVH^MC4R neurons implicates NTS^TH → PVH^MC4R input in stress-associated appetite disorders.