AI Summary
The hypothalamic melanocortin system plays a critical role in sensing stored energy and communicating this information to brain regions controlling motivation and emotion. A recent study has identified a novel pathway linking hypothalamic melanocortin neurons to melanocortin-3 receptor neurons in the paraventricular thalamus (PVT), which are activated by anorexigenic and aversive stimuli. Activation of PVT MC3R neurons increases anxiety-related behavior and reduces feeding in hungry mice, suggesting that these neurons may be important in regulating anxiety-related behavior and could be a potential target for disorders such as anorexia nervosa.
The hypothalamic melanocortin system is critically involved in sensing stored energy and communicating this information throughout the brain, including to brain regions controlling motivation and emotion. This system consists of first-order agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) neurons located in the hypothalamic arcuate nucleus and downstream neurons containing the melanocortin-3 (MC3R) and melanocortin-4 receptor (MC4R). Although extensive work has characterized the function of downstream MC4R neurons, the identity and function of MC3R-containing neurons are poorly understood. Here, we used neuroanatomical and circuit manipulation approaches in mice to identify a novel pathway linking hypothalamic melanocortin neurons to melanocortin-3 receptor neurons located in the paraventricular thalamus (PVT) in male and female mice. MC3R neurons in PVT are innervated by hypothalamic AgRP and POMC neurons and are activated by anorexigenic and aversive stimuli. Consistently, chemogenetic activation of PVT MC3R neurons increases anxiety-related behavior and reduces feeding in hungry mice, whereas inhibition of PVT MC3R neurons reduces anxiety-related behavior. These studies position PVT MC3R neurons as important cellular substrates linking energy status with neural circuitry regulating anxiety-related behavior and represent a promising potential target for diseases at the intersection of metabolism and anxiety-related behavior such as anorexia nervosa.
SIGNIFICANCE STATEMENT Animals must constantly adapt their behavior to changing internal and external challenges, and impairments in appropriately responding to these challenges are a hallmark of many neuropsychiatric disorders. Here,