Paraventricular ThalamicMC3RCircuits Link Energy Homeostasis with Anxiety-Related Behavior

Abstract

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 downstreamMC4Rneurons, the identity and function ofMC3R-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.MC3Rneurons in PVT are innervated by hypothalamic AgRP and POMC neurons and are activated by anorexigenic and aversive stimuli. Consistently, chemogenetic activation of PVTMC3Rneurons increases anxiety-related behavior and reduces feeding in hungry mice, whereas inhibition of PVTMC3Rneurons reduces anxiety-related behavior. These studies position PVTMC3Rneurons 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 STATEMENTAnimals 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, we demonstrate that paraventricular thalamic neurons containing the melanocortin-3 receptor respond to energy-state-related information and external challenges to regulate anxiety-related behavior in mice. Thus, these neurons represent a potential target for understanding the neurobiology of disorders at the intersection of metabolism and psychiatry such as anorexia nervosa.