Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

The paraventricular nucleus of hypothalamus (PVN), an integrative center in the brain, orchestrates a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVNMC4Rþ) is involved in feeding regulation, the neuroanatomical organization of PVNMC4Rþ connectivity and its role in other physiological regulations are incompletely understood. Here we aimed to better characterize the inputeoutput organization of PVNMC4Rþ neurons and test their physiological functions beyond feeding. Methods: Using a combination of viral tools, we mapped PVNMC4Rþ circuits and tested the effects of chemogenetic activation of PVNMC4Rþ neurons on thermoregulation, cardiovascular control, and other behavioral responses beyond feeding. Results: We found that PVNMC4Rþ neurons innervate many different brain regions that are known to be important not only for feeding but also for neuroendocrine and autonomic control of thermoregulation and cardiovascular function, including but not limited to the preoptic area, median eminence, parabrachial nucleus, pre-locus coeruleus, nucleus of solitary tract, ventrolateral medulla, and thoracic spinal cord. Contrary to these broad efferent projections, PVNMC4Rþ neurons receive monosynaptic inputs mainly from other hypothalamic nuclei (preoptic area, arcuate and dorsomedial hypothalamic nuclei, supraoptic nucleus, and premammillary nucleus), the circumventricular organs (subfornical organ and vascular organ of lamina terminalis), the bed nucleus of stria terminalis, and the parabrachial nucleus. Consistent with their broad efferent projections, chemogenetic activation of PVNMC4Rþ neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure, and brown adipose tissue temperature. These physiological changes accompanied acute transient hyperactivity followed by hypoactivity and restinglike behavior.