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

bioRxiv, ISSN: 2692-8205
2021
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Article Description

Objective: The paraventricular nucleus of hypothalamus (PVN) is an integrative center in the brain orchestrating a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVN) is undoubtedly involved in feeding regulation, the neuroanatomical organization of PVN pathway and its role in diverse physiological and behavioral regulations have not been fully understood. Here we aimed to better characterize the input-output organization of PVN neurons and further test their potential functional roles beyond feeding. Methods: Using a combination of viral tools, we performed a comprehensive mapping of PVN circuits and tested the effects of chemogenetic activation of PVN neurons on thermogenesis, cardiovascular control and other behavioral regulations beyond feeding. Results: We found that PVN neurons broadly innervate many different brain regions known to be important not only for feeding but also for neuroendocrine and autonomic control of thermogenesis and cardiovascular function, including but not limited to preoptic area, median eminence, parabrachial nucleus, locus coeruleus, nucleus of solitary tract, ventrolateral medulla and thoracic spinal cord. Contrary to broad efferent projections, PVN neurons receive monosynaptic inputs from limited brain regions, including medial preoptic nucleus, arcuate and dorsomedial hypothalamic nuclei, and supraoptic nucleus. Consistent with broad efferent projections, chemogenetic activation of PVN neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure and brown adipose tissue thermogenesis. Strikingly, these physiological changes accompanied an unexpected repetitive bedding-removing behavior followed by hypoactivity and resting-like behavior. Conclusions: Our results clarify the neuroanatomical organization of PVN circuits and shed new light on the roles of PVN pathways in autonomic control of thermogenesis, cardiovascular function and other behavioral regulations.

Bibliographic Details

Uday Singh; Kenji Saito; Brandon A. Toth; Jacob E. Dickey; Samuel R. Rodeghiero; Yue Deng; Guorui Deng; Jingwei Jiang; Huxing Cui; Baojian Xue; Zhiyong Zhu; Leonid V. Zingman

Cold Spring Harbor Laboratory

Biochemistry, Genetics and Molecular Biology; Agricultural and Biological Sciences; Immunology and Microbiology; Neuroscience; Pharmacology, Toxicology and Pharmaceutics

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