Dissecting Paraventricular Hypothalamic Neural Circuits Involved in Energy Balance Control.

Abstract

The dramatic increase in obesity and its comorbidities in recent years highlight the critical importance of understanding the factors contributing to dysregulated energy balance. While a relatively small percentage of genetic loci have been correlated with bodyweight, the genetic variations that have been characterized with obesity highlight hypothalamic circuits in the central nervous system (CNS) as an essential regulator of energy homeostasis. The paraventricular nucleus of the hypothalamus (PVH) is a necessary node in satiety regulation, since alterations in PVH development or function in mice and humans result in hyperphagic obesity. Yet, as a heterogenous nucleus, little is known about the specific cell-types used by the PVH to coordinate feeding suppression and/or energy expenditure. Therefore, we first identified the circuitry of genetically-defined PVH subpopulations in order to hypothesize their functional relevance based on projection targets. We combined this methodology with chemogenetic activation and neuronal ablation techniques to determine the function of separate PVH neuronal subpopulations in distinct energy balance parameters. Finally, we attempted to characterize the neural circuit map of afferent inputs to specific PVH cell populations based on their projection targets with the hypothesis that disparate PVH physiologic outputs may be regulated by non-overlapping neural populations. First, we identify a genetic PVH population expressing neuronal nitric oxide synthase 1 (Nos1) that is capable of feeding suppression, presumably through projections to hindbrain regions known to be involved in feeding control. Moreover, while PVH oxytocin (OXT) neurons, a subset of the Nos1PVH field, do not control feeding behavior, they are capable of increasing energy expenditure, likely through connections to the spinal cord. We then characterize a non-Nos1, non-OXT PVH population expressing insulin receptor substrate 4 (IRS4) that is necessary for normal feeding. IRS4PVH neurons also regulate energy expenditure, highlighting the significance of multiple, mutually exclusive, PVH populations in both feeding and energy expenditure control. Lastly, we highlight the dense interconnectivity of PVH subpopulations, with numerous PVH subtypes directly upstream of centrally-projecting PVH populations. Altogether, our results suggest the relevance of a complex intra-PVH network engaging distinct PVH subpopulations in order to ultimately coordinate feeding and energy expenditure regulation.