The AgRP / POMC à Paraventricular (PVH) à Parabrachial (PBN) à Limbic/Reward Satiety Circuit Because obesity is prevalent and is associated with morbidity and mortality, it is important to understand how energy balance regulates hunger / satiety, and ultimately causes or curtails eating. While much has been learned over the past 25 years including the roles of leptin action in the mediobasal hypothalamus, AgRP and POMC neurons in the ARC, and downstream satiety neurons in the PVH, we still do not know how this energy balance-regulated circuit controls eating. This is because we do not know what lies beyond the ARCàPVH circuit. While regulation of emotional valence and reward must be involved, because ARC and PVH neurons don’t directly engage brain sites controlling these processes, we are still very much in the dark. The goal of our studies is to address this huge gap in our knowledge. Given that parabrachial (PBN) neurons are downstream of the ARCàPVH circuit, and given that PBN neurons project to limbic / reward sites, we propose that PBN satiety neurons are the “missing link”. Barriers exist, however, that have prevented us from bridging this gap between the ARCàPVH circuit and the limbic / reward “higher brain sites”. They are: 1: We do not know the precise identity of the PVH satiety neurons. This hampers efforts to selectively image, manipulate and map these neurons, and creates confusion between studies utilizing different PVH “markers”. 2: The PBN is a complex hub that routes many different interoceptive signals to higher brain sites – including that related to energy balance. This complexity, and the inability to penetrate it, is a huge barrier. Such efforts would be greatly aided by: a) knowing the inventory of transcriptionally unique neurons that exist in the PBN, b) the PBN sub-nuclei “addresses” of each of these neurons, and c) having tools to “access” these neurons. 3: Related to “barrier 2”, we do not know the identity of the “missing link” PBN satiety neurons. To address these barriers, this grant proposes the following three aims: Aim 1: To build a transcriptomic neuronal atlas of the PVH, and to identify and study the specific neurons that correspond to the two genetically distinct PVH satiety neurons (one marked by Mc4r, the other by Pdyn). Aim 2: To build a transcriptomic neuronal atlas of the PBN, and use In Situ Sequencing to spatially assign each PBN neuron to its PBN sub-nuclei “address”. This atlas will be a valuable resource for all efforts aimed at understanding the “routing” of interoceptive information by the PBN – including that related to energy balance. Aim 3: To identify PBN satiety neurons and elucidate the neural mechanisms by which they regulate hunger / satiety and emotional valence. Given that these PBN neurons project to “higher sites” controlling emotional valence and reward, the discovery of these PBN satiety neurons provides the means for mechanistically understanding how caloric deficiency ultimately compels eating (and vice versa).

Given the obesity epidemic, it is critical that we understand how energy balance regulates hunger and satiety. While much has been learned, we still do not know how hypothalamic hunger / satiety neurons engage higher limbic/reward brain sites to control eating. This is because the “relay” between these hypothalamic neurons and the limbic/reward brain sites, the parabrachial nucleus (PBN), is a “black box”. This grant uses single neuron transcriptomics, mouse genetic engineering and neuron-specific neuroscience “tools” to: a) more clearly delineate the PVH satiety neurons that are upstream of the PBN, b) deconvolute the PBN interoceptive “black box” relay, and c) identify the PBN satiety neurons – ultimately leading to a mechanistic understanding of how alterations in energy balance compel or restrain eating.