The AgRP / POMC -> Paraventricular (PVH) -> Parabrachial (PBN) -> Limbic/Reward Satiety Circuit

AgRP / POMC à脑室旁（PVH）à臂旁（PBN）à边缘/奖赏饱腹回路 由于肥胖是普遍存在的，并与发病率和死亡率有关，因此了解肥胖是如何发生的是很重要的。 能量平衡调节饥饿/饱腹感，并最终导致或减少进食。虽然很多事情 在过去的25年里，我们了解到瘦素在下丘脑中的作用，AgRP和 ARC中的POMC神经元和PVH中的下游饱腹感神经元，我们仍然不知道这种能量是如何产生的。 平衡调节电路控制进食。这是因为我们不知道在ARCÁPVH之外还有什么 电路.然而，由于ARC和PVH神经元参与了情绪效价和奖赏的调节， 并不直接与控制这些过程的大脑部位接触，我们仍然处于黑暗之中。的目标 我们的研究就是为了填补我们知识上的巨大空白。鉴于臂旁（PBN）神经元是 下游的ARCàPVH电路，并考虑到PBN神经元的项目边缘/奖励网站，我们建议， PBN饱腹感神经元是“缺失的一环”。然而，存在的障碍使我们无法 ARCàPVH回路和边缘系统/奖励“更高的大脑部位”之间的间隙。它们是： 1：我们不知道PVH饱腹感神经元的确切身份。这阻碍了有选择地成像的努力， 操纵和映射这些神经元，并在利用不同PVH“标记物”的研究之间造成混淆。 图2：PBN是一个复杂的中枢，将许多不同的内感受信号传递到更高的大脑部位，包括 这与能量平衡有关。这种复杂性，以及无法穿透它，是一个巨大的障碍。这种努力 a）知道PBN中存在的转录上独特的神经元的清单， B）PBN亚核“寻址”这些神经元中的每一个，以及c）具有“访问”这些神经元的工具。 3：与“屏障2”相关，我们不知道“缺失环节”PBN饱腹感神经元的身份。 为了克服这些障碍，该赠款提出了以下三个目标： 目的1：建立PVH神经元转录组图谱，鉴定和研究PVH特异性神经元， 对应于两个遗传上不同的PVH饱腹感神经元（一个由Mc 4 r标记，另一个由Pdyn标记）。 目的二：建立PBN神经元转录组图谱，并利用原位测序技术进行空间定位 每个PBN神经元到其PBN亚核的“地址”。这一地图集将是一个宝贵的资源， 理解PBN对内感受信息的“路由”--包括与能量平衡有关的信息。 目的3：鉴定PBN饱腹感神经元并阐明其调节饥饿的神经机制。 饱腹感和情感效价。鉴于这些PBN神经元投射到控制情绪的“更高部位”， 价和奖励，这些PBN饱腹感神经元的发现提供了机械的手段， 了解热量缺乏如何最终迫使进食（反之亦然）。

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).