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

AgRP / POMC -> 室旁 (PVH) -> 臂旁 (PBN) -> 边缘/奖励饱腹感回路

• 批准号: 10602524
• 负责人: BRADFORD B LOWELL
• 金额: $ 51.04万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602524
• 关键词: Adaptive Behaviors; Address; Amygdaloid structure; Atlases; Behavioral Mechanisms; Brain; Cells; Complex; Confusion; Darkness; Eating; Elephants; Emotional; Enkephalins; Equipment and supply inventories; FOXP2 gene; Genes; Genetic Engineering; Genetic Transcription; Goals; Grant; Hunger; Hypothalamic structure; Image; Investigation; Knowledge; Label; Learning; Leptin; Link; Maps; Mediating; Modality; Morbidity - disease rate; Neurons; Neurosciences; Obesity; Obesity Epidemic; Penetration; Personal Satisfaction; Physiological; Play; Process; Resources; Rewards; Role; Route; Satiation; Signal Transduction; Site; blind; delta opioid receptor; emotion regulation; energy balance; high reward; in situ sequencing; men; mortality; motivated behavior; mouse genetics; neuromechanism; parabrachial nucleus; positive emotional state; prevent; response; restraint; tool; transcriptomics

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).

侧脑室旁核(PVH)和臂旁核(PBN)的AgRP/POMC？边缘/奖赏饱足环路 由于肥胖症很普遍，并且与发病率和死亡率有关，因此了解肥胖是如何 能量平衡调节饥饿/饱腹感，最终导致或限制进食。虽然已经发生了很多事情 在过去的25年中所学到的包括瘦素在下丘脑内侧基底核中的作用，AgRP和 POMC神经元在ARC，而下游饱腹神经元在PVH，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圆弧PVH之外有什么 巡回赛。而情绪价位和奖赏的调节必须涉及，因为ARC和PVH神经元 不要直接接触控制这些过程的大脑部位，我们仍然处于非常黑暗的状态。的目标是 我们的研究是为了解决我们知识中的这一巨大差距。鉴于臂旁核(PBN)神经元 在下丘脑室旁核回路下游，考虑到PBN神经元投射到边缘/奖赏部位，我们建议 这种PBN饱腹感神经元是“缺失的一环”。然而，存在着阻碍我们弥合的障碍。 这是拱形脑室旁路和边缘/奖赏“高级大脑部位”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。这阻碍了选择性地成像的努力， 操纵和绘制这些神经元的地图，造成使用不同PVH“标记物”的研究之间的混乱。 他说：PBN是一个复杂的中枢，将许多不同的内感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。这样的努力 将得到极大的帮助：a)了解存在于PBN中的转录独特神经元的清单， B)PBN亚核“寻址”每一个神经元，以及c)拥有“接触”这些神经元的工具。 3：与“屏障2”相关，我们不知道“缺失环节”的PBN饱腹神经元的身份。 为了解决这些障碍，这笔赠款提出了以下三个目标： 目的1：建立PVH的转录神经元图谱，并鉴定和研究 对应于两个遗传上不同的PVH饱腹神经元(一个标记为Mc4r，另一个标记为Pdyn)。 目的2：建立PBN的转录神经元图谱，并利用原位测序技术对其进行空间定位 每个PBN神经元到其PBN亚核的“地址”。这份地图集将是所有旨在 理解PBN传递相互感觉信息的“路径”--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/饥饿的神经机制 饱腹感和情感价值。鉴于这些PBN神经元投射到控制情绪的“更高部位” 价和报酬，这些PBN饱足神经元的发现提供了机械地 了解卡路里缺乏最终是如何迫使人们进食的(反之亦然)。

项目成果

A specific area of olfactory cortex involved in stress hormone responses to predator odours.

• DOI: 10.1038/nature17156
• 发表时间: 2016-04-07
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Kondoh, Kunio;Lu, Zhonghua;Ye, Xiaolan;Olson, David P.;Lowell, Bradford B.;Buck, Linda B.
• 通讯作者: Buck, Linda B.

A serotonin and melanocortin circuit mediates D-fenfluramine anorexia.

• DOI: 10.1523/jneurosci.5412-09.2010
• 发表时间: 2010-11-03
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Xu Y;Jones JE;Lauzon DA;Anderson JG;Balthasar N;Heisler LK;Zinn AR;Lowell BB;Elmquist JK
• 通讯作者: Elmquist JK