Project 2: Regulation, circuitry, and function of non-aversive and aversive PBN satiety systems

项目 2：非厌恶性和厌恶性 PBN 饱腹感系统的调节、电路和功能

基本信息

批准号：
10454939
负责人：
DAVID P OLSON
金额：
$ 47.39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454939
关键词：
Acute Agonist Amygdaloid structure Anatomy Anorexia Appetite Depressants Behavioral Blood Circulation Brain Brain Stem Calcitonin Gene-Related Peptide Cell Nucleus Cells Chronic Data Eating Emotional Fiber GCG gene GLP-I receptor Gastrointestinal tract structure Generations Goals Hypothalamic structure Mediating Medical Melanocortin 4 Receptor Metabolic Diseases Modeling Molecular Molecular Profiling Nature Nausea Negative Valence Neurons Nucleus solitarius Nutrient Pattern Peptides Peripheral Pharmacology Photometry Physiological Physiology Play Population Positive Valence Reagent Regulation Rewards Role Satiation Signal Transduction Stimulus Structure Structure of area postrema Symptoms System Taste aversion Testing Therapeutic Toxin Transgenes Travel Vagus nerve structure Viral Viral Vector cell type conditioned place preference energy balance feeding gut-brain axis in vivo neural circuit neuroregulation parabrachial nucleus relating to nervous system response targeted treatment

项目摘要

Hypothalamic circuits mediate their feeding and energy balance effects in part via descending projections to brainstem satiety systems. Cells within the parabrachial nucleus (PBN) respond both to descending hypothalamic control and to ascending inputs from the nucleus of the solitary tract (NTS) that encode peripheral satiety signals emanating from the gastrointestinal tract. Signals of gut status (including distention, nutrient content, etc.) travel via the vagus nerve and the circulation and converge on the area postrema (AP) and nucleus of the solitary tract (AP/NTS). The AP/NTS conveys this gut status information to the PBN and other rostral centers. The PBN relays this information rostrally to the central nucleus of the amygdala (CeA) and elsewhere to promote satiety. CeA-projecting CGRP-expressing PBN (CGRPPBN) neurons promote a negative-valence anorexia and play a requisite role in the generation of conditioned taste aversion to noxious GI stimuli. The observations that local administration of glucagon-like peptide 1 (GLP-1) receptor agonists into the PBN suppress feeding without aversion and that descending Mc4R+ hypothalamic inputs to the PBN suppress feeding with positive valence suggests the distinct nature of rewarding satiety systems and aversive anorexia circuits within the PBN. Importantly circuits mediating aversive symptoms such as nausea are intermingled with satiety systems within the PBN and this interaction limits medical therapies that target the brainstem satiety circuits for therapeutic advantage. Thus, it is crucial to distinguish the brain systems that encode satiety from those that promote nausea and other aversive symptoms. A thorough molecular-functional characterization of PBN cell types is lacking and is critical to understanding the acute and chronic regulation of feeding and anorexia. Our preliminary data reveal that glucagon-like peptide 1 receptor (GLP-1R)-expressing PBN neurons(GLP-1RPBN) are distinct from aversive CGRPPBN neurons and suppress feeding without aversion. We hypothesize that GLP-1RPBN cells are activated by nonaversive satiety signals that convey positive valence, whereas CGRPPBN cells are activated by and mediate the response to aversive GI stimuli. This proposal will test the hypotheses that 1) non-aversive GLP-1RPBN and aversive CGRPPBN neurons lie in distinct circuits and respond to differing stimuli, 2) GLP-1RPBN and CGRPPBN neurons activate different downstream circuits and mediate distinct physiological and behavioral functions and 3) and GLP-1RPBN and CGRPPBN neurons are differentially required for the physiological and pharmacological control of food intake.

下丘脑回路部分通过调节其进食和能量平衡效应对脑干饱腹感系统的下降预测。臂旁核 (PBN) 内的细胞对下丘脑的下行控制和来自下丘脑核的上行输入做出反应孤束（NTS），编码来自胃肠道的外周饱腹感信号道。肠道状态的信号（包括膨胀、营养成分等）通过迷走神经传播循环并汇聚于孤束的后区（AP）和核（美联社/NTS）。 AP/NTS 将肠道状态信息传递给 PBN 和其他吻端中心。 PBN 将这些信息转发到杏仁核 (CeA) 的中央核，其他地方可以促进饱腹感。 CeA 投射 CGRP 表达 PBN (CGRPPBN) 神经元促进负价厌食症并在条件性厌食症的产生中发挥必要的作用对有害胃肠道刺激的味觉厌恶。局部给予胰高血糖素样药物的观察结果肽 1 (GLP-1) 受体激动剂进入 PBN 抑制摄食而无厌恶感下行 Mc4R+ 下丘脑对 PBN 的输入抑制正价进食表明奖励性饱腹感系统和厌恶性厌食回路的不同性质 PBN。重要的是，介导恶心等厌恶症状的回路与 PBN 内的饱腹感系统和这种相互作用限制了针对脑干饱腹感回路具有治疗优势。因此，区分大脑至关重要。编码饱腹感的系统与那些促进恶心和其他厌恶症状的系统不同。 PBN 细胞类型的全面分子功能表征尚缺乏且至关重要了解进食和厌食的急性和慢性调节。我们的初步数据揭示表达胰高血糖素样肽 1 受体 (GLP-1R) 的 PBN 神经元 (GLP-1RPBN) 与厌恶的 CGRPPBN 神经元不同，并且在没有厌恶的情况下抑制进食。我们假设 GLP-1RPBN 细胞被传递正价的非厌恶性饱腹感信号激活，而 CGRPPBN 细胞被令人厌恶的胃肠道刺激激活并介导对厌恶性胃肠道刺激的反应。这该提案将测试以下假设：1）非厌恶性 GLP-1RPBN 和厌恶性 CGRPPBN 神经元位于不同的回路并对不同的刺激做出反应，2) GLP-1RPBN 和 CGRPPBN 神经元激活不同的下游回路并介导不同的生理和行为功能，3) GLP-1RPBN 和 CGRPPBN 神经元对于生理和功能的需求是不同的。食物摄入的药物控制。