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

• 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
• 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

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.

下丘脑电路介导其喂养和能量平衡的影响部分 对脑干饱腹感系统的降临。甲状腺核（PBN）内的细胞 对下丘脑对照的降低以及从核心的上升输入做出反应 编码从胃肠道散发出的外围饱腹感信号的孤立道（NTS） 道。肠道状态的信号（包括扩张，营养含量等）通过迷走神经传播 以及孤立区的循环和收敛于区域（AP）和核 （AP/NTS）。 AP/NTS将此直觉状态信息传达给PBN和其他延髓中心。 PBN将此信息定为杏仁核（CEA）和 在其他地方促进饱腹感。表达CGRP的PBN（CGRPPBN）神经元 促进负面因子厌食症，并在有条件的生成中起必要的作用 对有害的胃肠道刺激品尝厌恶。观察到胰高血糖素样的局部给药 肽1（GLP-1）受体激动剂进入PBN抑制喂养而无需厌恶，并且 降低MC4R+下丘脑输入到PBN抑制阳性价为正价的喂养 提出了奖励饱腹感系统和厌恶性厌食性电路的独特性质 PBN。重要的是，介导厌恶症状（例如恶心）的电路与 PBN内的饱腹感系统，这种相互作用限制了针对的医疗疗法 用于治疗优势的脑干饱足电路。因此，区分大脑至关重要 从促进恶心和其他厌恶症状的系统中编码饱腹感的系统。 缺少PBN细胞类型的彻底的分子功能表征，很关键 了解喂养和厌食症的急性和慢性调节。我们的初步数据 揭示胰高血糖素样肽1受体（GLP-1R）表达PBN神经元（GLP-1RPBN）是 不同于厌恶性的CGRPPBN神经元，并抑制喂养而不会厌恶。我们假设 GLP-1RPBN细胞通过非反应性饱腹感信号激活，这些信号传达了正价， 而CGRPPBN细胞通过对厌恶性GI刺激的反应激活并介导。这 提案将检验以下假设，即1）非耐药性GLP-1RPBN和厌恶性CGRPPBN神经元 位于不同的电路中并响应不同的刺激，2）GLP-1RPBN和CGRPPBN神经元激活 不同的下游电路并介导不同的生理和行为功能，3） 生理学和 食物摄入的药理控制。