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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：
10018886
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/10018886
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.

下丘脑回路调节它们的进食和能量平衡作用