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

下丘脑回路通过部分途径调节它们的摄食和能量平衡效应 脑干饱腹感系统的下行投射。臂旁核内的细胞 对下丘脑下行控制和来自下丘脑核团的上行输入都有反应 孤束(NTS)，编码来自胃肠道的外周饱腹感信号 一条小路。肠道状态的信号(包括膨胀、营养含量等)通过迷走神经旅行 和最后区(AP)和孤束核的循环和汇聚 (AP/NTS)。AP/NTS将该肠道状态信息传送到PBN和其他吻部中心。 PBN将这一信息传递到杏仁中央核(CEA)，并 在其他地方促进饱腹感。CEA投射CGRP阳性PBN(CGRPPBN)神经元 促进负价厌食，在条件性厌食症的产生中发挥必要的作用 对有害的胃肠道刺激的味觉厌恶。胰升糖素样局部给药的观察 进入PBN的多肽-1(GLP-1)受体激动剂抑制摄食，而不是厌恶 下丘脑下丘脑MC4R+传入下丘脑束核以正价抑制摄食 暗示了奖励性饱腹感系统和厌食症回路的独特性质 PBN。重要的是，调节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 脑干饱腹感回路的治疗优势。因此，区分大脑是至关重要的 编码饱腹感的系统与促进恶心和其他令人厌恶的症状的系统不同。 缺乏对PBN细胞类型的全面的分子功能表征，这一点至关重要 了解进食和厌食的急性和慢性调节。我们的初步数据 提示高血糖素样多肽1受体(GLP-1R)表达的PBN神经元(GLP-1RPBN) 与厌恶的CGRPPBN神经元不同，它们抑制进食而不产生厌恶。我们假设 GLP-1RPBN细胞被传递正价的非厌恶饱腹感信号激活， 而CGRPPBN细胞被厌恶的GI刺激激活并介导对其的反应。这 该提案将检验以下假设：1)非厌恶的GLP-1RPBN和厌恶的CGRPPBN神经元 位于不同的回路中，对不同的刺激做出反应，2)GLP-1RPBN和CGRPPBN神经元激活 不同的下游电路和调节不同的生理和行为功能和3) GLP-1RPBN和CGRPPBN神经元在生理和生理功能上存在差异 对食物摄入量的药物控制。

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.