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

下丘脑回路部分通过以下途径介导它们的进食和能量平衡效应： 下行投射到脑干饱腹感系统。臂旁核（PBN）内的细胞 对下行的下丘脑控制和来自下丘脑核的上行输入都有反应。 编码从胃肠道发出的外周饱腹感信号的孤束（NTS 道。肠道状态的信号（包括膨胀、营养成分等）通过迷走神经 在孤束最后区和孤束核有循环和汇聚 (AP/NTS）。AP/NTS将这些肠道状态信息传递给PBN和其他吻侧中枢。 PBN将此信息通过嘴传递到杏仁核中央核（CeA）， 在其他地方促进饱腹感。CeA投射CGRP表达PBN（CGRPPBN）神经元 促进负价厌食症，并在条件反射的产生中发挥必要的作用 对有害胃肠道刺激的味觉厌恶。观察到局部给予胰高血糖素样 肽1（GLP-1）受体激动剂进入PBN抑制进食而无厌恶， 下行Mc 4 R+下丘脑对PBN的输入抑制正效价摄食 这表明，在大脑中，奖赏性饱腹感系统和厌恶性厌食回路的性质是不同的。 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，这种相互作用限制了针对肥胖的医学治疗。 脑干饱腹感回路的治疗优势。因此，区分大脑 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。 一个彻底的PBN细胞类型的分子功能表征是缺乏的，是至关重要的 了解进食和厌食的急性和慢性调节。我们的初步数据 显示胰高血糖素样肽1受体（GLP-1 R）表达PBN神经元（GLP-1 RPBN） 与厌恶性CGRPPBN神经元不同，并且抑制进食而不厌恶。我们假设 GLP-1 RPBN细胞被传递正效价的非厌恶性饱足信号激活， 而CGRPPBN细胞被厌恶性GI刺激激活并介导对厌恶性GI刺激的应答。这 该提案将检验以下假设：1）非厌恶性GLP-1 RPBN和厌恶性CGRPPBN神经元 GLP-1 RPBN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，以及3） 和GLP-1 RPBN和CGRPPBN神经元是不同的生理和 药物控制食物摄入。

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.