Leptin, GABAergic Neurons and the Feedback / Feedforward Regulation of Energy Balance

瘦素、GABA能神经元与能量平衡的反馈/前馈调节 弓状核（ARC）内的神经元，尤其是AgRP和POMC神经元，在调节 能量平衡他们收到反馈信息的当前状态的脂肪储存（通过瘦素）， 关于能量平衡的未来、预期变化的“前馈”信息。的神经机制 然而，负责反馈和前馈调节的是未知的。先前的研究 表明GABA能神经元的重要作用;在ARC中中继反馈调节， 下丘脑背内侧核（DMH）在中继前馈调节。关于反馈调节， 由于缺乏关于存在于ARC中的“未知”神经元的知识，进展受到阻碍。在 简言之，我们缺乏一份“零件清单”。最近，使用单神经元转录组学，我们发现了许多新的 ARC中的GABA能神经元，包括一些表达LEPR的神经元（坎贝尔JN等人，Nat Neurosci， 2017年）。在这些发现的基础上，目标1和2将解决反馈调节机制。目标3 将扩展我们的发现，即vDMH GABA能神经元介导AgRP神经元的前馈调节。 目的1：利用单神经元转录组学技术研究瘦素对大鼠海马神经元基因表达的影响， ARCLepr和vDMHLepr神经元的亚型。通过捕获所有LEPR表达神经元的细胞核， ARC和vDMH，并在单核水平上观察瘦素的全基因组转录反应， 目的将确定细胞类型特异性转录影响的瘦素在所有亚型的LEPR表达神经元。 目的2：研究新的ARCGABA能神经元在能量平衡调节中的作用。的 将研究以下神经元：表达LEPR的GABA能ARCTrh/Cxcl 12神经元-其表达 ARC中LEPR的最高水平，LEPR表达，GABA能ARCTbx 19神经元-这是 在转录上类似于控制能量消耗的瘦素调节的“RIP-Cre”神经元，GABA能 ARCTrh-Lef 1神经元-其富含对应于人体质量指数（BMI）的转录物 GWAS连锁基因座，GABA能ARCSST神经元-其在转录上类似于AgRP神经元， 因此可能共享功能，最后是GABA能ARCHtr 3b神经元--它们在转录上是不同的 但表达有趣的独特的离子型5-羟色胺受体5-HT 3AB。 目的3：确定食物提示的“前馈”调节达到vDMHLepr的方式。 γ-氨基丁酸-AgRP回路。我们和其他人出乎意料地发现，AgRP神经元，除了是 受反馈信号如瘦素的调节，也受“预期”食物的感官线索的快速调节。 消费重要的是，这至少部分是由vDMHLepr-GABA能神经元介导的，所述神经元突触连接到 AgRP神经元。本文旨在探寻这一规定的渊源。我们的研究表明，一个功能上的关键作用， 下丘脑外侧区的一个独特的丘脑能神经元亚群。

Leptin, GABAergic Neurons and Feedback / Feedforward Regulation of Energy Balance Neurons in the arcuate nucleus (ARC), especially AgRP and POMC neurons, play key roles in regulating energy balance. They receive feedback information on the current status of fat stores (via leptin) and “feedforward” information on future, anticipated changes in energy balance. The neural mechanisms responsible for feedback and feedforward regulation, however, are unknown. Previous studies have suggested an important role for GABAergic neurons; in the ARC in relaying feedback regulation, and in the dorsomedial hypothalamus (DMH) in relaying feedforward regulation. With regards to feedback regulation, progress has been hampered by lack of knowledge regarding “unknown” neurons that reside in the ARC. In short, we have lacked a “parts list”. Recently, using single neuron transcriptomics, we discovered many novel GABAergic neurons in the ARC, including some which express LEPRs (Campbell JN et al., Nat Neurosci, 2017). Building on these discoveries, Aims 1 and 2 will address mechanisms of feedback regulation. Aim 3 will extend our discovery that vDMH GABAergic neurons mediate feedforward regulation of AgRP neurons. Aim 1: To use single neuron transcriptomics to assess leptin’s effects on gene expression in all subtypes of ARCLepr and vDMHLepr neurons. By capturing nuclei from all LEPR-expressing neurons in the ARC and vDMH, and looking at genome-wide transcriptional responses to leptin at the single nuclei level, this Aim will identify cell type-specific transcriptional effects of leptin in all subtypes of LEPR-expressing neurons. Aim 2: To investigate the role of novel ARCGABAergic neurons in regulating energy balance. The following neurons will be studied: LEPR-expressing, GABAergic ARCTrh/Cxcl12 neurons – which express the highest level of LEPRs in the ARC, LEPR-expressing, GABAergic ARCTbx19 neurons – which are transcriptionally similar to the leptin-regulated “RIP-Cre” neurons that control energy expenditure, GABAergic ARCTrh-Lef1 neurons – which are enriched for transcripts corresponding to human body mass index (BMI) GWAS-linked loci, GABAergic ARCSST neurons – which are transcriptionally similar to AgRP neurons and thus likely to share functions, and finally GABAergic ARCHtr3b neurons – which are transcriptionally distinct but express the interesting, unique ionotropic serotonin receptor, 5-HT3AB. Aim 3: To determine the means by which food-cue, “feedforward” regulation reaches the vDMHLepr- GABAergic à AgRP circuit. We and others unexpectedly found that AgRP neurons, in addition to being regulated by feedback signals such as leptin, are also regulated rapidly by sensory cues that “anticipate” food consumption. Importantly, this is mediated, at least in part, by vDMHLepr-GABAergic neurons which synapse onto AgRP neurons. This Aim seeks the source of this regulation. Our studies suggest a key role for a functionally distinct subset of glutamatergic neurons in the lateral hypothalamus.