A novel MC4R neural pathway in feeding

项目摘要 治疗肥胖症的治疗药物的开发由于不希望的副作用而没有成功 和有限的功效。我的长期研究目标是描绘负责体重的神经通路 体内平衡，并提供了针对肥胖症有效和特异性治疗的框架。尽管令人兴奋 黑皮质素受体4（Mc 4 Rs）调控摄食行为的研究已取得进展 和室旁下丘脑，下游神经元，介导他们的行动，进食还不清楚。 我们的初步研究结果表明，PVH神经元向外侧隔腹侧部发出丰富的投射 (LSv)，其中一个子集的瘦素受体（LepR）表达神经元的位置。体内光遗传学刺激 表达通道视紫红质2（ChR 2）的PVH→LSv纤维有效地抑制摄食，表明先前的 LSv神经元在介导PVH对进食的作用中的未被认识的作用。重要的是，LSv本地 谷氨酸受体拮抗剂的施用增加了摄食，表明持续的强直性谷氨酸能 LSV的摄食抑制作用。根据我们强有力的初步数据和PVH的既定作用， Mc 4 R神经元在摄食时，我们假设单突触PVH Mc 4 R →LSv神经元投射 通过控制LSv LepR神经元活性来调节摄食。目的一是检测其对PVH的抑制作用 Mc 4 R-LSv激发焦虑和焦虑相关的食欲减退。目标2将确定Mc 4 R的作用， LSV投射PVH神经元在体重调节中的谷氨酸释放。目标3将决定是否 PVH直接下游神经元LSv在体重调节中的作用。 该提案利用光遗传学和小鼠遗传学的组合来揭示一种以前未知的 PVH→LSV神经通路在摄食调节中的作用，并将LSV中LepR神经元作为一种新的直接介导 PVH下游目标用于摄食调节。这种新颖的电路将潜在地桥接下丘脑进食 调节与边缘LSV区域相关的功能，如压力和焦虑，代表了一种 在理解与人类肥胖更相关的复杂进食行为方面迈出了重要的一步 与焦虑相关的暴饮暴食有关

Project Summary The development of therapeutic drugs to cure obesity has not been successful due to unwanted side effects and limited efficacy. My long term research goal is to delineate neural pathways responsible for body weight homeostasis, and provide a framework for effective and specific therapeutics against obesity. Despite exciting progress has been made in understanding feeding behavior regulated by melanocortin receptors 4 (Mc4Rs) and paraventricular hypothalamus, downstream neurons that mediate their action on feeding are not clear. Our preliminary data showed that PVH neurons sent abundant projections to the ventral part of lateral septum (LSv), where a subset of leptin receptor (LepR)-expressing neurons are located. In vivo optogenetic stimulation of channelrhodopsin 2 (ChR2)-expressing PVH→LSv fibers potently inhibited feeding, suggesting a previously unappreciated role for LSv neurons in mediating the PVH action on feeding. Importantly, LSv local administration of glutamate receptor antagonists increased feeding, suggesting an ongoing tonic glutamatergic action in LSV on feeding inhibition. Based on our strong preliminary data and the established role for PVH Mc4R neurons in feeding, we hypothesize that monosynaptic PVH Mc4R→LSv glutamatergic projections regulate feeding through controlling LSv LepR neuron activity. Aim 1 will test the effects on inhibiting PVH Mc4R-LSv firers on anxiety and anxiety related hypophagia. Aim 2 will determine the role of Mc4Rs and glutamate release from LSv-projecting PVH neurons in body weight regulation. Aim 3 will determine whether the role of PVH direct downstream neurons the LSv in body weight regulation. This proposal utilizes a combination of optogenetics and mouse genetics to reveal a previously unknown PVH→LSV neural pathway in feeding regulation and will establish LepR neurons in LSV as a novel direct downstream target of PVH for feeding regulation. This novel circuit will potentially bridge hypothalamic feeding regulation with functions associated with limbic LSV regions such as stress and anxiety, representing a significant step in understanding the complex feeding behavior with more relevance to human obesity associated with anxiety-related overeating.