A Genetic-Neuroanatomic Dissection of MC4R function

MC4R 功能的遗传神经解剖学剖析

• 批准号: 8459591
• 负责人: BRADFORD B LOWELL
• 金额: $ 35.26万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459591
• 关键词: Accounting; Address; Agonist; Amygdaloid structure; Body Weight; Body Weight decreased; Brain; Brain region; Complex; Dissection; Dynorphins; Eating; Excision; Food Energy; Food Intake Regulation; Genes; Genetic; Glutamates; Goals; Hyperphagia; Injection of therapeutic agent; Investigation; Lateral; Light; Maps; Mediating; Melanocortin 4 Receptor; Modeling; Mus; Neurons; Neurotransmitters; Nucleus solitarius; Obesity; Pathway interactions; Prosencephalon; Regulation; Role; Satiation; Signal Transduction; Site; System; Technology; Testing; Work; base; comparative; energy balance; excitatory neuron; hindbrain; in vivo; inhibitory neuron; interest; mind control; neural circuit; novel; novel strategies; optogenetics; parabrachial nucleus; paraventricular nucleus; prevent; public health relevance; receptor expression; receptor function; relating to nervous system

DESCRIPTION (provided by applicant): Glutamatergic Neurocircuitry Underlying MC4R Action Brain control of energy balance prevents obesity. An important component of this central regulation is the melanocortin system, which, working through melanocortin-4 receptors (MC4Rs), promotes weight loss. Indeed, absence of MC4Rs causes marked hyperphagia and massive obesity. Despite certainty regarding the importance of MC4Rs, there is a comparative lack of information regarding the underlying neurocircuitry. The goal of our studies is to understand the neural basis for MC4R-mediated regulation of energy balance. We have discovered that MC4Rs on both Sim1+ (likely the paraventricular nucleus - PVN) and Sim1- neurons (see below) control food intake. Of interest, MC4Rs on these two classes of neurons (Sim1+ and Sim1-) are functionally redundant, suggesting that they are interconnected. In a parallel set of studies, we have also discovered that the food intake- and body weight-regulating MC4Rs are located exclusively on glutamatergic (excitatory) neurons (marked by VGLUT2). Based upon these findings, and the work of others, we propose a novel, interconnected "glutamatergic network" to account for MC4R action. In this model, MC4Rs controlling food intake is on three groups of glutamatergic (excitatory) neurons. Two groups are Sim1-, are in the hindbrain, and constitute a linear, ascending, glutamatergic pathway that relays satiety signals from the gut to the forebrain (vagal afferents -> NTS -> lateral parabrachial nucleus (L-PBN)). The third group is Sim1+, is in the PVN, and sends descending, excitatory projections to the ascending pathway (at the NTS and L-PBN). AgRP and POMC neurons project to and engage MC4R-bearing glutamatergic neurons at each of these three sites. By placing MC4R-expressing neurons into an interconnecting pathway regulating satiety, this distributed model of melanocortin action accounts for the redundancy of MC4Rs on Sim1+ versus Sim1- neurons. Three Aims will probe this model. In Aim 1, we will test the underlying premises upon which the model is based (sufficiency versus necessity of MC4Rs on Sim1+ neurons, VGLUT2+ neurons, as well as on neurons in the PVN, NTS and L-PBN). In Aim 2, we will a) identify the key Sim1+/VGLUT2+ neurons within the PVN, b) use optogenetics to test connectivity (PVN -> NTS and PVN -> L-PBN), and then c) use DREADD technology to remotely, acutely and reversibly modulate function in vivo. In Aim 3, we will focus on the Sim1-/VGLUT2+ neurons in the NTS and L-PBN. In total, investigation of this distributed, interconnected, glutamatergic model of MC4R action should shed new light on neural circuits regulating food intake and energy balance.

描述（由申请人提供）：谷氨酸能神经回路基础MC4R作用大脑控制能量平衡防止肥胖。这种中枢调节的一个重要组成部分是黑素皮质素系统，它通过黑素皮质素-4受体（MC4Rs）起作用，促进体重减轻。事实上，缺乏MC4Rs会导致明显的贪食和大量肥胖。尽管MC4Rs的重要性是确定的，但关于潜在神经回路的信息相对缺乏。我们研究的目的是了解mc4r介导的能量平衡调节的神经基础。我们已经发现Sim1+（可能是室旁核- PVN）和Sim1-神经元（见下文）上的MC4Rs控制食物摄入。有趣的是，这两类神经元（Sim1+和Sim1-）上的mc4r在功能上是冗余的，这表明它们是相互关联的。在一组平行的研究中，我们还发现调节食物摄入和体重的MC4Rs仅位于谷氨酸能（兴奋性）神经元上（以VGLUT2为标志）。基于这些发现和其他人的工作，我们提出了一个新的、相互关联的“谷氨酸网络”来解释MC4R的作用。在这个模型中，控制食物摄入的MC4Rs位于三组谷氨酸能（兴奋性）神经元上。两组是Sim1-，位于后脑，构成一条线性上升的谷氨酸能通路，将饱腹感信号从肠道传递到前脑（迷走神经传入-> NTS ->外侧臂旁核（L-PBN））。第三组是Sim1+，位于PVN，向上升通路（NTS和L-PBN）发送下行兴奋性投射。AgRP和POMC神经元在这三个位点中的每一个都投射并参与携带mc4r的谷氨酸能神经元。通过将表达mc4r的神经元置于调节饱腹感的相互连接通路中，这种黑素皮质素作用的分布模型解释了Sim1+与Sim1-神经元上mc4r的冗余。Three Aims将探讨这一模式。在目标1中，我们将测试模型所基于的基本前提（MC4Rs在Sim1+神经元、VGLUT2+神经元以及PVN、NTS和L-PBN中的神经元上的充分性与必要性）。在Aim 2中，我们将a)确定PVN内关键的Sim1+/VGLUT2+神经元，b)使用光遗传学测试连通性（PVN -> NTS和PVN -> L-PBN），然后c)使用DREADD技术在体内远程，急性和可逆地调节功能。在Aim 3中，我们将重点关注NTS和L-PBN中的Sim1-/VGLUT2+神经元。总之，对这种分布的、相互关联的MC4R作用的谷氨酸能模型的研究将为调节食物摄入和能量平衡的神经回路提供新的思路。