Lateral Hypothalamic Leptin Receptor-Neurotensin Neurons in Energy Balance

项目总结/摘要 肥胖相关的（2型）糖尿病会造成严重的健康损失，但很少有疾病改善 治疗来阻止这种“糖尿病流行病”。“更好地理解调节能量的机制 需要体内平衡来鉴定用于治疗干预潜在途径。脂肪来源的 激素瘦素通过大脑中表达长型瘦素受体（LepRb）的神经元起作用， 减少食物摄入量和增强能量消耗。瘦素通过LepRb神经元的作用的许多方面 内侧基底下丘脑的特点，但他们没有解释瘦素的调节能力， 食物的激励作用一个潜在的位点瘦素这方面的行动是外侧下丘脑 (LHA)它含有Orexin（OX）神经元，这些神经元投射并调节中脑边缘多巴胺（DA）系统 改变动机行为（包括食物摄入和活动）。我在马丁·迈尔斯博士实验室的工作 已经开始表征LHA LepRb神经元，包括一个与LHA LepRb神经元离散的亚群， 与OX神经元突触相连LHA LepRb神经元的这个亚群共表达相反的LepRb蛋白。 神经递质：抑制性神经递质GABA和兴奋性神经肽神经降压素（Nts），已知的神经降压素是一种神经递质。 中脑边缘多巴胺（DA）系统的调节剂;因此，我们将这一群体称为LHA LepRbNts 神经元我假设来自LHA LepRbNts神经元的GABA和Nts信号传导相反， 能量稳态的调节作用，特别是通过中脑边缘DA系统。在K99指导期间， 在第一阶段，我将在Nts信号传导无效的小鼠（Aim 1）中探索这一假设，同时开发一种新的小鼠 模型（NtsFRT Neo-Cre小鼠），以选择性地鉴定LHA LepRbNts神经元（Aim 2a），从而允许它们的功能 审讯迈尔斯博士在创造新颖的小鼠品系方面有着丰富的记录， K99阶段对于我学习创造NtsFRT所必需的分子遗传学技能的能力至关重要 Neo-Cre小鼠（以及随后的新型小鼠模型）将用于我的独立研究计划。 在R 00阶段，我将使NtsFRT Neo-Cre小鼠和现有的小鼠模型杂交，以产生 选择性消融所有LHA LepRbNts神经元（Aim 2）或其GABA信号传导（Aim 3），以确定 这些神经元的整体和解析GABA在能量稳态的具体作用。总的来说， 和职业培训方面的辅导K99阶段将提供工具，以建立我的独立 在R 00阶段的研究计划，支持我过渡到一个富有成效的研究教师的立场， 肥胖领域。总的来说，这一系列的研究将确定LHA LepRbNts 神经元有助于能量稳态，以及它们在肥胖症发病机制中的作用。 .

Project Summary / Abstract Obesity-linked (type-2) diabetes exacts a significant health toll, but there are few disease-modifying treatments to stem this "diabesity epidemic." Better understanding of the mechanisms that regulate energy homeostasis are needed to identify potential pathways for therapeutic intervention. The adipose-derived hormone leptin acts via neurons in the brain that express the long form of the leptin receptor (LepRb) to decrease food intake and potentiate energy expenditure. Many aspects of leptin action via LepRb neurons of the medialbasal hypothalamus have been characterized, but they do not account for leptin's ability to modulate the incentive salience of food. A potential locus for this aspect of leptin action is the lateral hypothalamus (LHA), which contains Orexin (OX) neurons that project to and regulate the mesolimbic dopamine (DA) system to alter motivated behavior (including food intake and activity). My work in the laboratory of Dr. Martin Myers has begun to characterize LHA LepRb neurons, including a subpopulation that are discrete from, but synaptically connected with, OX neurons. This subpopulation of LHA LepRb neurons co-express opposing transmitters: the inhibitory neurotransmitter GABA and the excitatory neuropeptide neurotensin (Nts), a known regulator of the mesolimbic dopamine (DA) system; we therefore refer to this population as LHA LepRbNts neurons. I hypothesize that opposing GABA and Nts signaling from LHA LepRbNts neurons mediate distinct regulatory effects in energy homeostasis, particularly via the mesolimbic DA system. During the K99 mentored phase, I will explore this hypothesis in mice null for Nts signaling (Aim 1) while developing a novel mouse model (NtsFRT Neo-Cre mice) to selectively identify LHA LepRbNts neurons (Aim 2a) allowing for their functional interrogation. Dr. Myers has a substantial track record in creating novel mouse lines, and his mentorship during the K99 phase is essential for my ability to learn the molecular genetics skills necessary to create the NtsFRT Neo-Cre mice (and subsequent novel mouse models) that will be utilized for my independent research program. During the R00 phase, I will interbreed NtsFRT Neo-Cre mice and existing mouse models to generate mice that either selectively ablate all LHA LepRbNts neurons (Aim 2) or their GABA signaling (Aim 3) to identify the roles of these neurons overall and parse the specific role of GABA in energy homeostasis. Collectively, the scientific and career training facets of the mentored K99 phase will provide the tools to establish my independent research program in the R00 phase, supporting my transition to a productive research faculty position in the field of obesity. Overall, this line of research will determine the signaling mechanisms by which LHA LepRbNts neurons contribute to energy homeostasis, and their role in the pathogenesis of obesity. .