Lateral Hypothalamic Leptin Receptor-Neurotensin Neurons in Energy Balance

项目摘要/摘要 与肥胖相关的(2型)糖尿病会造成巨大的健康损失，但几乎没有改善疾病的方法 遏制这种“肥胖流行病”的治疗方法。更好地理解调节能源的机制 动态平衡是确定治疗干预的潜在途径所必需的。脂肪衍生的 激素瘦素通过大脑中表达长型瘦素受体(LepRb)的神经元作用于 减少食物摄入量，增加能量消耗。瘦素通过LepRb神经元的多方面作用 内侧基础下丘脑的特征已经被描述，但它们不能解释瘦素的调节能力 食物的激励作用。瘦素在这方面发挥作用的一个潜在部位是外侧下丘脑。 (LHA)，它含有食欲素(OX)神经元，投射到中脑边缘多巴胺(DA)系统并进行调节 改变动机行为(包括食物摄入量和活动量)。我在马丁·迈尔斯博士实验室的工作 已经开始描述LHA LepRb神经元的特征，包括一个离散的亚群，但 与OX神经元突触相连。LHA LepRb神经元的这一亚群共同表达相反的 递质：抑制性神经递质GABA和兴奋性神经肽神经降压素(NTS)，一种已知的 中脑边缘多巴胺(DA)系统的调节者；因此我们将这一群体称为LHA LepRbNts 神经元。我假设来自LHA LepRbNts神经元的相反的GABA和NTS信号在不同的 能量动态平衡的调节作用，特别是通过中脑边缘DA系统。在K99指导期间 阶段，我将在NTS信号为零的小鼠(目标1)中探索这一假说，同时开发一种新的小鼠 选择性鉴定LHA LepRbNts神经元(Aim 2a)的模型(NtsFRT Neo-Cre小鼠) 审问。迈尔斯博士在创造新的老鼠品系方面有着丰富的记录，他在 K99阶段对于我学习创建NtsFRT所需的分子遗传学技能是必不可少的 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R00阶段，我将杂交NtsFRT Neo-Cre小鼠和现有的小鼠模型，以产生 选择性地消融所有LHA LepRbNts神经元(Aim 2)或它们的GABA信号(Aim 3)以确定其作用 并解析GABA在能量平衡中的具体作用。总而言之，科学的 和职业培训方面的指导K99阶段将提供工具，以建立我的独立 R00阶段的研究计划，支持我过渡到一个富有成效的研究人员职位 肥胖症领域。总体而言，这项研究将确定LHA LepRbNts通过什么信号机制 神经元有助于能量平衡，以及它们在肥胖发病机制中的作用。 。

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. .