Role of Lateral Hypothalamic Neurotensin Neurons in Energy Balance

描述（由申请人提供）：下丘脑外侧区（LHA）的神经元通过不完全理解的神经元回路对摄食和能量平衡进行反向控制。许多LHA神经元表达食欲神经肽并调节边缘脑区域，包括中脑多巴胺（DA）神经元，以诱导享乐进食并促进体重增加。LHA神经元的单独群体表达厌食神经肽神经降压素（Nts），并且这些LHA Nts神经元被抑制进食的刺激选择性地激活。通过LHA Nts神经元的行动损失促进暴饮暴食并减弱导致肥胖的能量消耗和DA信号传导，这表明LHA Nts神经元与DA回路相互作用以调节能量平衡。事实上，LHA Nts神经元突触调节中脑，其中许多DA神经元表达神经降压素受体，神经降压素受体-1（NtsR 1）和神经降压素受体-2（NtsR 2）。Nts通过这些受体激活DA神经元并抑制摄食，但Nts通过NtsR 1的作用丧失促进享乐摄食和肥胖。总的来说，这些数据暗示了一种新的LHA Nts神经元回路，其协同厌食线索和DA信号传导以促进体重减轻。为了确定LHA Nts神经元调节能量平衡的机制，该提议结合使用新型遗传试剂和现有技术分子工具来询问LHA Nts神经元回路内的组成神经元。目的1建立LHA Nts协调生理线索和行为以适应性调节能量平衡的神经元机制。目的2将确定LHA Nts神经元如何与DA回路接口，测试Nts通过中脑NtsR 1和/或NtsR 2神经元调节DA信号传导以调节能量平衡的假设。目的3将选择性地激活LHA Nts神经元，以测试经由LHA Nts神经元回路的作用抑制享乐性摄入并促进自发活动以诱导体重减轻的假设。总的来说，这些研究将确定LHA Nts神经元调节DA介导的进食和能量消耗的精确机制，以及在治疗肥胖中调节该回路的潜力。

DESCRIPTION (provided by applicant): Neurons in the lateral hypothalamic area (LHA) exert opposing control of feeding and energy balance via incompletely understood neuronal circuits. Many LHA neurons express orexigenic neuropeptides and regulate limbic brain regions, including midbrain dopamine (DA) neurons, to induce hedonic feeding and promote weight gain. A separate population of LHA neurons expresses the anorectic neuropeptide neurotensin (Nts) and these LHA Nts neurons are selectively activated by stimuli that suppress feeding. Loss of action via LHA Nts neurons promotes overeating and blunts energy expenditure and DA signaling that leads to obesity, suggesting that LHA Nts neurons interface with DA circuits to regulate energy balance. Indeed, LHA Nts neurons synaptically regulate the midbrain, where many DA neurons express the receptors for neurotensin, neurotensin receptor-1 (NtsR1) and neurotensin receptor-2 (NtsR2). Nts acts via these receptors to activate DA neurons and suppress feeding, but loss of Nts action via NtsR1 promotes hedonic feeding and obesity. Collectively, these data implicate a novel LHA Nts neuronal circuit that synergizes anorectic cues and DA signaling to promote weight loss. To determine the mechanism(s) by which LHA Nts neurons regulate energy balance this proposal combines the use of novel genetic reagents and state of the art molecular tools to interrogate the constituent neurons within the LHA Nts neuronal circuit. Aim 1 will establish the LHA Nts neuronal mechanisms that coordinate physiologic cues and behavior to adaptively regulate energy balance. Aim 2 will determine how LHA Nts neurons interface with DA circuits, testing the hypothesis that Nts action via midbrain NtsR1 and/or NtsR2 neurons modulates DA signaling to regulate energy balance. Aim 3 will selectively activate LHA Nts neurons to test the hypothesis that action via the LHA Nts neuronal circuit suppresses hedonic intake and promotes locomotor activity to induce weight loss. Collectively, these studies will determine the precise mechanisms by which LHA Nts neurons regulate DA- mediated feeding and energy expenditure, and the potential for modulation of this circuit in treating obesity.