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施加相反的控制。许多LHA神经元表达供氧神经肽，并调节边缘脑区域，包括中脑多巴胺（DA）神经元，诱导享乐性进食和促进体重增加。LHA神经元的单独群体表达厌食神经肽神经紧张素（Nts），这些LHA Nts神经元被抑制进食的刺激选择性激活。LHA Nts神经元的活动丧失会促进暴饮暴食，降低能量消耗和DA信号，从而导致肥胖，这表明LHA Nts神经元与DA电路连接以调节能量平衡。事实上，LHA Nts神经元突触调节中脑，其中许多DA神经元表达神经紧张素，神经紧张素受体-1 （NtsR1）和神经紧张素受体-2 （NtsR2）的受体。Nts通过这些受体激活DA神经元并抑制摄食，但Nts通过NtsR1的作用缺失会促进享乐性摄食和肥胖。总的来说，这些数据暗示了一种新的LHA Nts神经元回路，它可以协同厌食信号和DA信号来促进体重减轻。为了确定LHA Nts神经元调节能量平衡的机制，本建议结合使用新的遗传试剂和最先进的分子工具来询问LHA Nts神经元回路中的组成神经元。目的1将建立LHA Nts神经元机制，协调生理信号和行为，自适应调节能量平衡。目的2将确定LHA Nts神经元如何与DA电路连接，验证Nts通过中脑NtsR1和/或NtsR2神经元调节DA信号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，以验证LHA Nts神经元回路抑制享乐摄入并促进运动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确切机制，以及调节该回路治疗肥胖的潜力。

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.