Role of Lateral Hypothalamic Neurotensin Neurons in Energy Balance

描述(申请人提供)：下丘脑外侧区(LHA)的神经元通过不完全了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神经元表达促食欲素神经肽，调节边缘脑区，包括中脑多巴胺(DA)神经元，以诱导享乐喂养和促进体重增加。一组单独的LHA神经元表达厌食神经肽神经降压素(NTS)，这些LHA NTS神经元被抑制摄食的刺激选择性地激活。LHA NTS神经元的活动丧失促进了暴饮暴食，并钝化了导致肥胖的能量消耗和DA信号，表明LHA NTS神经元与DA回路相互作用，调节能量平衡。事实上，LHA NTS神经元对中脑起突触调节作用，许多DA神经元表达神经降压素、神经降压素受体1(NtsR1)和神经降压素受体2(NtsR2)的受体。NTS通过这些受体激活DA神经元并抑制摄食，但通过NtsR1失去NTS的作用会促进享乐性摄食和肥胖。总而言之，这些数据暗示了一个新的LHA NTS神经元电路，它协同厌食信号和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(S)，该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。目标1将建立协调生理线索和行为的LHA NTS神经元机制，以适应调节能量平衡。目的2将确定LHA NTS神经元与DA回路的相互作用，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，以验证通过LHA NTS神经元回路的作用抑制享乐性摄取并促进运动活动以诱导体重减轻的假说。总而言之，这些研究将确定LHA NTS神经元调节DA介导的摄食和能量消耗的确切机制，以及在治疗肥胖症中调节这一回路的可能性。

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.