A direct LH to PVH projection for antagonistic regulation of feeding

LH 到 PVH 的直接预测，用于拮抗调节摄食

• 批准号: 9901515
• 负责人: Qingchun Tong
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901515
• 关键词: ART protein; Body Weight; Complex; Data; Development; Duodenum; Energy Metabolism; Feeding behaviors; Fiber; Foundations; GABA Receptor; Glutamate Receptor; Glutamates; Goals; Homeobox; Homeostasis; Hypothalamic structure; Lateral; Lesion; Light; Mediating; Melanocortin 4 Receptor; Methods; Neural Pathways; Neurons; Obesity; Obesity Epidemic; Pancreas; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Physiological; Play; Regulation; Research; Role; Testing; Therapeutic; Time; Transgenic Mice; effective therapy; feeding; gamma-Aminobutyric Acid; genetic approach; mouse genetics; novel; optogenetics; paraventricular nucleus; postsynaptic; promoter; relating to nervous system; side effect; therapeutic development

Project Summary The development of therapeutic drugs to cure obesity has not been successful due to unwanted side effects and limited efficacy. My long term research goal is to delineate neural pathways responsible for body weight homeostasis, and provide a framework for effective and specific therapeutics against obesity. Despite exciting progress has been made in understanding feeding behavior regulated by agouti-related protein (AgRP) neurons, these neurons only represent a small percent of Arc GABAergic neurons and the role of the majority of other hypothalamic neurons in feeding regulation is unknown. Recent studies suggest that activation of the lateral hypothalamus (LH) glutamatergic neurons inhibit feeding, which is in stark contrast to the hypophagia phenotype induced by LH lesion, suggesting a potential role of other LH neurons, including GABAergic neurons in feeding regulation. We previously demonstrated that, when channelrhodopsin2 (ChR2) is expressed in LH Pdx1-Cre neurons, photo-stimulation of ChR2-expressing fibers located in the PVH induced voracious feeding, which depends on GABA release. In addition, disruption of GABA release from LH neurons reduces feeding and body weight, suggesting physiological relevance for LH GABAergic neurons in feeding regulation. Our preliminary data showed that LH Pdx1-Cre neurons send monosynaptic excitatory and inhibitory inputs to PVH neurons and that activation of LH→Pdx1-Cre fibers lacking GABA release in the PVH inhibited fast-refeeding. These results, in combination with the previous results that PVH neuron activity levels dictate feeding promotion versus inhibition, prompt us to hypothesize that competing inhibitory and excitatory monosynaptic LH→PVH projections regulate feeding through controlling PVH MC4R neuron activity. Aim 1 will determine whether 1) selective activation of inhibitory LH→PVH projections in feeding promotion is mediated by PVH; and 2) whether inhibition of LH→PVH GABAergic fibers is sufficient to reduce feeding behavior. Aim 2 will test 1) whether selective activation of excitatory LH→PVH projections inhibits fast-refeeding; 2) whether glutamate release from LH Pdx1-Cre neurons is required for feeding inhibition; 3) whether feeding inhibition elicited by LH→PVH glutamatergic projections is mediated by PVH. Aim 3 will determine whether LH→PVH GABAergic and glutamatergic monosynaptic projections target and modulate the activity of PVH MC4R neurons to exert effects on feeding promotion or inhibition, respectively. The results will establish, for first time, competing and parallel glutamatergic and GABAergic LH→PVH projections that play opposite roles in feeding by controlling PVH MC4R neuron activity and will represent a significant step in understanding the neural basis for feeding regulation.

项目摘要 治疗肥胖症的治疗药物的开发由于不希望的副作用而尚未成功， 有限的功效。我的长期研究目标是描绘负责体重的神经通路 体内平衡，并提供了针对肥胖症有效和特异性治疗的框架。尽管令人兴奋 在理解由刺豚鼠相关蛋白（AgRP）神经元调节的进食行为方面已经取得了进展， 这些神经元仅代表Arc GABA能神经元的一小部分，而大多数其他神经元的作用与Arc GABA能神经元无关。 下丘脑神经元在摄食调节中的作用尚不清楚。 最近的研究表明，激活外侧下丘脑（LH）多巴胺能神经元抑制摄食， 这与LH损伤诱导的食欲减退表型形成鲜明对比，提示其他因子的潜在作用。 LH神经元，包括GABA能神经元在摄食调节中的作用。我们以前证明，当 通道视紫红质2（ChR 2）在LH Pdx 1-Cre神经元中表达，ChR 2表达纤维的光刺激 位于PVH诱导的贪婪进食，这取决于GABA的释放。此外，GABA的破坏 LH神经元的释放减少进食和体重，表明LH GABA能的生理相关性 神经元的摄食调节。我们的初步数据表明，LH Pdx 1-Cre神经元发送单突触 PVH神经元的兴奋性和抑制性输入以及缺乏GABA释放的LH→ Pdx 1-Cre纤维的激活 在PVH抑制快速再喂养。这些结果，结合先前的结果，PVH神经元 活动水平决定进食促进与抑制，促使我们假设竞争性抑制和 兴奋性单突触LH→PVH投射通过控制PVH MC 4 R神经元的活动来调节摄食。 目的1将确定1）在促摄食过程中是否选择性激活抑制性LH→PVH投射， PVH介导; 2）LH→PVH GABA能纤维的抑制是否足以减少摄食 行为目的2：1）选择性激活LH→PVH投射是否抑制快速再摄食; 2)是否需要LH Pdx 1-Cre神经元释放谷氨酸来抑制摄食; 3）是否需要摄食 由LH→PVH神经元投射引起的抑制由PVH介导。目标3将决定是否 LH→PVH GABA能和多巴胺能单突触投射靶向并调节PVH MC 4 R的活性 神经元分别对摄食促进或抑制发挥作用。 结果将首次建立竞争性和平行的谷氨酸能和GABA能LH→PVH 投射通过控制PVH MC 4 R神经元活动在进食中发挥相反的作用，并将代表一个 这是理解摄食调节神经基础的重要一步。