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.

项目概要 由于副作用和副作用，治疗肥胖症的治疗药物的开发尚未成功。 我的长期研究目标是描绘与体重有关的神经通路。 尽管令人兴奋，但仍为有效和特异性的肥胖治疗提供了框架。 在理解刺鼠相关蛋白（AgRP）神经元调节的摄食行为方面取得了进展， 这些神经元仅代表 Arc GABA 能神经元的一小部分，而代表了大多数其他神经元的作用 下丘脑神经元的摄食调节尚不清楚。 最近的研究表明，下丘脑外侧 (LH) 谷氨酸能神经元的激活会抑制进食， 这与 LH 损伤引起的吞咽功能减退表型形成鲜明对比，表明其他因素的潜在作用 LH 神经元，包括 GABA 能神经元，我们之前已经证明，当 视紫红质通道蛋白 2 (ChR2) 在 LH Pdx1-Cre 神经元中表达，光刺激表达 ChR2 的纤维 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 神经元的释放减少了摄食和体重，表明 LH GABA 能的生理相关性 我们的初步数据表明 LH Pdx1-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→Pdx1-Cre 纤维的激活 这些结果与之前的结果相结合表明PVH神经元抑制了快速再进食。 活动水平决定了进食促进与抑制，促使我们参与竞争性抑制和 兴奋性单突触 LH→PVH 投射通过控制 PVH MC4R 神经元活动来调节进食。 目标 1 将确定 1) 在促进摄食过程中选择性激活抑制性 LH→PVH 预测是否有效 由PVH介导；2) LH→PVH GABA能纤维的抑制是否足以减少摄食 目标 2 将测试 1) 兴奋性 LH→PVH 投射的选择性激活是否会抑制快速再进食； 2) LH Pdx1-Cre 神经元释放谷氨酸是否是抑制摄食所必需的；3) 是否摄食； LH→PVH 谷氨酸能投射引起的抑制是由 PVH 介导的，目的 3 将决定是否。 LH→PVH GABA 能和谷氨酸能单突触投射靶向并调节 PVH MC4R 的活性 神经元分别发挥促进或抑制摄食的作用。 结果将首次建立竞争性且平行的谷氨酸能和 GABA 能 LH→PVH 通过控制 PVH MC4R 神经元活动在进食中发挥相反作用的预测将代表 在理解进食调节的神经基础方面迈出了重要的一步。