A novel MC4R neural pathway in feeding

一种新型的 MC4R 进食神经通路

• 批准号: 10615847
• 负责人: Qingchun Tong
• 金额: $ 39.92万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615847
• 关键词: Aggressive behavior; Anxiety; Body Weight; Brain Stem; Brain region; Chronic; Complex; Data; Emotions; Energy Metabolism; Excitatory Amino Acid Antagonists; Feeding behaviors; Fiber; Foundations; Functional disorder; Glutamate Receptor; Glutamates; Goals; Homeostasis; Hormones; Human; Hyperphagia; Hypothalamic structure; Infusion procedures; Lateral; Light; LoxP-flanked allele; Mediating; Melanocortin 4 Receptor; Mus; Mutation; Neural Pathways; Neurons; Obesity; Obesity Epidemic; Pharmaceutical Preparations; Prosencephalon; Proteins; Psychiatry; Regulation; Research; Role; Satiation; Site; Stress; Synapses; Testing; Thalamic structure; Therapeutic; Thyroxine; Viral; agouti protein; antagonist; associated symptom; design; designer receptors exclusively activated by designer drugs; diencephalon; effective therapy; feeding; genetic approach; in vivo; leptin receptor; midbrain central gray substance; mouse genetics; novel; obesity development; optogenetics; parabrachial nucleus; paraventricular nucleus; prodynorphin; receptor; side effect; therapeutic development; vector; vesicular glutamate transporter 2

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 melanocortin receptors 4 (Mc4Rs) and paraventricular hypothalamus, downstream neurons that mediate their action on feeding are not clear. Our preliminary data showed that PVH neurons sent abundant projections to the ventral part of lateral septum (LSv), where a subset of leptin receptor (LepR)-expressing neurons are located. In vivo optogenetic stimulation of channelrhodopsin 2 (ChR2)-expressing PVH→LSv fibers potently inhibited feeding, suggesting a previously unappreciated role for LSv neurons in mediating the PVH action on feeding. Importantly, LSv local administration of glutamate receptor antagonists increased feeding, suggesting an ongoing tonic glutamatergic action in LSV on feeding inhibition. Based on our strong preliminary data and the established role for PVH Mc4R neurons in feeding, we hypothesize that monosynaptic PVH Mc4R→LSv glutamatergic projections regulate feeding through controlling LSv LepR neuron activity. Aim 1 will test the effects on inhibiting PVH Mc4R-LSv firers on anxiety and anxiety related hypophagia. Aim 2 will determine the role of Mc4Rs and glutamate release from LSv-projecting PVH neurons in body weight regulation. Aim 3 will determine whether the role of PVH direct downstream neurons the LSv in body weight regulation. This proposal utilizes a combination of optogenetics and mouse genetics to reveal a previously unknown PVH→LSV neural pathway in feeding regulation and will establish LepR neurons in LSV as a novel direct downstream target of PVH for feeding regulation. This novel circuit will potentially bridge hypothalamic feeding regulation with functions associated with limbic LSV regions such as stress and anxiety, representing a significant step in understanding the complex feeding behavior with more relevance to human obesity associated with anxiety-related overeating.

项目概要 由于副作用，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。 在理解黑皮质素受体 4 (Mc4Rs) 调节的进食行为方面取得了进展 和室旁下丘脑，介导其进食行为的下游神经元尚不清楚。 我们的初步数据表明，PVH 神经元向外侧隔膜的腹侧部分发送了丰富的投射 （LSv），表达瘦素受体（LepR）的神经元的子集位于体内光遗传学刺激。 表达通道视紫红质 2 (ChR2) 的 PVH→LSv 纤维有效抑制摄食，这表明以前 LSv 神经元在介导 PVH 摄食作用中的作用未被重视。重要的是，LSv 是局部的。 给予谷氨酸受体拮抗剂增加摄食，表明持续的强效谷氨酸能 LSV 对摄食抑制的作用基于我们强有力的初步数据和 PVH 的既定作用。 Mc4R 神经元在进食时，我们追踪单突触 PVH Mc4R→LSv 谷氨酸能投射 通过控制 LSv LepR 神经元活性来调节进食，目标 1 将测试抑制 PVH 的效果。 Mc4R-LSv 激发焦虑和焦虑相关的吞咽功能减退症，目标 2 将决定 Mc4R 和 LSv 的作用。 LSv 投射的 PVH 神经元释放的谷氨酸将决定体重调节是否有效。 PVH 直接下游神经元 LSv 在体重调节中的作用。 该提案利用光遗传学和小鼠遗传学的结合来揭示以前未知的 PVH→LSV 神经通路在摄食调节中的作用，并将在 LSV 中建立 LepR 神经元作为一种新的直接 这种新颖的电路可能会桥接下丘脑的进食调节。 与边缘 LSV 相关的区域（例如压力和焦虑）的调节，代表 在理解与人类肥胖更相关的复杂喂养行为方面迈出了重要一步 与焦虑相关的暴饮暴食有关。