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.

项目摘要 由于不必要的副作用，治疗药物的开发尚未成功 和有限的效率。我的长期研究目标是描述负责体重的神经途径 体内平衡，并为抗肥胖症提供了有效和特定的治疗剂的框架。尽管令人兴奋 在理解黑素皮质素受体4（MC4RS）调节的喂养行为方面取得了进展 和旁脑室下丘脑，下游神经元介导其对喂养作用的作用尚不清楚。 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项目 （LSV），其中表达神经元的瘦素受体（LEPR）的子集。体内光遗传学刺激 表达pVH→LSV纤维可能会抑制进食的通道Rhopopsin 2（ChR2）的pVH→LSV纤维 LSV神经元在介导PVH喂养作用方面的不欣赏作用。重要的是，LSV本地 谷氨酸受体拮抗剂的给药增加了喂养 LSV在进食抑制中的作用。基于我们强大的初步数据和PVH的既定作用 MC4R神经元在喂养中，我们假设单突触PVH MC4R→LSV谷氨酸能项目 通过控制LSV LEPR神经元活性来调节进食。 AIM 1将测试对抑制PVH的影响 MC4R-LSV火器上有关焦虑和焦虑相关的下降。 AIM 2将决定MC4R和 在体重调节中，谷氨酸从LSV射击PVH神经元释放。 AIM 3将确定是否 PVH直接下游神经元在体重调节中的作用。 该建议利用光遗传学和小鼠遗传学的组合揭示了先前未知的 PVH→喂养调节中的LSV神经元，并将在LSV中建立LEPR神经元作为新型直接 PVH的下游目标用于进食调节。这个新颖的电路可能会桥接下丘脑进食 调节与边缘LSV区域（例如压力和动画）相关的功能，代表A 与人类肥胖更相关的复杂喂养行为的重要步骤 与动画相关的暴饮暴食有关。