Centrifugal regulation of olfactory function by melanin-concentrating hormone

黑色素浓缩激素对嗅觉功能的离心调节

• 批准号: 10458804
• 负责人: Jeremy McIntyre
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458804
• 关键词: Address; Animals; Area; Behavior; Behavioral; Biochemical; Brain; Cilia; Detection; Discrimination; Eating; Environment; Excision; Feeding behaviors; Food; Food deprivation (experimental); Functional disorder; Future; Goals; Health; Human; Hypothalamic structure; Lateral; MCHR1 gene; Mediating; Molecular; Neurons; Neuropeptides; Odors; Olfactory Pathways; Organism; Pathway interactions; Patients; Peptides; Physiological; Play; Population; Quality of life; Regulation; Research; Role; Satiation; Signal Pathway; Site; Sleep; Sleep Deprivation; Smell Perception; Techniques; Testing; Wakefulness; cellular targeting; ciliopathy; design; experimental study; feeding; food restriction; habituation; hormonal signals; insight; melanin-concentrating hormone; melanin-concentrating hormone receptor; mitral cell; mouse model; olfactory bulb; response; sensory mechanism

Project Summary The sense of smell is essential for maintaining full human health and quality of life. It plays an important role in the detection of environmental dangers as well guiding decisions such as what foods to eat. However, olfactory processing is influenced by the physiological state of an organism. Both sleep deprivation and changes in satiety are connected with changes in the function of the olfactory system. Physiological changes such as these are integrated in the hypothalamus, where different neuropeptides are expressed by specific populations of neurons. These peptides can regulate transitions between wakefulness and sleep, or promote feeding behaviors. One peptide that functions in both promoting feeding and sleep is melanin-concentrating hormone (MCH). Neurons expressing MCH project to several areas of the brain including the olfactory bulb (OB), where the MCH receptor, MCHR1, is expressed. This connection represents a previously understudied pathway providing a potential mechanism for sleep or satiety induced changes in olfactory function. The proposed research will investigate the role of MCH signaling and hypothalamic MCH neurons in contributing to odor processing. The aims of this proposal will test the central hypothesis centrifugal MCH neurons integrate physiological states and regulate olfactory function. Aim 1 will use molecular and biochemical techniques to investigate changes in MCH levels in the OB in response to food restriction. It will also use complementary mouse models to determine the cellular targets of hypothalamic MCH neurons in olfactory regions. Aim 2 will investigate the effects of MCH on the activity of mitral cells in the olfactory bulb, and how changes in MCH effect odor threshold detection and cross-habituation in animals that lack components of the MCH signaling pathway. It will also test how activation of hypothalamic MCH neurons modulates these behaviors. Using AAV mediated approaches, we will target MCHR1 removal specifically in the OB to isolate its contribution to regulating behavioral changes. Finally, in Aim 3 we will investigate how disruption of primary cilia, the cellular site of MCHR1 localization, on neurons in the OB impacts an animal's ability to detect and discriminate odors. Completion of the proposed studies will provide new mechanistic insight into the role of the lateral hypothalamus in regulating olfactory function. The results from the proposed research will be important for understanding how changes in satiety or in wakefulness can impact the sense of smell. It will also provide insight into mechanisms of sensory dysfunction that occur in some ciliopathy patients. Completion of this project will establish future experiments to address the molecular mechanisms of MCH modulation in the OB.

项目摘要 嗅觉对于维持人类的健康和生活质量至关重要。它扮演一个 在发现环境危险以及指导决定（例如什么）中的重要作用 吃的食物。但是，嗅觉加工受生物体生理状态的影响。 睡眠剥夺和饱腹感的变化都与功能的变化有关 嗅觉系统。诸如此类的生理变化都集成在下丘脑中，其中 不同的神经肽由特定的神经元群体表达。这些肽可以 调节清醒和睡眠之间的过渡，或促进喂养行为。一个肽 促进喂养和睡眠的功能是黑色素浓缩激素（MCH）。 向大脑多个区域表达MCH项目的神经元，包括嗅球（OB）， MCH受体MCHR1的表达。此连接代表以前的 研究的途径为睡眠或饱腹感提供了潜在的机制 嗅觉功能。拟议的研究将调查MCH信号传导和 下丘脑MCH神经元有助于气味加工。该提案的目的将测试 中央假设离心MCH神经元整合生理状态并调节 嗅觉功能。 AIM 1将使用分子和生化技术来研究变化 OB中的MCH水平响应食物限制。它也将使用互补的鼠标 确定嗅觉区域下丘脑MCH神经元的细胞靶标。目的 2将研究MCH对嗅球中二尖瓣活性的影响，以及如何 MCH影响气味阈值检测和跨企业的变化缺乏 MCH信号通路的组件。它还将测试下丘脑MCH的激活 神经元调节这些行为。使用AAV介导的方法，我们将针对MCHR1 在OB中特别拆除其对调节行为变化的贡献。最后， 在AIM 3中，我们将研究MCHR1的细胞部位的原发性纤毛的破坏 在OB中的神经元上的定位会影响动物检测和区分气味的能力。 拟议研究的完成将为横向作用提供新的机械洞察力 下丘脑调节嗅觉功能。拟议研究的结果将是 对于了解饱腹感或清醒的变化如何影响 闻。它还将提供有关某些感觉的感觉功能障碍机制的见解 纤毛病患者。该项目的完成将建立未来的实验，以解决 MCH调制的分子机制。