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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

基本信息

批准号：
10610404
负责人：
Karina Alvina
金额：
$ 31.68万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/10610404
关键词：
Ablation Acute Address Affect Animals Anterior Area Axon Behavior Behavioral Biochemical Biological Assay Brain Brain region Cells Central Nervous System Chemicals Cilia Detection Discrimination Eating Environment Excision Feeding behaviors Food Food deprivation (experimental)Functional disorder Future Gene Expression Genes Genetic Goals Grant Health Human Hunger Hypothalamic structure Image Immediate-Early Genes Interneurons Lateral MCHR1 gene Maps Mediating Modeling Molecular Monitor Mus Mutant Strains Mice Nasal cavity Neurons Neuropeptides Neurophysiology - biologic function Obesity Odors Olfactory Epithelium Olfactory Pathways Olfactory tubercle Organelles Organism Pathway interactions Patients Peptides Phenotype Physiological Play Population Process Quality of life REM Sleep Regulation Research Role Satiation Sensory Signal Pathway Signal Transduction Site Sleep Sleep Deprivation Smell Perception Techniques Testing Viral Volatilization Wakefulness Western Blotting Whole Body Plethysmography behavior test behavioral outcome behavioral response cellular targeting ciliopathy circadian design experimental study feeding food restriction genetic manipulation glutamatergic signaling habituation hormonal signals insight melanin-concentrating hormone melanin-concentrating hormone receptor mitral cell mouse model mutant neuroregulation olfactory bulb olfactory nuclei olfactory sensory neurons open field behavior pharmacologic piriform cortex receptor response sensory mechanism sensory system sleep pattern transmission process

项目摘要

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.

项目摘要嗅觉对于保持人类的全面健康和生活质量至关重要。它播放了一个在检测环境危险以及指导决策方面发挥重要作用，如吃的食物。然而，嗅觉处理受到生物体的生理状态的影响。睡眠不足和饱腹感的改变都与大脑功能的改变有关。嗅觉系统。像这样的生理变化整合在下丘脑中，在那里不同的神经肽由特定的神经元群体表达。这些多肽可以调节清醒和睡眠之间的转换，或促进进食行为。一种多肽在促进进食和睡眠方面起作用的是黑色素浓缩激素(MCH)。表达MCH的神经元投射到大脑的几个区域，包括嗅球(OB)，其中表达了MCH受体MCHR1。此连接表示以前的未被研究的通路提供了睡眠或饱腹感引起的改变的潜在机制嗅觉功能。拟议的研究将调查妇幼保健素信号和下丘脑MCH神经元参与气味加工。这项提案的目的将考验中枢假说离心式MCH神经元整合生理状态和调节嗅觉功能。目标1将使用分子和生化技术来研究 OB中的MCH水平对食物限制的反应。它还将使用互补的鼠标确定嗅觉区下丘脑MCH神经元细胞靶点的模型。目标 2将研究MCH对嗅球二尖瓣细胞活动的影响，以及如何缺乏MCH效应的动物嗅觉阈值检测和交叉习服的变化 MCH信号通路的组成部分。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 特别是在OB中去除，以隔离其对调节行为变化的贡献。最后，在目标3中，我们将研究初级纤毛是如何破坏MCHR1的细胞位置的 OB区神经元的定位会影响动物检测和辨别气味的能力。拟议研究的完成将为侧翼的作用提供新的机械洞察力下丘脑参与调节嗅觉功能。拟议研究的结果将是对于了解饱腹感或清醒状态的变化如何影响闻。它还将提供对感觉障碍的机制的洞察，这些机制发生在一些纤毛病患者。该项目的完成将建立未来的实验，以解决失眠状态下MCH调节的分子机制。