Role of MCHR1 signaling in olfactory function

MCHR1 信号在嗅觉功能中的作用

• 批准号: 10269924
• 负责人: Kalene R Jasso
• 金额: $ 4.13万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-28 至 2022-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269924
• 关键词: Ablation; Address; Affect; Animal Testing; Animals; Appetite Stimulants; Area; Arousal; Behavior; Binding; Biological Assay; Brain; Brain region; Calcium; Cells; Chemicals; Cilia; Data; Decision Making; Detection; Environment; Feeding behaviors; Food; Food deprivation (experimental); Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Generations; Genetic Techniques; Goals; Health; Hormones; Human; Hypothalamic structure; Image; Influentials; Inhalation; Knockout Mice; Lateral; Link; Location; MCHR1 gene; Maps; Maternal Behavior; Mediating; Molecular; Molecular Genetics; Mouse Strains; Mus; Natural Increases; Neurons; Neuropeptides; Neurotransmitters; Nose; Odors; Pathway interactions; Pharmacology; Physiological; Population; Process; Property; Quality of life; Regulation; Research; Rodent; Role; Sampling; Satiation; Secure; Sensory; Sensory Disorders; Signal Transduction; Site; Smell Perception; Stimulus; Synapses; System; Testing; Transgenic Mice; Tyrosine 3-Monooxygenase; Viral; Weight; base; behavior influence; behavioral outcome; detection assay; experimental study; feeding; granule cell; hormonal signals; imaging study; insight; interest; melanin-concentrating hormone; mitral cell; mouse model; nerve supply; neuroregulation; novel; olfactory bulb; olfactory sensory neurons; raphe nuclei; receptor; response; small hairpin RNA

Project Summary The sense of smell is critical for maintaining full human health and quality of life. Olfaction is a necessary sensory function that allows us to sample our external environment, and subsequently make decisions regarding those external stimuli. Physiological states, such as changes in satiety, can modulate our ability to perceive our environment and are integrated into our system through the hypothalamus. The hypothalamus is a region of brain with distinct neuronal populations that express neuropeptides which project throughout the brain and promote feeding behaviors. Our hormone of interest is melanin concentrating hormone (MCH), an orexigenic neuropeptide, synthesized by neurons in the lateral hypothalamus (LH). These neurons project to numerous areas within the brain, including the olfactory bulb (OB). MCH has been shown to contribute to the regulation of several chemosensory driven behaviors, such as feeding and arousal. The pathway between the OB and the lateral hypothalamus has been well established; however, the direct connection between MCH signaling and olfactory function is understudied. In rodents, MCH binds a single receptor, melanin concentrating hormone receptor 1 (MCHR1), a G protein-coupled receptor enriched in primary cilia. How MCHR1 contributes to olfactory sensory processing in the OB and the importance of its location on the primary cilium has yet to be determined. Our central hypothesis is MCHR1 signaling modulates mitral/tufted cell activity, and its localization to primary cilia is essential for proper MCHR1 function. To explore how MCHR1 modulates olfactory behavior, we will use olfactory assays to determine the effects of systemic MCHR1 and cilia loss on odor detection. In aim 1, we will use calcium imaging studies to determine the effect of MCHR1 loss on the response of mitral cells to an odorant. Likewise, we will explore the effects of MCHR1 loss, both systemically and in the OB, on olfactory function using olfactory detection assays. We will manipulate olfactory function during these assays to assess the effects physiological states through food deprivation. In aim 2, I will use novel transgenic mouse strains to study the interaction between MCHR1 and primary cilium. We will use the same calcium imaging studies to assess mitral cell response in the absence of primary cilia on MCHR1 positive neurons. Additionally, we will establish the effects of MCHR1 positive and OB specific cilia loss on olfactory function using olfactory detection assays. These experiments will aid in us determining the importance of ciliary localization of MCHR1 in modulating olfactory signaling. Together, the results from this project will provide insight into how MCHR1 signaling modulates olfactory function and address some of the molecular mechanisms for its action.

项目概要 嗅觉对于维持人类健康和生活质量至关重要。嗅觉是必要的感官 功能使我们能够对外部环境进行采样，并随后做出有关这些环境的决策 外部刺激。生理状态，例如饱腹感的变化，可以调节我们感知自己的能力 环境并通过下丘脑整合到我们的系统中。下丘脑是一个区域 大脑具有不同的神经元群，这些神经元群表达神经肽，投射到整个大脑， 促进进食行为。我们感兴趣的激素是黑色素浓缩激素 (MCH)，一种促进食欲的激素 神经肽，由下丘脑外侧 (LH) 的神经元合成。这些神经元投射到许多 大脑内的区域，包括嗅球（OB）。 MCH 已被证明有助于调节 几种化学感应驱动的行为，例如进食和唤醒。 OB和OB之间的路径 下丘脑外侧已经很成熟；然而，MCH信令和之间的直接连接 嗅觉功能尚未得到充分研究。在啮齿类动物中，MCH 结合单一受体，即黑色素浓缩激素 受体 1 (MCHR1)，一种富含初级纤毛的 G 蛋白偶联受体。 MCHR1 如何促进嗅觉 OB 中的感觉处理及其在初级纤毛上的位置的重要性尚未确定。 我们的中心假设是 MCHR1 信号调节二尖瓣/簇状细胞活性，及其定位于 初级纤毛对于 MCHR1 的正常功能至关重要。为了探索 MCHR1 如何调节嗅觉行为， 我们将使用嗅觉测定来确定全身性 MCHR1 和纤毛损失对气味检测的影响。瞄准目标 1，我们将使用钙成像研究来确定MCHR1缺失对二尖瓣细胞反应的影响 一种气味剂。同样，我们将探讨 MCHR1 缺失（系统性和产科）对嗅觉的影响 使用嗅觉检测测定的功能。我们将在这些测定过程中操纵嗅觉功能来评估 通过剥夺食物来影响生理状态。在目标 2 中，我将使用新型转基因小鼠品系 研究 MCHR1 和初级纤毛之间的相互作用。我们将使用相同的钙成像研究来 评估 MCHR1 阳性神经元上没有初级纤毛的情况下二尖瓣细胞的反应。此外，我们将 使用嗅觉检测确定 MCHR1 阳性和 OB 特异性纤毛丢失对嗅觉功能的影响 化验。这些实验将帮助我们确定 MCHR1 纤毛定位的重要性 调节嗅觉信号。总之，该项目的结果将深入了解 MCHR1 如何 信号传导调节嗅觉功能并解决其作用的一些分子机制。