Role of MCHR1 signaling in olfactory function

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。嗅觉是一种必要的感官 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，如饱腹感的变化，可以调节我们感知自我的能力 并通过下丘脑整合到我们的系统中。下丘脑是一个 大脑有不同的神经细胞群，表达神经肽，神经肽投射到整个大脑和 促进进食行为。我们感兴趣的荷尔蒙是黑色素浓缩荷尔蒙(MCH)，一种促食欲素 神经肽，由下丘脑外侧区神经元合成。这些神经元投射到许多 大脑的区域，包括嗅球(OB)。妇幼保健素已被证明有助于调节 一些化学感觉驱动的行为，如进食和唤醒。OB和OB之间的路径 外侧下丘脑已经被很好地建立；然而，MCH信号和 嗅觉功能的研究还不够深入。在啮齿动物中，MCH结合一种单一的受体，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对嗅觉的贡献 OB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/簇状细胞活动，并将其定位于 初级纤毛对于MCHR1的正常功能是必不可少的。为了探索MCHR1如何调节嗅觉行为， 我们将使用嗅觉分析来确定全身MCHR1和纤毛丢失对气味检测的影响。在AIM 1，我们将使用钙成像研究来确定MCHR1缺失对二尖瓣细胞对 一种气味。同样，我们将从系统和OB两个方面探讨MCHR1缺失对嗅觉的影响 功能使用嗅觉检测分析。我们将在这些化验过程中操纵嗅觉功能以评估 通过食物匮乏来影响生理状态。在目标2中，我将使用新的转基因小鼠品系 研究MCHR1与原生纤毛的相互作用。我们将使用相同的钙成像研究来 评估MCHR1阳性神经元在初级纤毛缺失时的二尖瓣细胞反应。此外，我们还将 用嗅觉检测建立MCHR1阳性和OB特异性纤毛缺失对嗅觉功能的影响 化验。这些实验将有助于我们确定MCHR1纤毛定位的重要性。 调制嗅觉信号。综上所述，该项目的结果将使我们深入了解MCHR1如何 信号调节嗅觉功能，并解决其作用的一些分子机制。

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.