Role of MCHR1 signaling in olfactory function

项目摘要 嗅觉对于维持人类健康和生活质量至关重要。嗅觉是一种必要的感觉 函数，允许我们对外部环境进行采样，并随后对这些环境做出决策。 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 具有表达神经肽的不同神经元群的脑，所述神经肽投射到整个脑， 促进进食行为。我们感兴趣的激素是黑色素浓缩激素（MCH）， 神经肽，由外侧下丘脑（LH）中的神经元合成。这些神经元投射到许多 大脑中的区域，包括嗅球（OB）。妇幼保健已被证明有助于调节 几种化学感觉驱动的行为，如进食和唤醒。OB和 外侧下丘脑已经很好地建立;然而，MCH信号传导和 嗅觉功能研究不足。在啮齿类动物中，MCH结合单一受体，黑色素浓缩激素 受体1（MCHR1），一种在初级纤毛中富集的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，其定位于 初级纤毛对于MCHR1的正常功能是必需的。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系统性MCHR1和纤毛损失对气味检测的影响。在aim中 1，我们将使用钙成像研究，以确定MCHR1损失对二尖瓣细胞反应的影响， 气味剂。同样，我们将探讨MCHR1缺失对嗅觉的影响，包括全身性和OB， 功能使用嗅觉检测分析。我们将在这些试验中操纵嗅觉功能， 通过剥夺食物来影响生理状态。在目标2中，我将使用新的转基因小鼠品系， 研究MCHR1与初级纤毛的相互作用。我们将使用相同的钙成像研究， 评估MCHR1阳性神经元上初级纤毛缺失时的二尖瓣细胞反应。此外，我们将 通过嗅觉检测确定MCHR1阳性和OB特异性纤毛缺失对嗅觉功能的影响 测定。这些实验将有助于我们确定MCHR1纤毛定位在 调节嗅觉信号。总之，该项目的结果将提供深入了解MCHR1 信号传导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.