Centrifugal regulation of olfactory function by melanin-concentrating hormone

项目摘要 嗅觉对于维持人类健康和生活质量至关重要。发挥着 在检测环境危险以及指导决策方面发挥着重要作用， 吃的食物然而，嗅觉加工受到生物体的生理状态的影响。 睡眠剥夺和饱腹感的变化都与大脑皮层功能的变化有关。 嗅觉系统诸如此类的生理变化整合在下丘脑中， 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，或促进进食行为。一种肽 在促进进食和睡眠的功能是黑色素浓缩激素（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MCH受体MCHR1。此连接表示以前的 研究不足的途径提供了睡眠或饱腹感诱导的变化的潜在机制， 嗅觉功能拟议的研究将调查MCH信号的作用， 下丘脑MCH神经元参与气味加工。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 嗅觉功能目的1将使用分子和生物化学技术来研究 OB中的MCH水平对食物限制的反应。它还将使用互补鼠标 模型，以确定嗅觉区下丘脑MCH神经元的细胞靶点。目的 2将研究MCH对嗅球中僧帽细胞活性的影响，以及如何影响嗅球中僧帽细胞的活性。 MCH的变化影响动物的气味阈值检测和交叉习惯， 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，我们将靶向MCHR1， 特别是在OB中去除，以分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的破坏，MCHR1的细胞位点， 在OB中的神经元上的局部化影响动物检测和辨别气味的能力。 完成拟议的研究将提供新的机制洞察的作用，外侧 下丘脑对嗅觉功能的调节拟议研究的结果将是 对于理解饱腹感或清醒感的变化如何影响 味道它还将提供深入了解感觉功能障碍的机制，发生在一些 睫状体病患者该项目的完成将建立未来的实验，以解决 在OB中MCH调节的分子机制。

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.