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.