Centrifugal regulation of olfactory function by melanin-concentrating hormone

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.