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.

Grant Number: 5R01DC019379-05
NIH Institute/Center: NIH
Principal Investigator: Karina Alvina