CAREER: Defining the role of orexin input to the mouse olfactory bulb

An organism’s survival depends on its ability to coordinate decisions about its current sensory environment with its internal energy state. The sense of smell (olfaction) is a primary sensory system linked to metabolic health and plays a crucial role in driving food-seeking behavior, dietary choice, and nutritional balance. However, the brain does not process odors in the same way at all times. Olfactory sensitivity is influenced by an organism’s physiological state; hunger can increase odor sensitivity, while being full (satiation) can reduce it. Understanding the fundamental neural mechanisms underlying this relationship is essential to gaining insight into chronic disorders where this link becomes dysregulated, which can drive maladaptive eating behaviors that impact public health. This proposal tests the hypothesis that a key biological interface between sensory processing and metabolic state is a group of specialized neurons in the hypothalamus (a brain region involved in energy regulation) that produce the chemical messenger orexin. Orexin neurons are involved in arousal and energy sensing, and connect broadly throughout the brain, including to the olfactory bulb, the first stage of chemical sensing in the brain. This research will promote scientific progress and advance national health through its goal of defining the role of orexin neurons in sensory processing, and whether they act as a mechanism to tune olfactory sensitivity based on internal state. Furthermore, this project integrates research with education through a program designed to broaden access to neuroscience for learners of different ages and educational backgrounds. By developing novel curricula incorporating hands-on research opportunities, this proposal creates new tools for STEM education, increases public scientific literacy through public engagement, and facilitates the development of a robust and globally competitive STEM workforce. This project advances NSF’s priorities in Biotechnology. This research will define how hypothalamic orexin neurons, which have been canonically associated with feeding behavior and energy homeostasis, modulate sensory processing within the olfactory bulb across different metabolic states. Precisely how neural circuits involved in energy homeostasis influence sensory pathways remains a major knowledge gap in sensory neuroscience. Additionally, subsets of orexin neurons can co-release other neurotransmitters, and how neural circuits decipher the functional significance of such multi-chemical signaling remains poorly integrated into current models of brain function. This project leverages a state-of-the-art experimental toolkit available in mice to define how orexin neurons transform olfactory sensory processing using high-resolution tools to record from and manipulate specific cell types and projections in the brain. These methods will be used to disentangle the functional role of orexin versus non-orexin neurochemical release on olfactory bulb circuits, test whether the orexin pathway acts broadly or selectively across the olfactory bulb to modulate the flow of sensory information, and establish how changes in hunger state alter orexin activity and downstream olfactory bulb circuit dynamics. This proposal will advance scientific understanding of how non-canonical neurochemical signaling impacts neural coding, and will further the field’s mechanistic understanding of the fundamental relationship between brain activity and metabolism. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.