PROJECT SUMMARY / ABSTRACT Despite Obesity Hypoventilation Syndrome (OHS) affecting the health of 1 in every 220 US Americans, current treatments lack effectiveness or have poor compliance. The development of new treatments has been hindered by the field’s near exclusive focus on an individual’s physical body mechanics or metabolic rate as the primary cause of obesity-related respiratory pathophysiology. Our long-term goal is to identify new strategies that can effectively treat obesity-related respiratory diseases. The overall objective of this proposal is to define the circuitry that links metabolic neurobiology to a reduction in chemosensitivity. Our central hypothesis is that hypothalamic modulation of the midbrain periaqueductal gray (PAG) results in obesity- related reductions in chemosensitivity. The rationale is that by defining the circuitry that links obesity-induced hypothalamic changes to reduced chemosensitivity, the outcomes of this proposal are likely to foster the development of new pharmaceutical treatments designed to combat OHS. The central hypothesis will be tested in the following specific aims: Aim 1. Identify the hypothalamic populations that modulate the PAG. Using a combination of transgenic mouse models, immunohistochemistry, and viral tracing, this aim identifies the hypothalamic brain regions and signaling mechanisms involved in the modulation of chemosensitivity via the midbrain PAG Aim 2. Determine the neuronal targets that maximally affect in vivo chemosensitivity. Using chemogenic technology and whole-body plethysmography, this aim determines the extent to which each of our candidate regions modulate breathing in the context of obesity. This proposal is expected to define a novel neurobiological circuit by which obesity affects chemosensitivity. This proposal is innovative because it moves beyond the popularly held view that obesity-related respiratory disease principally results from physical body mechanics, and instead, identifies key neuronal populations that modulate in vivo chemosensitivity. This contribution is expected to significantly increase the field’s understanding of obesity-related respiratory pathophysiology. Ultimately, we believe this contribution will catalyze the development of new, more effective treatments for obesity-related respiratory diseases that target the underlying neuro-pathophysiology.

PROJECT NARRATIVE The proposed research is relevant to public health because it seeks to uncover the neurobiological circuit by which obesity effects chemosensitivity. Once the underlying mechanisms are defined, there is the potential for the development of new, centrally-mediated treatment options for obesity-associated respiratory diseases that target the root cause of disordered breathing. Thus, the proposed research is relevant to the mission of NIH and NHLBI that pertains to reducing illness and the development of novel therapeutic strategies to prevent, treat, and cure respiratory diseases.