Mapping the developmental, genetic, and functional organization of noradrenergic respiratory neural circuits

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 DESCRIPTION (provided by applicant) the goal of this project is to map distinct respiratory functions onto brainstem noradrenergic neurons. Several respiratory pathophysiologies including SIDS, Rett syndrome, and CCHS feature both disordered breathing and are associated with brainstem noradrenergic system abnormalities and, noradrenergic signaling appears to be important in obstructive sleep apnea. In multiple model systems, the central NA system has been shown to be involved in respiratory control. However, prior experimental techniques, including lesions, gene knockouts, and pharmacological manipulations have been hampered by the imprecision inherent in these techniques. To clearly delineate and access NA subtypes, we are using intersectional genetics to subdivide NA neurons by rhombomere of origin. We hypothesize that the early developmental gene expression programs intrinsic to each rhombomere underlie the organization of the NA system into distinct functional modules with in the central respiratory network. Within each NA rhombomeric subset, we will use new mouse intersectional genetic tools to anatomically, functionally, and molecularly map circuit organization. We propose to test our hypothesis in three separate Aims. In Aim 1, we will anatomically map NA rhombomeric subtype projections to known brainstem respiratory centers to determine the flow of information from NA neurons. In Aim 2, we will use pharmacogenetic (Dreadd) neuron manipulations in combination with whole body barometric plethysmography to assign distinct respiratory functions to NA subtypes. In Aim 3, we will test the hypothesis that early developmental rhombomeric subdivisions carry into the adult brainstem at the molecular level through molecular profiling. The resulting integrated framework of anatomical, functional, and molecular characterizations across rhombomeric NA subtypes will add clarity to our understanding of central NA neuron organization and its role respiratory disorders. Ultimately, we expect this approach to enable the development of highly targeted diagnostics and therapeutics that are directed to the required sites of action with minimal side effects on the other behavioral and physiological functions served by the NA system.