This project aims to define brainstem GABAergic (Gamma-aminobutryc acid (GABA) - producing) respiratory neurons in terms of their developmental gene expression and ultimately their function in respiratory control. Powerful genetic tools available in the mouse model system will be used to delineate GABAergic subtypes molecularly and upon this map, functional properties will then be delineated and plotted. We hypothesize that GABAergic respiratory neuron subtypes in the lower brainstem are organized by rhombomeric origin, resulting in circuit modules capable of regulating distinct respiratory parameters such as respiratory volume, frequency and shape, and that when disrupted, may play a role in congenital respiratory abnormalities such as SIDS - the leading cause of post-neonatal infant mortality in the United States, and Rett syndrome - the leading cause of developmental disabilities in young girls. This research program proposes to use tools developed in the Dymecki lab to 1) define the fates of respiratory GABAergic neurons as a function of developmental gene expression, and 2) determine the role played by these genetically-defined GABAergic neuron subtypes in regulating respiratory homeostasis. By linking early gene expression to groups of GABAergic neurons with distinct fates and functions, we will uncover candidate developmental pathways that can be used to model respiratory defects seen in humans.
Relevance to public health: The proposed studies will contribute to building and applying a genetic system for defining and delineating neural mechanisms important to the control of breathing. The resulting findings will lead to a deeper understanding of respiratory function and dysfunction, including that associated with many common and debilitating, even life-threatening disorders, such as the respiratory abnormalities associated with infant prematurity, with Retts syndrome, Joubert syndrome, and sudden infant death syndrome,
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