Defining Astrocyte Heterogeneity in the Retrotrapezoid Nucleus

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 DESCRIPTION (provided by applicant): Central chemoreception is the mechanism by which the brain regulates breathing in response to changes in tissue pH -CO2/H+ sensors located in the brainstem sense pH changes to regulate depth and frequency of breathing. Chemosensitivity is especially important during sleep and its disruption has been associated with several pathological states including sleep apnea, Rett syndrome, sudden unexplained death in epilepsy and stroke-induced respiratory dysfunction. Despite concerted investigation, the cellular and molecular basis for chemoreception has not been fully elucidated. In particular, a subset of brainstem astrocytes have been shown to function as central chemoreceptors, yet nothing is known regarding the molecular identify of these cells. The long term objective of this research is to understand the unique function of astrocyte chemoreceptors, and how these cells are specialized to support the process of breathing. The central hypothesis of this application is that astrocyte chemoreceptors are a functionally discrete population that expresses a unique molecular signature that can then be used to distinguish these cells from the larger astroglial population. I also propose that astrocyte chemoreceptors are specialized to regulate respiratory control and as such are unique to chemosensitive respiratory centres. The proposed research will use a combination of electrophysiological and single-cell transcriptome analysis to determine the unique molecular signature of chemosensitive astrocytes in the RTN. The two aims of this project are: 1) determine the transcriptome of functionally distinct populations of RTN astrocytes, and 2) investigate whether chemosensitive astrocytes are found in other medullary brainstem respiratory centers. Results of this work will identify the molecular signature of chemosensitive RTN astrocytes, and in doing so make possible the development of molecular tools that will allow selective labeling and manipulation of this specific astrocyte subset. This work may also have immediate clinical relevance by identifying new potential therapeutic targets for the treatment of respiratory control problems. Furthermore, as part of this research training plan I will learn a variety of new molecular, cellular and genetic approaches that I can bring to bear on issues important for understanding glial physiology and thus place me in a competitive position to obtain an independent academic research position.