Friday, April 19, 2024
4/19/2024
Maintaining the balance of excitatory glutamate and inhibitory GABA signaling is critical for homeostasis and generating proper reflexes in response to hypoxia. Our previous studies established glutamate signaling in the nucleus tractus solitarii (nTS), the first central site for carotid body sensory integration, is exaggerated after chronic intermittent hypoxia (CIH). However, the specific contribution of GABA, which counter-balances glutamate signaling, in the exaggerated excitation is unknown. Our current goal is to address this knowledge gap and determine the extent that inhibitory GABA signaling contributes to overexcitation of the nTS after CIH. GABA signaling is controlled or modulated by GABA release, receptor (GABARs) activation, the chloride (Cl-) equilibrium potential that is set by Cl- co-transporters (NKCC1 and KCC2), and astrocytic GABA uptake via transporters (GATs). Given the present literature and our supporting preliminary data, our overarching hypothesis is that CIH shifts nTS activity to an overexcited state due to attenuated GABA signaling via reduced GABA inhibition and increased astrocyte GAT activity. Reduced GABA tips the balance of Glu and GABA signaling, and their influence on each other (i.e., cross-talk), towards greater excitation to ultimately increase chemoreflex responses. Aim 1 will determine the extent GABA signaling is altered in CIH to increase nTS excitability. Working hypothesis: Reduced GABA inhibition increases nTS excitability and cardiorespiratory function in CIH. GABA inhibition is attenuated in CIH due to reduced GABA release or GABARs on Glu neurons, altered Cl- transport and/or augmented astrocyte GAT. Aim 2 will define the magnitude nTS GABA and astrocyte GABA transporters influence Glu signaling in CIH to control neuronal and cardiorespiratory function. Working hypothesis: GABA-Glu balance is shifted towards excitation after CIH, in part due to altered GAT function, to ultimately to increase nTS excitability and cardiorespiratory function. In this application, we will utilize a multi-faceted, synergistic and integrative approach. We will use a range of techniques including single cell electrophysiology, live-cell imaging, DREADD cellular manipulation and molecular biology to ultimately decipher physiological function. We will also use AAV expression and Cre-technology in transgenic rats that allows specific recording and manipulation in GABA neurons from the single cell to whole animal. Each technique directly complements the other, allowing an unparalleled depth of study. Together, these techniques allow the vertical study of the system and meticulous cellular investigation. Upon completion of the proposed research, we expect to identify the significance and mechanisms of elevated nTS activity due to reduced GABA signaling that result in cardiorespiratory abnormalities in IH diseases.
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