Enhanced central chemoreception contributes to breathing problems in hypertension

PROJECT SUMMARY/ABSTRACT Central chemoreception is the mechanism by which the brain regulates breathing in response to changes in blood CO2/H+. The retrotrapezoid nucleus (RTN) is an important site for central respiratory chemoreception, and there is evidence suggesting RTN chemoreception is hyper-active in spontaneously hypertensive rats (SHRs) and this contributes to unstable periodic breathing. This is significant because breathing abnormalities can lead to enhanced sympathetic outflow, which further exacerbates the progression of hypertension. Despite this significance, the cellular and molecular basis for disordered breathing in hypertension is unclear. My central hypothesis is that over-activation of RTN chemoreception contributes to disordered breathing in hypertension, and treatments that limit RTN chemoreception will improve cardiorespiratory function in SHRs. To test this, I will: use a combination of electrophysiology and imaging approaches to characterize the CO2/H+ response of RTN neurons, astrocytes, and arterioles in slices from SHRs and control rats (Aim 1) and determine whether key elements of RTN chemoreception can be targeted to improve breathing and blood pressure in SHRs (Aim 2). Important outcomes of this work include 1) determining the cellular and molecular basis of RTN dysfunction in SHRs, 2) identifying candidate therapeutic targets for the treatment of unstable breathing in hypertension, and 3) providing valuable training in the molecular, cellular, and whole-animal approaches which will poise me to achieve my goal of becoming an independent investigator.