Activation of GABAergic neurons in the nucleus tractus solitarii of the brainstem blunts cardiorespiratory reflex responses

The nucleus tractus solitarii (nTS) of the brainstem receives and integrates input from the heart, lungs, and other viscera, playing an important role in the cardiorespiratory regulation and reflexes. GABA, the primary inhibitory neurotransmitter in the nTS is crucial to cardiorespiratory function. Changes in nTS GABA signaling are associated with altered physiological function, and may play a role in cardiorespiratory conditions such as hypertension and obstructive sleep apnea. We hypothesized that activation of GABA neurons in the nTS would elicit changes in cardiovascular and respiratory function, and that activation of these neurons would also blunt cardiorespiratory reflexes. Gad2-Cre mice (Gad2 tm2(cre)Zjh /J) were injected in the nTS with a Cre-dependent virus (pAAV-EF1a-double floxed-hChR2(H134R)-mCherry-WPRE-HGHpA) to express channelrhodopsin in GABAergic nTS neurons. 2-4 weeks later the mice were anesthetized with isoflurane and instrumented to record blood pressure, ECG, respiration, and sympathetic nerve activity. Electrodes were placed around the intact vagus nerve for vagal stimulation and a femoral venous catheter was placed for KCN injection to elicit the chemoreflex. The brainstem was exposed and an optogenetic probe was lowered onto the surface. Mice were acclimated to reach stable baseline parameters and then GABA neurons were activated with light (20Hz, 5ms pulse width, 20-60 s stimulation). Vagal stimulation and KCN injection were performed with and without concurrent optogenetic stimulation and physiological responses were monitored for 5 minutes between stimuli. GABA neuron activation on its own increased mean arterial pressure (MAP) and reduced respiration (frequency and amplitude) compared to sham stimulation. Vagal stimulation elicited a drop in MAP and HR and a reduction in respiration. Concurrent optogenetic stimulation attenuated the reduction in MAP and the decrease in respiratory amplitude. KCN injection, used to activate the chemoreflex, increased respiration. Concurrent optogenetic stimulation with KCN enhanced the increase in respiratory rate, but blunted the increase in respiratory amplitude. After experiments were performed, brainstems were collected and sectioned to confirm viral expression in the nTS. Activation of GABAergic nTS neurons elicits cardiorespiratory responses in the anesthetized animal, and overall blunts cardiorespiratory responses to vagal and chemoreflex stimulation. These studies indicate that increased GABA signaling in the nTS directly influences cardiorespiratory basal function and its reflexes, and may play an important role in cardiovascular and respiratory health and disease. 5R01HL166183 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.