Corticotropin-Releasing Hormone differentially modulates GABA and non-GABA nucleus Tractus Solitarii neurons

Peripheral cardiorespiratory reflexes respond to various stressors and are processed in the brainstem nucleus tractus solitarii (nTS). The paraventricular nucleus of the hypothalamus is reciprocally connected to the nTS and influences cardiorespiratory function partly through corticotropin-releasing hormone (CRH) projections to the nTS. Our previous studies showed that CRH enhances nTS activity and increases cardiorespiratory responses to hypoxia. However, the specific effects of CRH on the unique nTS neuron phenotypes remain unclear. We hypothesized that CRH's general excitatory effect on nTS function results from its differential influence on nTS phenotypes. To test this hypothesis, we examined the electrophysiological and dynamic calcium fluorescent responses to CRH, as well as the CRH receptor profiles, of GABA neurons within the nTS of Gad1-EGFP mice (male and female) and compared them to non-GABA neurons. CRH-positive synaptic terminals were adjacent to both neuron phenotypes. The expression of the CRH receptor, crhr1, was greater in GABA vs. non-GABA neurons in the medial nTS. Functionally, CRH reduced afferent (TS)-evoked EPSC amplitudes in GABA neurons but increased current amplitude in non-GABA neurons. Applying a CRH receptor blocker before CRH abolished synaptic responses in both groups, confirming the specificity of CRH action. GABA neuron synaptic activity was tonically restrained by CRH, as CRH receptor blockade increased TS-EPSC amplitude. Our findings show that CRH effects on nTS activity differ by neuron type, with GABA neuron activity inhibited by CRH. Such responses likely contribute to CRH's excitatory influence in the nTS and to the elevated breathing and sympathoexcitation observed during hypoxia.Significance Statement Stress and homeostatic challenges influence vital autonomic functions, yet the underlying central neural circuit mechanisms remain incompletely understood. This study reveals that corticotropin-releasing hormone shifts the balance of brainstem sensory processing through distinct, cell-type-specific processes by simultaneously suppressing excitatory input to local inhibitory GABA neurons and enhancing transmission to non-GABA cells. These findings demonstrate how stress neurochemicals may alter specific brainstem networks to coordinate physiological function.