Characterizing the role of central nucleus of the amygdala and the hypothalamic paraventricular nucleus in stress-augmentedcardiogenic sympathetic afferent reflex in the RAT

The National Institute of General Medical Sciences awarded East Tennessee State University a $152,000 Project Grant (CFDA 93.859, Biomedical Research and Research Training) on August 15, 2026, to characterize the role of the central amygdala and hypothalamic paraventricular nucleus in stress-augmented cardiogenic sympathetic afferent reflex in rats.

The research uses optogenetics to inhibit activation of rostral ventrolateral medulla-projecting neurons from these brain regions and assesses the effect on renal sympathetic nerve activity, heart rate, and blood pressure following epicardial bradykinin application to model ischemic events. The work addresses how chronic stress over-activates the sympathetic nervous system and augments the dangerous sympathetic reflex triggered by myocardial ischemia, with implications for understanding stress-related hypertension and cardiac complications.

Performance occurs in Johnson City, Tennessee, with a period of performance through April 30, 2030.

Abstract

This proposal aims to characterize the role of the central amygdala (CEA) and the paraventricular (PVN) nucleus of the hypothalamus on the sympathetic outflow that originates in the rostral ventrolateral medulla (rvlm) in the brainstem and to evaluate the effects of stress on this circuitry. Stress activates the sympathetic nervous system, triggering the release of hormones and neurotransmitters that increase heart rate, contractility and blood pressure. Chronic stress can over activate this system, potentially leading to diseases such as hypertension. Notably, myocardial ischemia elicits a dangerous sympathetic reflex, the cardiogenic sympathetic afferent reflex (csar), and chronic elevated sympathetic activity caused by chronic stress augments that reflex. In this proposal we hypothesize that stress increases the activity of rvlm-projecting CEA and PVN neurons and that these sympathetic pathways play a key role in the stress-induced augmented csar. Retrograde labeling of rvlm-projecting neurons from our laboratories clearly demonstrates that the CEA and PVN provide a significant portion of the input to the rvlm, identifying them as likely control centers of rvlm sympathetic outflow. Additionally, our preliminary data show that foot shock stress increases basal renal sympathetic nerve activity (rsna) and arterial pressure, while augmenting the csar following epicardial bradykinin application. Our first aim is to determine whether cells from these brain regions are responsible for the stress-augmented response of the csar. We will use optogenetics to inhibit activation of the rvlm-projecting CEA and PVN neurons and assess the effect on renal sympathetic nerve activity, heart rate and blood pressure after epicardial bradykinin application to model an ischemic event. In the second aim, we will determine if the development of stress-induced increases in sympathetic activity and the augmented csar rely on intact rvlm-projecting CEA and PVN pathways. To address this aim we will transfect rvlm-projecting neurons with a suicide gene to selectively lesion cells from these regions prior to stress exposure. In the final aim, we will characterize the spinally-projecting rvlm neurons involved in the augmented csar. To address this aim we will compare the changes in glutamatergic, gabaergic, and corticotropic neurons as well as cfos activation within these nuclei. The proposal integrates cutting-edge technology with neurohistological and electrophysiology experimentation to provide quality and meaningful research experiences for students.