Investigating the Mechanisms of Brain-Heart Communication Under Stress - Project Summary/Abstract Stress-induced disruptions in brain and heart communication can perturb the balance between sympathetic and parasympathetic responses, potentially causing health consequences across multiple domains. Our laboratory has focused on understanding the mechanisms of organ-organ communications under stress via two pathways: vagus nerve-to-brain and brain-to-heart. The vagus-to-brain communication involves the nodose ganglion, transmitting sensory interoceptive information such as heart rate to the nucleus of the solitary tract (NTS), the brain's visceral center. The parasympathetic regulation of the cardiovascular system occurs through the nucleus ambiguus (NAmb) brain region, a crucial brain-to-heart communication circuit. The Principal Investigator (PI) has made significant strides in investigating brain and heart interactions through pilot studies. Our preliminary findings show that ethologically relevant stressors negatively affect these two parasympathetic regulations, leading to disruptions in behavior, cardiorespiratory, immune, and other functions. We have further discovered the role of the neuropeptide pituitary adenylate cyclase polypeptide (PACAP) and its receptor PAC1 in modulating the nodose ganglion of the vagus nerve to NTS and the NAmb to heart circuits, shedding light on cellular mechanisms of interoceptive signaling during stress. The Maximizing Investigators' Research Award (MIRA) R35 project will elucidate the intricate neural mechanisms connecting the brain and heart during stress, focusing on two communication mechanisms: bottom-up (nodose ganglion to NTS) and top-down (NAmb to heart). The current project fits well with NIGMS's focus on multiorgan physiology under stress in the Division of Pharmacology, Physiology, and Biological Chemistry. In this proposal, we will explore the impact of the nodosePACAP to NTS and NAmbPACAP to heart on behavior, cardiorespiratory, and cardiovascular functions. The MIRA for Early-Stage Investigators (ESI) allows simultaneously investigating the brain and heart communication in stress through complementary top-down and bottom-up pathway analyses. In the next five years, our research will uncover stress-related organ-organ communication mechanisms, focusing on neuropeptide pathways and understanding the intricate processing of bodily signals. The project's overarching vision is to rigorously investigate stress-related effects on brain-body communication, addressing a critical gap in stress biology research. While rooted in basic science in mice, the research has broader implications for practical applications to general medicine.
