Neural Control of Cardiovascular Physiology via A Heart-to-Brain Pathway

About This Grant

Project Summary / Abstract Maintaining cardiovascular stability during blood loss is essential to prevent fainting, organ failure, and death. While it is well-established that the nervous system can adaptively regulate heart rate and blood pressure during hemorrhage, the sensory pathways that detect circulatory compromise remain poorly understood. Recent evidence suggests that vagal sensory neurons—those that connect the heart to the brain—play a critical role in monitoring internal hemodynamic and metabolic states. However, the specific types of vagal neurons involved, the signals they detect, and their downstream central circuits have not been comprehensively defined. The goal of this proposal is to elucidate how genetically distinct populations of vagal cardiac sensory neurons detect and respond to varying degrees of blood loss, and how these signals engage brainstem circuits to regulate autonomic output. My preliminary studies identified two vagal sensory subtypes, with distinct roles in detecting mechanical and chemical cardiac signals, respectively. Mechanosensory neurons encode blood volume through stretch-sensitive activity, while chemosensory neurons are likely responsive to injury or inflammatory cues. Selective ablation of mechanosensory neurons results in postural hypotension and impaired survival after hemorrhage, suggesting a critical role in cardiovascular compensation. These findings support the concept of a dual sensory system in the heart that enables graded physiological responses to blood loss. In the mentored K99 phase, I will combine in vivo calcium imaging, genetic tools, and chemogenetics to (1) characterize how these vagal neuron subtypes respond dynamically to mild versus severe hemorrhage and (2) identify stress-related chemical signals that activate vagal cardiac neurons. In the R00 phase, I will transition to independence by applying large-scale multi-electrode recordings and circuit-mapping techniques to (3) define the downstream brainstem networks that receive and respond to these signals from the heart. This project integrates molecular genetics, systems neuroscience, and cardiovascular physiology to dissect a poorly understood heart-brain axis. It has the potential to uncover how internal sensory pathways detect life-threatening physiological perturbations and coordinate protective reflexes. Understanding these mechanisms could ultimately inform new strategies for treating disorders such as orthostatic hypotension, vasovagal syncope, and hemorrhagic shock. The proposed training plan includes technical instruction in in vivo imaging and electrophysiology, as well as mentorship in scientific communication, grant writing, and career development by an accomplished and collaborative team. These efforts will prepare me for a successful transition to an independent academic career investigating the neural circuits of interoception and cardiovascular control.