Molecular and Functional Characterization of Cortical Circuits Regulating the Adrenal Medulla During Stress

About This Grant

Project Summary/Abstract Research: Fear activates the fight or flight stress-response, leading to rapid changes in behavior and physiological accommodations via the sympathetic nervous system. While the stress response facilitates survival from an acute threat, inappropriate activation or delayed termination after threats have passed can be maladaptive. Indeed, inappropriate sympathetic activation is a hallmark of psychiatric diseases such as post- traumatic stress disorder and major depressive disorder. Conversely, non-invasive brain modulation techniques such as transcranial direct current stimulation, which induces diverse physical and mental health benefits, may function in large part through its ability to mitigate the stress response. Together, this suggests that the neural circuits regulating the sympathetic nervous system could be an important therapeutic target. To map the central circuits regulating the adrenal gland, an essential effector of the fight-or-flight sympathetic response and the principal source of circulating epinephrine, I will use monosynaptic rabies. My preliminary data show that the adrenal medulla receives innervation not only from well-established hypothalamic nuclei, but also, surprisingly, from the motor cortex. The proposed project will expand upon this finding: In Aim 1) I will rigorously map the connections between the motor cortex and the adrenal gland and in Aim 2) I will investigate how these cortical neurons modulate epinephrine release and the physiological and behavioral response to stress. These aims will expand our understanding of this newly discovered neural circuit and its role underlying important mind-body interactions. Career development: This five-year research career development program will advance the career of a promising physician-scientist studying the neural circuits underlying mind-body connections as they relate to the physiological effects of stress. This proposal builds upon the candidate’s extensive background in molecular neuroscience and behavioral genetics, by promoting Dr. Greene’s acquisition of several necessary technical skills and extensive training to ensure that the candidate develops superb professional skills. The training goals are reflected in the expertise of the mentors (Dr. Andrés Bendesky and Dr. Rui Costa), tailored seminars and didactics, and the strong neuroscience training environment at Zuckerman Mind Brain and Behavior Institute. By completing the proposed studies and training plan, the candidate will acquire a unique and highly valued skill set that will support a successful transition to becoming an independent investigator.