Serotonergic control of the sympathoadrenal stress response

点击翻译按钮获取中文摘要

The serotonin transporter (SERT) is a key physiological regulator of serotonin (5-HT) signaling and availability, and thus the diverse, clinically important roles of this neuromodulator. Genetic variations in SERT are associated with depression, anxiety, obsessive-compulsive disorder, and autism. Moreover, SERT is a clinically relevant target for antidepressant medications, including selective serotonin reuptake inhibitors (SSRI’s). In contrast to its well-known roles in CNS serotonergic neurons, the robust expression of SERT in adrenal chromaffin cells remains understudied and enigmatic. Adrenal chromaffin cells comprise the neuroendocrine arm of the sympathetic nervous system, synthesizing, storing, and secreting catecholamines (epinephrine, norepinephrine) and neuropeptides which coordinate the response to physiological stressors. Aberrant control of this sympathoadrenal stress response contributes to autonomic dysfunction and related comorbidities evident in patients with depression, anxiety, and other diseases linked to serotonergic signaling. However, the mechanisms by which SERT / 5-HT signaling controls these stress responses remain unclear. We postulate that adrenal chromaffin cells are a key peripheral hub for serotonergic regulation of the sympathetic stress response. Our published and preliminary data suggest that SERT / 5-HT signaling acts through several distinct mechanisms to exert both acute and chronic control over adrenal catecholamine secretion. We show that adrenal chromaffin cells accumulate small amounts of 5-HT due to SERT-mediated uptake and that an interplay between SERT and 5-HT1A receptors on chromaffin cells controls catecholamine secretion. Our data also point to an additional level of control in which 5-HT acts as an intracellular messenger following SERT-mediated uptake to control catecholamine exocytosis. To dissect the role of SERT, we developed the first mouse model with conditional excision of SERT in the sympathetic nervous system (SERTΔTH mice). We propose three specific aims that integrate in vivo physiology with detailed in vitro mechanistic investigations that leverage this novel mouse and the experimental advantages of adrenal chromaffin cells as a neurosecretory model: Aim-1 tests the hypothesis that the sympathoadrenal stress response is regulated by expression of SERT in adrenal chromaffin cells. Aim-2 focuses on in vitro mechanistic studies and tests the hypothesis that signaling via SERT / 5-HT1A receptors is fine-tuned to control stress-evoked catecholamine secretion. Aim-3 tests the hypothesis that 5-HT acts as an intracellular messenger following SERT-mediated uptake to control the kinetics and quantal size of vesicular neurotransmitter release. The project will provide new mechanistic understanding of the sympathoadrenal system and autonomic dysfunction associated with altered serotonergic signaling. It will also enhance the research environment and provide meaningful research experiences for undergraduate and medical students.