Serotonergic control of the sympathoadrenal stress response

5-羟色胺转运体(SERT)是5-羟色胺(5-HT)信号和可用性的关键生理调节因子。 因此，这种神经调节剂在临床上扮演着不同的重要角色。SERT的遗传变异有 与抑郁、焦虑、强迫症和自闭症有关。此外，SERT是一种 抗抑郁药物的临床相关靶点，包括选择性5-羟色胺再摄取抑制剂 (SSRI的)。与其在中枢神经系统5-羟色胺能神经元中众所周知的作用不同，SERT在 肾上腺嗜铬细胞仍未得到充分研究，仍是个谜。肾上腺嗜铬细胞组成 交感神经系统的神经内分泌臂，合成、储存和分泌儿茶酚胺 (肾上腺素、去甲肾上腺素)和神经肽，协调对生理应激源的反应。 交感-肾上腺应激反应的异常控制有助于自主神经功能障碍和相关 抑郁症、焦虑症和其他与5-羟色胺能信号有关的疾病患者存在明显的共病。 然而，SERT/5-HT信号控制这些应激反应的机制仍不清楚。 我们推测肾上腺嗜铬细胞是5-羟色胺能调节的关键外周中枢。 交感应激反应。我们已发表的和初步的数据表明，SERT/5-HT信号作用于 通过几种不同的机制对肾上腺儿茶酚胺实施急性和慢性控制 分泌物。我们发现肾上腺嗜铬细胞由于SERT的介导积累了少量的5-羟色胺。 嗜铬细胞摄取SERT和5-HT1a受体的相互作用控制儿茶酚胺 分泌物。我们的数据还指出了5-羟色胺作为细胞内信使的另一种控制水平 通过SERT介导的摄取来控制儿茶酚胺的胞吐。为了剖析SERT的作用，我们 建立了第一个有条件切除交感神经系统SERT的小鼠模型 (SERTΔTH小鼠)。我们提出了三个具体的目标，将体内生理学和详细的体外研究结合起来 利用这一新的小鼠和肾上腺的实验优势的机制研究 嗜铬细胞作为神经分泌模型：AIM-1验证交感-肾上腺应激的假设 反应受肾上腺嗜铬细胞SERT表达的调节。AIM-2主要研究体外 机制研究和测试假设，通过SERT/5-HT1a受体信号微调控制 压力引起的儿茶酚胺分泌。AIM-3验证了5-羟色胺作为细胞内激素的假说 信使跟随SERT介导的摄取控制囊泡的动力学和量子大小 神经递质释放。该项目将为交感肾上腺提供新的机制理解。 与5-羟色胺能信号改变相关的系统和自主神经功能障碍。它还将加强 并为本科生和医学生提供有意义的研究经验。

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.