Serotonergic control of the sympathoadrenal stress response

交感肾上腺应激反应的血清素控制

基本信息

批准号：
10654226
负责人：
KEVIN P CURRIE
金额：
$ 48.3万
依托单位：
ROWAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654226
关键词：
Action Potentials Acute Adrenal Glands Antidepressive Agents Anxiety Autonomic Dysfunction Biomedical Research Blood Calcium Catecholamines Cells Chromaffin Cells Chronic Clinical Data Disease Electrophysiology (science)Environment Epinephrine Event Excision Exocytosis Failure Functional disorder Funding G-Protein-Coupled Receptors Gene Expression Genetic Genetic Variation Glutaminase Heart failure Human Hyperalgesia Hypertension Hypoglycemia Image In Vitro Investigation Kinetics Knock-out Knockout Mice Link Measures Mediating Medical Students Mental Depression Modeling Mus Nature Nervous System Neuromodulator Neurons Neuropeptides Neurosecretory Systems Neurotransmitters Norepinephrine Obsessive-Compulsive Disorder Pathway interactions Patients Peripheral Peripheral Nervous System Diseases Pharmaceutical Preparations Physiological Physiology Play Post-Translational Protein Processing Post-Traumatic Stress Disorders Prevalence Process Publishing Receptor Inhibition Reporting Research Rodent Role Selective Serotonin Reuptake Inhibitor Serotonin Serotonin Receptor 5-HT1A Signal Transduction Site Stimulus Stress Sympathetic Nervous System System Testing Tissues Tyrosine 3-Monooxygenase Up-Regulation Vesicle Work arm autism spectrum disorder biological adaptation to stress carbon fiber clinically relevant comorbidity fighting in vivo insight monoamine mouse model neurotransmitter release novel patch clamp pharmacologic physiologic stressor pituitary adenylate cyclase activating polypeptide response restraint serotonergic regulation serotonin transporter stressor therapeutic target tool undergraduate research experience undergraduate student uptake

Action Potentials Acute Adrenal Glands Antidepressive Agents Anxiety Autonomic Dysfunction Biomedical Research Blood Calcium Catecholamines Cells Chromaffin Cells Chronic Clinical Data Disease Electrophysiology (science)Environment Epinephrine Event Excision Exocytosis Failure Functional disorder Funding G-Protein-Coupled Receptors Gene Expression Genetic Genetic Variation Glutaminase Heart failure Human Hyperalgesia Hypertension Hypoglycemia Image In Vitro Investigation Kinetics Knock-out Knockout Mice Link Measures Mediating Medical Students Mental Depression Modeling Mus Nature Nervous System Neuromodulator Neurons Neuropeptides Neurosecretory Systems Neurotransmitters Norepinephrine Obsessive-Compulsive Disorder Pathway interactions Patients Peripheral Peripheral Nervous System Diseases Pharmaceutical Preparations Physiological Physiology Play Post-Translational Protein Processing Post-Traumatic Stress Disorders Prevalence Process Publishing Receptor Inhibition Reporting Research Rodent Role Selective Serotonin Reuptake Inhibitor Serotonin Serotonin Receptor 5-HT1A Signal Transduction Site Stimulus Stress Sympathetic Nervous System System Testing Tissues Tyrosine 3-Monooxygenase Up-Regulation Vesicle Work arm autism spectrum disorder biological adaptation to stress carbon fiber clinically relevant comorbidity fighting in vivo insight monoamine mouse model neurotransmitter release novel patch clamp pharmacologic physiologic stressor pituitary adenylate cyclase activating polypeptide response restraint serotonergic regulation serotonin transporter stressor therapeutic target tool undergraduate research experience undergraduate student uptake

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项目摘要

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.