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Locus coeruleus-norepinephrine regulation of stress-induced anxiety and opioid reinstatement

蓝斑-去甲肾上腺素对应激性焦虑和阿片类药物恢复的调节

基本信息

批准号：
10677132
负责人：
Cora Smiley
金额：
$ 6.95万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
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：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677132
关键词：
Address Adrenergic Agents Adrenergic Receptor Affect Amygdaloid structure Animal Model Animals Anxiety Behavior Behavioral Brain Brain region Clinical Cues Data Development Disease Experimental Designs Exposure to Extinction Female Future Genetic Genetic Techniques Goals Implant Incidence Inflammation Investigation Marble Measures Mediating Mediator Mental Depression Mental disorders Microdialysis Microglia Mission Modeling Neuroimmune Norepinephrine Opioid Oral Output Oxycodone Patients Pattern Pharmaceutical Preparations Physiological Population Post-Traumatic Stress Disorders Pre-Clinical Model Predisposition Preventive treatment Process Psychosocial Stress Public Health Rattus Regulation Research Scientist Sensory Sex Differences Signal Transduction Stimulus Stress Substance Use Disorder System Techniques Testing Training United States National Institutes of Health addiction anxiety-like behavior anxiety-related behavior behavioral pharmacology biological adaptation to stress brain tissue career comorbidity conditioned place preference design designer receptors exclusively activated by designer drugs drug seeking behavior experience experimental study glial activation immune function locus ceruleus structure male men neural neuroinflammation neuromechanism neuropsychiatric disorder neuropsychiatry neurotransmission noradrenergic novel opioid abuse opioid epidemic opioid use opioid use disorder psychologic receptor expression social defeat social stress transmission process

项目摘要

PROJECT SUMMARY Exposure to psychosocial stress has widespread deleterious effects on the body and brain that lead to the development of many physiological and neuropsychiatric disorders. Importantly, conditions such as anxiety and opioid use disorder (OUD) are two of the most common stress comorbidities that not only cause drastic effects on the patient but also represent an extreme public health crisis. Notably, females often suffer from these conditions at twice the rate of men, but research into the potential sex differences that allow for this susceptibility has traditionally been under studied. Further, the underlying neural mechanisms by which stress confers susceptibility to future psychiatric illness has not been fully explored. The overall goal of this project is to determine the neural alterations induced by psychosocial stress in discrete stress-sensitive brain regions in animal models utilizing both male and female rats. Specifically, these experiments aim to investigate neuroimmune signaling within the locus coeruleus (LC) to determine how stress-induced alteration of microglial activation influences noradrenergic output and subsequent anxiety-like and drug seeking behaviors. Increased neuroimmune signaling in this brain region has been associated with increased norepinephrine (NE) output, but the downstream impact of stress-induced microglial alterations of LC-NE activity on projection regions involved in the control of anxiety and drug seeking behaviors has not been assessed. Therefore, these experiments have been designed to test the hypothesis that stress exposure augments microglial signaling within the LC which, in turn, affects noradrenergic tone in downstream regions including the basolateral amygdala (BLA), a region known for its control of anxiety- and drug-related behaviors. This hypothesis will be tested using a variety of techniques including behavioral pharmacology, chemogenetics, and microdialysis to modulate and measure the impact of stress-induced LC microglial activation on anxiety-like and opioid seeking behaviors. Male and female rats will be exposed to our model of vicarious social stress, witness stress, where a rat experiences the sensory and psychological aspects of a social defeat encounter. Aim 1 is designed to determine the effects of LC microglia modulation, through intra-LC DREADD mediated inactivation of microglia, on anxiety-like and opioid reinstatement behaviors using marble burying and opioid conditioned place preference testing. These animals will also be implanted with microdialysis probes within the BLA for Aim 2 which is designed to determine the downstream effects of LC microglial modulation on NE activity in the BLA. These studies have the potential to identify novel mediators of maladaptive stress responses that escalate to opioid use disorder with the ultimate goal of determining preventative treatments for stress-induced comorbidities. These data support the mission of the NIH in the search for a cure for the opioid epidemic and allows for the training necessary to create an independent scientist that will continue to pursue this goal throughout their career.

项目总结