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

• 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
• 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

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.

项目概要 暴露于社会心理压力会对身体和大脑产生广泛的有害影响，从而导致 许多生理和神经精神疾病的发展。重要的是，焦虑等情况 和阿片类药物使用障碍 (OUD) 是两种最常见的压力合并症，不仅会导致严重的 对患者的影响，但也代表着一场极端的公共卫生危机。值得注意的是，女性经常遭受这些 其患病率是男性的两倍，但对导致这种易感性的潜在性别差异进行了研究 传统上一直在研究中。此外，压力赋予的潜在神经机制 未来精神疾病的易感性尚未得到充分探讨。该项目的总体目标是 确定离散压力敏感大脑区域中心理社会压力引起的神经改变 使用雄性和雌性大鼠的动物模型。具体来说，这些实验旨在研究 蓝斑 (LC) 内的神经免疫信号传导，以确定应激如何诱导小胶质细胞的改变 激活影响去甲肾上腺素能输出和随后的焦虑样行为和药物寻求行为。增加 该大脑区域的神经免疫信号传导与去甲肾上腺素 (NE) 输出增加有关，但是 应激诱导的小胶质细胞 LC-NE 活性改变对所涉及的投影区域的下游影响 在控制焦虑和药物寻求行为方面尚未进行评估。因此，这些实验 旨在测试压力暴露增强 LC 内小胶质细胞信号传导的假设， 转，影响下游区域的去甲肾上腺素能张力，包括基底外侧杏仁核 (BLA)，该区域 以其控制焦虑和药物相关行为而闻名。该假设将使用多种方法进行检验 包括行为药理学、化学遗传学和微透析在内的技术来调节和测量 压力诱导的 LC 小胶质细胞激活对焦虑样和阿片类药物寻求行为的影响。男女 老鼠将暴露于我们的替代社会压力、目击者压力模型中，老鼠在其中经历感官刺激 以及社交失败遭遇的心理方面。目标 1 旨在确定 LC 的效果 通过LC内DREADD介导的小胶质细胞失活对焦虑样药物和阿片类药物进行小胶质细胞调节 使用大理石埋葬和阿片类药物条件位置偏好测试来恢复行为。这些动物 还将在 Aim 2 的 BLA 内植入微透析探针，旨在确定 LC 小胶质细胞调节对 BLA NE 活性的下游影响。这些研究有潜力 确定适应不良应激反应的新介质，最终升级为阿片类药物使用障碍 确定压力引起的合并症的预防性治疗的目标。这些数据支持我们的使命 NIH 致力于寻找治疗阿片类药物流行病的方法，并允许进行必要的培训，以建立一个 独立科学家将在整个职业生涯中继续追求这一目标。