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

项目摘要 暴露于心理社会压力对身体和大脑具有广泛的有害影响， 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 对病人的影响，但也代表了一个极端的公共卫生危机。值得注意的是，女性经常遭受这些 条件的两倍，男性，但研究潜在的性别差异，使这种易感性 传统上一直在研究。此外，潜在的神经机制，压力赋予 对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 确定在离散的压力敏感的大脑区域中由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，以确定应激诱导的小胶质细胞改变如何 激活影响去甲肾上腺素能输出和随后的焦虑样和药物寻求行为。增加 该脑区的神经免疫信号传导与去甲肾上腺素（NE）输出增加有关，但 应激诱导的小胶质细胞LC-NE活性改变对投射区域的下游影响 在控制焦虑和寻求药物行为方面的作用尚未得到评估。因此，这些实验 被设计来测试这一假设，即应激暴露增强LC内的小胶质细胞信号传导， 转，影响下游区域的去甲肾上腺素能紧张，包括基底外侧杏仁核（BLA），一个区域 以控制焦虑和毒品相关行为而闻名。这一假设将使用各种不同的 包括行为药理学，化学遗传学和微透析技术来调节和测量 应激诱导的LC小胶质细胞活化对焦虑样和阿片类药物寻求行为的影响男女 大鼠将暴露于我们的替代性社会压力模型，证人压力，其中大鼠经历感官 和心理方面的问题。目的1旨在确定LC的影响 通过LC内DREADD介导的小胶质细胞失活对焦虑样和阿片样物质的小胶质细胞调节 使用大理石掩埋和阿片类条件性位置偏爱测试恢复行为。这些动物 还将在Aim 2的BLA内植入微透析探针，该探针旨在确定 LC小胶质细胞调节对BLA中NE活性的下游影响。这些研究有可能 确定适应不良应激反应的新介质，这些介质升级为阿片类药物使用障碍， 目的是确定对应激诱导的合并症的预防性治疗。这些数据支持的使命 美国国立卫生研究院在寻找治疗阿片类药物流行病，并允许必要的培训，以创造一个 独立科学家将在其职业生涯中继续追求这一目标。

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.