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

项目总结 暴露在心理社会压力下会对身体和大脑产生广泛的有害影响，导致 许多生理和神经精神障碍的发展。重要的是，焦虑等情况 和阿片类药物使用障碍(OUD)是两种最常见的应激共病，不仅会导致剧烈的 对患者的影响也代表着一场极端的公共卫生危机。值得注意的是，女性经常遭受这些痛苦 这种情况的发病率是男性的两倍，但对导致这种易感性的潜在性别差异的研究 传统上一直处于研究阶段。此外，压力带来的潜在神经机制 对未来精神疾病的易感性尚未得到充分研究。这个项目的总体目标是 确定心理社会应激在脑内离散的应激敏感脑区引起的神经改变 采用雄性和雌性大鼠的动物模型。具体地说，这些实验的目的是研究 蓝斑(LC)内神经免疫信号决定应激诱导小胶质细胞改变的机制 激活会影响去甲肾上腺素的输出，以及随后的焦虑症和寻药行为。增加了 这一脑区的神经免疫信号与去甲肾上腺素(NE)产量的增加有关，但 应激诱导的小胶质细胞LC-NE活性改变对投射相关区域的下游影响 在控制焦虑和寻求毒品行为方面还没有得到评估。因此，这些实验已经 旨在测试应激暴露增强LC内小胶质细胞信号的假设，在 反过来，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)，这是一个区域 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在内的技术来调节和测量 应激诱导的LC小胶质细胞激活对焦虑样行为和阿片类药物寻求行为的影响。男性和女性 大鼠将暴露在我们的替代社会压力模型中，见证压力，在那里大鼠体验感觉 和心理方面的社会失败遭遇。AIM 1旨在确定LC的效果 小胶质细胞通过LC内DREADD介导的小胶质细胞失活对焦虑样和阿片样物质的调节 用大理石掩埋和阿片类药物条件性位置偏好测试恢复行为。这些动物 也将在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 识别升级为阿片类药物使用障碍的不良适应应激反应的新介质 确定应激引起的合并症的预防性治疗的目标。这些数据支持美国国家航空航天局 NIH正在寻找治疗阿片类药物流行的方法，并允许进行必要的培训，以创建 独立科学家将在他们的整个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.