Hippocampal-dependent neural immune interactions regulate heroin-conditioned immunomodulation

项目摘要/摘要 海洛因使用的负面后果并不局限于毒品的成瘾性质所产生的后果。 海洛因和其他类阿片类药物会对宿主的免疫力产生负面影响，从而使吸毒者更容易感染疾病 与海洛因滥用有关。这些免疫调节作用会受到环境的制约。 重复上下文后的刺激-海洛因配对。海洛因条件刺激的呈现足以 导致在没有海洛因本身的情况下明显抑制外周促炎措施。穿过 在控制良好的动物模型中，我们的实验室已经证明，海洛因条件免疫调节是一种 经典的条件反射，遵循学习的原则。始终如一地，背景-海洛因 联结是通过背侧海马区的突起来控制的。在卫生署内，我们发现 海洛因诱导的外周免疫反应需要完整的神经免疫信号。我们 已有研究表明，水解型白介素1受体(IL-1β，IL-1β)及其活性受体IL-1受体1(IL-1 Receptor 1，IL-1R1)， 关键地调节海洛因条件免疫调节的表达。为了进一步研究海马区 神经免疫参与了这种条件性反应，我们利用最先进的化学遗传学工具 在体内选择性地操纵水解酶的星形胶质细胞信号。星形胶质细胞GI偶联设计受体的刺激作用 在海洛因条件刺激中被特制药物(DREADD)独占激活 外周免疫措施的条件性抑制。因此，DHIL-1信号和星形胶质细胞 在呈现海洛因配对线索以引发条件性免疫反应时，活动是必要的。 然而，目前尚不清楚水解型星形胶质细胞活性与IL-1之间是否存在机制关系 在这种巴甫洛夫式的反应中发出信号。有证据表明海马区星形胶质细胞的支持机制 通过IL-1β和IL-1R1对学习和记忆的影响。目前的提案是一种有针对性的方法，以 探讨海洛因条件性免疫调节中水解型星形胶质细胞与IL-1信号的关系。 特定的目标验证了最重要的假设，即DH型星形胶质细胞是IL-1信号的关键组成部分 对于海洛因条件下的免疫调节是必要的。AIM 1将检测IL-1β中星形胶质细胞的特异性变化 以及IL-1R1mRNA和蛋白，作为暴露于海洛因条件刺激的结果。AIM 2将聘用 在这些海洛因配对呈现过程中选择性刺激DH型星形胶质细胞GI信号的化学发生工具 提示确定这种体内操作是否减弱海洛因所需的IL-1β和IL-1R1的表达- 发生条件性免疫调节。总而言之，有目的的实验将增进我们的理解 控制海洛因条件性反应的关键神经免疫机制，并将提供有价值的培训 有机会培养我的科学生涯的独立性。

Project Summary/Abstract Negative consequences of heroin use are not limited to those produced by the addictive qualities of the drug. Heroin and other opioids negatively alter host immunity, leaving users more susceptible to diseases commonly associated with heroin abuse. These immunomodulatory effects can become conditioned to environmental stimuli following repeated context-heroin pairings. The presentation of heroin-conditioned stimuli is sufficient to elicit pronounced suppression of peripheral pro-inflammatory measures in the absence of heroin itself. Through well-controlled animal models, our laboratory has demonstrated that heroin-conditioned immunomodulation is a classically conditioned response and follows the principles of learning. Consistently, the context-heroin association is governed through dorsal hippocampal (DH) processes. Within the DH, we have discovered that intact neuroimmune signaling is required for the heroin-conditioned peripheral immune response to occur. We have elegantly shown that both DH interleukin-1β (IL-1β) and its active receptor, IL-1 receptor type 1 (IL-1R1), critically mediate the expression of heroin-conditioned immunomodulation. To further investigate hippocampal neuroimmune involvement in this conditioned response, we employed state-of-the-art chemogenetic tools to selectively manipulate DH astroglial signaling in vivo. Stimulation of astroglial Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs) during the exposure to heroin-conditioned stimuli disrupted conditioned suppression of peripheral immune measures. Thus, separately, DH IL-1 signaling and astroglial activity are necessary during presentation of heroin-paired cues to elicit the conditioned immune response. However, it is presently unknown if there is a mechanistic relationship between DH astroglial activity and IL-1 signaling in this Pavlovian response. There is evidence to suggest hippocampal astroglia support mechanisms of learning and memory through both IL-1β and IL-1R1. The current proposal is a targeted approach to investigate the relationship between DH astroglia and IL-1 signaling in heroin-conditioned immunomodulation. The specific aims test the overarching hypothesis that DH astroglia are a critical component of the IL-1 signaling necessary for heroin-conditioned immunomodulation. Aim 1 will examine astroglial-specific alterations in IL-1β and IL-1R1 mRNA and protein as a consequence of exposure to heroin-conditioned stimuli. Aim 2 will employ chemogenetic tools to selectively stimulate DH astroglial Gi-signaling during presentation of these heroin-paired cues to determine if this in vivo manipulation attenuates the IL-1β and IL-1R1 expression required for heroin- conditioned immunomodulation to occur. Collectively, the purposed experiments will enhance our understanding of critical neuroimmune mechanisms governing heroin-conditioned responses and will provide a valuable training opportunity to foster independence of my scientific career.