Neural-Glial Interactions and Opioid Abuse: Modulation by Early-Life Experience

描述(由申请人提供)：影响个人成瘾风险的因素很多，包括遗传、环境和生理因素。在这些因素中，个人的早期生活环境，包括产妇护理，可能特别关键。我们的研究提供了强有力的证据，表明产妇护理可以永久性地改变大脑中的神经胶质细胞功能，这对神经功能和行为有长期影响。值得注意的是，胶质细胞(星形胶质细胞和小胶质细胞)被滥用药物激活，它们的激活和随后细胞因子和趋化因子的释放可以显著影响包括吗啡在内的滥用药物的生理和成瘾特性。在这个提案中，我们描述了我们的新假设，即伏隔核(NAC)内小胶质细胞驱动的趋化因子的表达是吗啡诱导成瘾模型复发的基础，此外，在生命早期进行母婴护理通过诱导小胶质细胞的抗炎表型来诱导幼鼠对成年期药物复发的弹性。具体地说，我们发现：(1)吗啡深刻激活成年大鼠NAC内的胶质细胞，诱导趋化因子快速(几分钟)增加；(2)用胶质细胞调节剂异丁司特抑制吗啡诱导的趋化因子反应，完全防止吗啡诱导的CPP恢复，几个月后进行评估，而不改变初始CPP保持在较高水平；(3)新生儿处理通过完全阻止成年后吗啡诱导的趋化因子在NAC内的表达来模仿胶质调节因子，并防止吗啡CPP的恢复。此外，与未处理的对照组大鼠相比，处理过的大鼠大脑中抗炎细胞因子IL-10的基础表达增加，这种表达是在生命早期建立的，并通过减少小胶质细胞内IL-10基因的甲基化而维持到成年。我们的中心假设是，通过加强母体护理，这种表观遗传学诱导的小胶质细胞IL-10的结构性增加阻止了吗啡诱导的神经胶质细胞趋化因子反应，从而防止了药物诱导的吗啡CPP恢复的神经可塑性变化，而不依赖于奖赏或应激反应的变化。因此，这项应用的总体目标是首先建立小胶质细胞IL-10与新型脑趋化因子的弹性之间的因果关系 对吗啡和随后的药物诱导的恢复的反应。其次，我们将确定IL-10是否通过抑制小胶质细胞内典型的促炎基因转录来影响趋化因子的表达。

DESCRIPTION (provided by applicant): Many factors affect an individual's risk of addiction, including genetic, environmental, and physiological factors. Of these factors, the early-life environment of an individual, including maternal care, may be especially critical. Our research provides strong evidence that maternal care can permanently alter glial cell function within the brain, which has long-term consequences for neural function and behavior. Notably, glial cells (astrocytes and microglia) are activated by drugs of abuse, and their activation and subsequent release of cytokines and chemokines can markedly impact the physiological and addictive properties of drugs of abuse, including morphine. In this proposal, we describe our novel hypothesis that microglial-driven chemokine expression within the nucleus accumbens (NAc) underlies morphine-induced relapse in a model of addiction, and moreover that nurturing maternal care early in life induces resilience of the pups to drug relapse in adulthood by inducing an anti-inflammatory phenotype in microglia. Specifically, we show that: (1) Morphine profoundly activates glia within the adult rat NAc, inducing a rapid (minutes) increase in chemokines; (2) Inhibiting this morphine-induced chemokine response with a glial modulator, Ibudilast, completely prevents morphine- induced reinstatement of CPP assessed months later, without altering initial CPP which remains high; and (3) Neonatal handling mimics the glial modulator by completely preventing morphine-induced chemokine expression within the NAc in adulthood, and prevents the reinstatement of morphine CPP. Moreover, handled rats exhibit increased basal expression of the anti-inflammatory cytokine IL-10 within the brain compared to non-handled control rats, which is established early in life and maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. Our central hypothesis is that this epigenetically induced constitutive increase in microglial IL-10 by enhanced maternal care prevents the morphine-induced chemokine response by glia and thereby prevents the neural plasticity changes underlying drug-induced reinstatement of morphine CPP, independent of changes in reward or stress reactivity. Thus, the overall objective of this application is to fist establish a causal relationship for microglial IL-10 in the resilience to the novel brain chemokine response to morphine and subsequent drug-induced reinstatement. Second, we will determine whether IL-10 impacts chemokine expression by inhibiting canonical proinflammatory gene transcription within microglia.