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

神经胶质相互作用和阿片类药物滥用：早期生活经历的调节

• 批准号: 8792843
• 负责人: Staci D Bilbo
• 金额: $ 34.02万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792843
• 关键词: Abstinence; Addictive Behavior; Adult; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Behavior; Brain; Caring; Cell physiology; Cells; Childhood; Dependency; Development; Drug abuse; Drug usage; Environment; Event; Exhibits; Extinction (Psychology); Fluorescence-Activated Cell Sorting; Genes; Genetic; Genetic Transcription; Goals; Health; Human; Illicit Drugs; Individual; Infusion procedures; Interleukin-10; Knock-out; Lead; Life; Life Experience; Life Stress; Link; Luciferases; Measures; Methylation; Microglia; Modeling; Morphine; Mus; Neonatal; Neuroglia; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Nuclear; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Play; Property; Rattus; Recording of previous events; Relapse; Relative (related person); Reporter; Research; Rewards; Risk; Rodent; Role; Self Administration; Self-Administered; Societies; Source; Specificity; Stress; Substance abuse problem; Synaptic plasticity; Techniques; Time; Transcription factor genes; Transgenic Mice; Transgenic Organisms; addiction; behavioral response; brain behavior; cell type; chemokine; conditioning; cytokine; drug of abuse; drug relapse; drug seeking behavior; neglect; neutralizing antibody; novel; novel strategies; opioid abuse; preference; prevent; programs; pup; relating to nervous system; resilience; response; stress reactivity

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.

描述（由申请人提供）：影响个体成瘾风险的因素有很多，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，包括孕产妇护理，可能尤其重要。我们的研究提供了强有力的证据，表明孕产妇护理可以永久改变大脑内的神经胶质细胞功能，这对神经功能和行为产生长期影响。值得注意的是，神经胶质细胞（星形胶质细胞和小胶质细胞）被滥用药物激活，它们的激活和随后释放的细胞因子和趋化因子可以显着影响滥用药物（包括吗啡）的生理和成瘾特性。在这项提议中，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表达是成瘾模型中吗啡诱导的复发的基础，此外，生命早期的母性护理通过诱导小胶质细胞中的抗炎表型，诱导幼崽对成年后药物复发的恢复能力。具体来说，我们表明：（1）吗啡深度激活成年大鼠 NAc 内的神经胶质细胞，诱导趋化因子快速（几分钟）增加； (2) 用神经胶质调节剂 Ibudilast 抑制这种吗啡诱导的趋化因子反应，完全防止几个月后评估的吗啡诱导的 CPP 恢复，而不会改变仍处于高水平的初始 CPP； (3) 新生儿处理通过完全阻止成年期 NAc 内吗啡诱导的趋化因子表达来模仿神经胶质调节剂，并防止吗啡 CPP 的恢复。此外，与未处理的对照大鼠相比，处理过的大鼠大脑内抗炎细胞因子IL-10的基础表达增加，这种表达在生命早期就已形成，并通过小胶质细胞内IL-10基因甲基化的减少而维持到成年期。我们的中心假设是，通过加强孕产妇护理，表观遗传诱导的小胶质细胞 IL-10 的组成性增加阻止了吗啡诱导的神经胶质细胞的趋化因子反应，从而阻止了药物诱导的吗啡 CPP 恢复的神经可塑性变化，而与奖励或应激反应性的变化无关。因此，本申请的总体目标是首先建立小胶质细胞 IL-10 对新型脑趋化因子的恢复力的因果关系 对吗啡的反应和随后的药物诱导的恢复。其次，我们将确定 IL-10 是否通过抑制小胶质细胞内典型促炎基因转录来影响趋化因子表达。