Main Research Component 3: Developmental sensitivities to alcohol: opposing actions of cytokines on fear conditioning during intoxication and withdrawal

项目总结/摘要 主要研究构成部分3 酒精的使用和滥用对公众健康构成重大威胁。第一次接触酒精的年龄是一个关键因素， 发育轨迹和随后的健康状况的决定因素， 作为发育时期出现的时期，在此期间酒精暴露特别普遍。 酒精的神经免疫后果已经成为可能导致变化的新机制 酒精强化，依赖，并最终发展为酒精相关的脑损伤。 重要的是，暴露于急性，酗酒样剂量的乙醇（EtOH）在啮齿动物产生时间依赖性 细胞因子表达的变化，其中白细胞介素-6（IL-6）在关键边缘结构中显著升高 （杏仁核，PVN和海马）在急性EtOH中毒。与此相反，IL-1β和IL-10的表达均与IL-10的表达有关。 在急性EtOH暴露的戒断过程中，TNFα倾向于在这些相同的结构中激增。令人惊讶的是， 青春期大鼠（P31-33）对急性EtOH中毒的细胞因子反应严重降低。这些 研究结果表明，青春期大鼠可能有一个功能不成熟的神经免疫反应， 年轻人然而，奇怪的是，青少年慢性间歇性EtOH（CIE）暴露使 醉酒相关的IL-6反应诱发的暴食样剂量的乙醇在以后的生活（P70年轻人）。因此，在本发明中， 青少年似乎对急性EtOH诱导的细胞因子反应不太敏感，同时 易受青少年CIE引起的神经免疫过程的长期致敏作用的影响 exposure.然而，观察到的这些急性EtOH诱导的细胞因子变化的功能意义 在醉酒-戒断循环中的作用仍然不清楚。这个建议将利用情境恐惧条件反射 程序作为情绪学习的动物模型，并测试EtOH依赖的功能相关性， 细胞因子的表达。一致的研究结果表明，乙醇损害恐惧条件反射时，训练 在EtOH暴露后的短时间范围内发生（即，中毒期间），而条件反射期间 乙醇戒断倾向于增强恐惧条件反射。因此，这里提出的研究将审查 EtOH对恐惧条件反射的阶段特异性影响。我们的中心假设是， 基底外侧杏仁核（BLA）中的细胞因子对BLA兴奋性产生相反的作用， 恐惧条件反射这些研究还将检查神经免疫功能的长期适应， 青少年CIE后的结果。这样，拟议的研究将是第一批 研究阶段特异性，EtOH诱导的细胞因子表达如何转化为年龄特异性，认知和 早期EtOH暴露的行为结果。

PROJECT SUMMARY/ABSTRACT MAIN RESEARCH COMPONENT 3 Alcohol use and abuse represents a substantial threat to public health. Age of first alcohol exposure is a critical determinant of developmental trajectory and subsequent health status later in life, with prenatal and adolescent periods emerging as developmental epochs during which alcohol exposure is particularly prevalent. Neuroimmune consequences of alcohol have emerged as novel mechanisms that may contribute to changes in alcohol reinforcement, dependence, and ultimately the development of alcohol-related brain damage. Importantly, exposure to acute, binge-like doses of ethanol (EtOH) in rodents produce time-dependent changes in cytokine expression in which Interleukin-6 (IL-6) is substantially elevated in key limbic structures (amygdala, PVN and hippocampus) during acute EtOH intoxication. In contrast, expression of both IL-1β and TNFα tends to surge in these same structures during withdrawal from acute EtOH exposure. Surprisingly, adolescent rats (P31-33) displayed severely reduced cytokine responses to acute EtOH intoxication. These findings suggest that adolescent rats may have a functionally immature neuroimmune response relative to young adults. Paradoxically, however, adolescent Chronic Intermittent EtOH (CIE) exposure sensitized the intoxication-related IL-6 response evoked by a binge-like dose of EtOH later in life (P70 young adults). Thus, adolescents appear to be less sensitive to acute EtOH-induced cytokine responses, while at the same time being vulnerable to long-term sensitization of neuroimmune processes resulting from adolescent CIE exposure. However, the functional significance of these acute, EtOH-induced cytokine changes observed across the intoxication-withdrawal cycle remain obscure. This proposal will utilize contextual fear conditioning procedures as an animal model of emotional learning, and to test the functional relevance of EtOH-dependent expression of cytokines. Consistent findings demonstrate that EtOH impairs fear conditioning when training occurs within a short time-frame after EtOH exposure (i.e., during intoxication), whereas conditioning during EtOH withdrawal tends to enhance fear conditioning. The studies proposed here will therefore examine the phase-specific influence of EtOH on fear conditioning. Our central hypothesis is that phase-specific expression of cytokines in the basolateral amygdala (BLA) produce opposing actions on BLA excitability and subsequent fear conditioning. These studies will also examine long-term adaptations in neuroimmune function and resultant consequences following adolescent CIE. In this way, the proposed studies will be among the first to examine how phase-specific, EtOH-induced cytokine expression translates into age-specific, cognitive and behavioral outcomes of early EtOH exposure.