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

项目摘要/摘要 主要研究部分3 酒精的使用和滥用是对公众健康的重大威胁。第一次接触酒精的年龄是一个关键因素 产前和青春期发育轨迹和随后的健康状况的决定因素 酒精暴露特别普遍的发育期。 酒精的神经免疫后果已成为可能有助于改变的新机制 在酒精强化、依赖的情况下，最终发展成与酒精相关的脑损伤。 重要的是，在啮齿类动物中，暴露在急性、暴饮式剂量的乙醇(Etoh)中会产生时间依赖性的 白介素6(IL-6)在关键边缘结构中显著升高的细胞因子表达的变化 (杏仁核、室旁核和海马体)在急性乙醇中毒。相反，IL-1β和IL-1 mRNA的表达 在停止急性乙醇暴露期间，肿瘤坏死因子α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)对急性乙醇中毒的细胞因子反应严重降低。这些 研究结果表明，青春期大鼠可能存在功能不成熟的神经免疫反应，与 年轻人。然而，矛盾的是，青少年慢性间歇性乙醇(CIE)暴露使 醉酒相关的IL-6反应引起的暴饮式酒精类似剂量的生活(p70年轻人)。因此， 青少年似乎对乙醇诱导的急性细胞因子反应不那么敏感，同时 易受青春期CIE引起的神经免疫过程的长期敏感化 曝光。然而，观察到这些急性的、乙醇诱导的细胞因子变化的功能意义 在整个醉酒-戒断循环中，人们仍然不清楚。这一提议将利用背景恐惧条件反射 程序作为情绪学习的动物模型，并检验乙醇依赖的功能相关性 细胞因子的表达。一致的研究结果表明，乙醇在训练时会损害恐惧条件反射 发生在乙醇暴露后的短时间内(即，在醉酒期间)，而条件作用在 酒精戒断倾向于增强恐惧的条件反射。因此，这里建议的研究将审查 乙醇对恐惧条件反射的阶段性影响。我们的中心假设是特定阶段的表达 基底外侧杏仁核(BLA)中的多种细胞因子在BLA兴奋性和随后的 恐惧条件反射。这些研究还将检查神经免疫功能和 青少年CIE的后果。如此一来，拟议的研究将是首批 研究乙醇诱导的特定阶段的细胞因子表达如何转化为特定年龄的、认知的和 早期接触乙醇的行为结果。

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.