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

主要研究部分 3：对酒精的发育敏感性：细胞因子对中毒和戒断过程中的恐惧调节的相反作用

• 批准号: 10006501
• 负责人: Terrence Deak
• 金额: $ 30.31万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006501
• 关键词: Acute; Adolescence; Adolescent; Adult; Age; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcohols; Amygdaloid structure; Animal Model; Behavioral; Brain Injuries; Chronic; Cognitive; Complex; Dependence; Development; Dose; Electrophysiology (science); Emotional; Ethanol; Ethanol dependence; Exposure to; Fright; Health Status; Hippocampus (Brain); Impairment; In Vitro; Interleukin-1; Interleukin-1 beta; Interleukin-6; Intoxication; Learning; Life; Longevity; Mediating; Memory impairment; Nervous System Physiology; Neuraxis; Neuroimmune; Neuroimmunomodulation; Outcome; Pharmacology; Phase; Procedures; Process; Public Health; Rattus; Research; Rodent; Rodent Model; Role; ST5 gene; Sex Differences; Signal Transduction; Site; Stimulus; Structure; Synaptic Transmission; TNF gene; Testing; Time; Training; Translating; Withdrawal; alcohol consequences; alcohol exposure; alcohol reinforcement; alcohol research; alcohol sensitivity; behavioral outcome; conditioned fear; conditioning; cytokine; gamma-Aminobutyric Acid; in vivo; novel; prenatal; response; synaptic function; transmission process; young adult

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.

项目概要/摘要 主要研究部分3 饮酒和滥用酒精对公共健康构成重大威胁。首次接触酒精的年龄是一个关键因素 发育轨迹和随后生命后期健康状况的决定因素，包括产前和青少年 作为发育时期出现的时期，在此期间酒精暴露尤其普遍。 酒精的神经免疫后果已成为可能促成变化的新机制 酒精强化、依赖性，并最终发展为与酒精相关的脑损伤。 重要的是，啮齿类动物接触急性、暴饮暴食剂量的乙醇 (EtOH) 会产生时间依赖性 细胞因子表达的变化，其中关键边缘结构中白细胞介素 6 (IL-6) 显着升高 （杏仁核、PVN 和海马）在急性乙醇中毒期间。相反，IL-1β和IL-1β的表达 当从急性乙醇暴露中撤出时，这些相同结构中的 TNFα 往往会激增。出奇， 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，与成年大鼠相比，青春期大鼠可能具有功能上不成熟的神经免疫反应 年轻人。然而，矛盾的是，青少年慢性间歇性乙醇（CIE）暴露使 晚年（P70 年轻人）暴饮暴食剂量的 EtOH 会引起与中毒相关的 IL-6 反应。因此， 青少年似乎对急性乙醇诱导的细胞因子反应不太敏感，但同时 容易受到青少年 CIE 引起的神经免疫过程的长期敏感化 接触。然而，观察到的这些急性乙醇诱导的细胞因子变化的功能意义 整个中毒-戒断周期仍然不清楚。该提案将利用情境恐惧调节 程序作为情绪学习的动物模型，并测试乙醇依赖性的功能相关性 细胞因子的表达。一致的研究结果表明，乙醇会损害训练时的恐惧条件反射 发生在 EtOH 暴露后的短时间内（即中毒期间），而调节期间 乙醇戒断往往会增强恐惧条件反射。因此，这里提出的研究将检验 乙醇对恐惧调节的阶段特异性影响。我们的中心假设是阶段特异性表达 基底外侧杏仁核 (BLA) 中的细胞因子对 BLA 兴奋性和随后的反应产生相反的作用 恐惧调节。这些研究还将检查神经免疫功能的长期适应和 青少年 CIE 后的后果。这样，所提出的研究将成为最先进行的研究之一。 检查阶段特异性、乙醇诱导的细胞因子表达如何转化为年龄特异性、认知和 早期乙醇暴露的行为结果。