Research Component 1 - Neuroimmune Signaling in Networks Underlying Chronic Etha

研究部分 1 - 慢性 Etha 网络中的神经免疫信号传导

• 批准号: 8776232
• 负责人: FULTON T CREWS
• 金额: $ 22.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776232
• 关键词: Abstinence; Affect; Affective; Agonist; Alcohol dependence; Alcoholism; Alcohols; Amygdaloid structure; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Anxiety; Arousal; Behavior; Behavioral; Brain; Brain Pathology; Brain region; CCL2 gene; Cell Nucleus; Chronic; Cognition; Cognitive; Cognitive deficits; Dose; Drug Addiction; Drug usage; Ethanol; FOS gene; Funding; Gene Expression; Genes; Genetic Transcription; Glutamates; HMGB1 gene; Hippocampus (Brain); Human; Injection of therapeutic agent; Knockout Mice; Lead; Light; Link; Minocycline; Molecular; Mus; NF-kappa B; Naltrexone; Nerve Degeneration; Neurobiology; Neurons; Nucleus Accumbens; Pathogenesis; Pharmaceutical Preparations; Proteins; Psychopathology; Research; Reversal Learning; Signal Transduction; Social Interaction; Stimulus; System; TLR4 gene; Testing; Toll-like receptors; Translating; Ventral Striatum; Western Blotting; addiction; anxiety-like behavior; base; chemokine; cytokine; frontal lobe; gene induction; immunoreactivity; indexing; novel; optogenetics; problem drinker; protein expression; receptor; relating to nervous system; research study; stressor; transmission process

This ARC proposal tests the hypothesis that repeated ethanol binges (REB) persistently change neuroimmune signaling that alters neuronal activation in frontal cortical (FC), amygdala (Amyg), ventral striatum (VS, nucleus accumbens) and hippocampus (Hip) that contributes to the psychopathology of alcohol dependence. Progress in the previous funding cycle discovered that neuroimmune signals are activated by REB altering behavior consistent with addiction. Breese progress linked ethanol cycles, stressors and/or brain injection of neuroimmune agonists into Amyg with decreased social interaction, an index of negative affect. In parallel. Crews discovered REB induces neuroimmune genes through glial NFKB transcription of chemokines, cytokines, toll-like receptors (TLR) and the TLR agonist HMGB1 that persist for long periods of abstinence and contribute to neurodegeneratlon and reversal learning cognitive deficits. Increased neuroimmune protein expression was also discovered in post-mortem human alcoholic brain. These labs partner within this renewal component. REB induced changes in neuronal activation using cfos and Zif268 markers (Aim 1) will be related to increases in neuroimmune signals (Aim 2) within FC, Amyg, VS and Hip during abstinenece following REB. These brain regions are networked and associated with the persistent alcohol induced arousal that occurs in alcohol dependence. Optogenetics will investigate changes in FC circuits. Naltrexone, minocycline and knock out mice will test causal relationships between neuroimmune induction and altered neuronal activation (Aim 3) as well as addiction related behaviors (Aim 4). These experiments will enhance understanding of the molecular and cellular mechanisms of alcohol induced brain pathology. Ethanol induced neuroimmune activation could become central to the neurobiology of addiction and translate to new treatments. The ARC broadens and strengthens the proposed experiments with additional related studies on binge induced alterations in neurocircuits, addiction-like behaviors and signaling mechanisms.

该 ARC 提案测试了反复酗酒 (REB) 的假设 持续改变神经免疫信号，改变额叶皮质 (FC)、杏仁核的神经元激活 (Amyg)、腹侧纹状体 (VS，伏隔核) 和海马体 (Hip) 有助于 酒精依赖的精神病理学。上一个融资周期的进展发现 REB 激活神经免疫信号，改变与成瘾一致的行为。布里斯的进步 将乙醇循环、应激源和/或向 Amyg 中脑部注射神经免疫激动剂与减少 社会互动，负面影响的指标。并联。克鲁斯发现 REB 会诱导神经免疫 通过神经胶质 NFKB 转录趋化因子、细胞因子、Toll 样受体 (TLR) 和 TLR 来调节基因 激动剂 HMGB1，可长期禁欲并有助于神经退行性变和逆转 学习认知缺陷。尸检中还发现神经免疫蛋白表达增加 人类酒精大脑。这些实验室在这个更新组件中进行合作。 REB 引起的变化 使用 cfos 和 Zif268 标记物的神经元激活（目标 1）将与神经免疫的增加相关 REB 后禁欲期间 FC、Amyg、VS 和 Hip 内的信号（目标 2）。这些大脑区域是 网络化并与酒精依赖中发生的持续酒精诱发的唤醒有关。 光遗传学将研究 FC 电路的变化。纳曲酮、米诺环素和基因敲除小鼠将进行测试 神经免疫诱导与神经元激活改变之间的因果关系（目标 3）以及 成瘾相关行为（目标 4）。这些实验将增强对分子和 酒精引起的脑病理学的细胞机制。乙醇诱导的神经免疫激活可能 成为成瘾神经生物学的核心，并转化为新的治疗方法。 ARC 扩大并 加强了拟议的实验，并进行了关于暴饮暴食引起的改变的额外相关研究 神经回路、成瘾样行为和信号机制。