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: 8593204
• 负责人: FULTON T CREWS
• 金额: $ 21.57万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8593204
• 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; 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.

这个ARC提案检验了重复酒精狂欢（REB） 持续改变神经免疫信号，改变额叶皮质（FC）、杏仁核 （Amyg）、腹侧纹状体（VS，背侧核）和海马体（Hip），它们对神经元的功能起着重要的作用。 酒精依赖的精神病理学上一个供资周期的进展发现， 神经免疫信号被REB激活，改变与成瘾一致的行为。布里斯进步 关联的乙醇循环、应激源和/或脑内注射神经免疫激动剂到Amyg中， 社会互动，负面影响的指数。并联研究人员发现REB诱导神经免疫 通过胶质细胞NF κ B转录趋化因子、细胞因子、toll样受体（TLR）和TLR HMGB 1激动剂，可持续长期戒断，并促进神经退行性变和逆转 学习认知缺陷死后神经免疫蛋白的表达也有所增加 人类酗酒大脑这些实验室在此更新组件中合作。REB诱导的变化 使用cfos和Zif 268标记物的神经元活化（Aim 1）将与神经免疫应答的增加相关。 REB后禁欲期间FC、Amyg、VS和Hip内的信号（Aim 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导的觉醒相关。 光遗传学将研究FC电路的变化。纳洛酮、米诺环素和基因敲除小鼠将测试 神经免疫诱导和改变的神经元激活之间的因果关系（目的3），以及 成瘾相关行为（目标4）。这些实验将增强对分子和 酒精诱发脑病理的细胞机制。乙醇诱导的神经免疫激活可以 成为成瘾神经生物学的核心，并转化为新的治疗方法。弧变宽， 加强了拟议的实验，增加了对狂欢引起的改变的相关研究， 神经回路，成瘾样行为和信号机制。