5/8 NADIA U01 Adolescent Alcohol and Adult Brian Dysfunction

5/8 NADIA U01 青少年酒精和成人布莱恩功能障碍

基本信息

批准号：
9133244
负责人：
FULTON T CREWS
金额：
$ 50.26万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9133244
关键词：
Acetylcholine Address Adolescence Adolescent Adult Agonist Alcohol abuse Anti-Inflammatory Agents Anti-inflammatory BDNF gene Behavioral Biological Neural Networks Brain Brain-Derived Neurotrophic Factor CCL2 gene Choline O-Acetyltransferase Cholinesterase Inhibitors Cognition Collaborations Data Development Enzyme-Linked Immunosorbent Assay Enzymes Ethanol Exercise Female Female Adolescents Functional Magnetic Resonance Imaging Functional disorder Gene Expression Genes Glycyrrhizic Acid HMGB1 gene Health Heavy Drinking Hippocampus (Brain)Human Immune Immunohistochemistry Indomethacin Inflammatory Lead Learning Link Lipopolysaccharides Longitudinal Studies Measures Messenger RNA Modeling Neurons PTGS2 gene Pathology Patients Primates Prosencephalon Proteins Rattus Research Rest Reversal Learning Reverse Transcriptase Polymerase Chain Reaction Running Signal Transduction TLR4 gene Testing Time Western Blotting Wistar Rats adolescent alcohol adolescent alcohol exposure adolescent binge drinking adult neurogenesis alcohol effect alcohol response alcohol sensitivity basal forebrain binge drinking cholinergic cholinergic neuron cognitive testing density designer receptors exclusively activated by designer drugs drinking flexibility gene induction male morris water maze neurogenesis neuropathology problem drinker receptor relating to nervous system resilience response sex underage drinking

项目摘要

DESCRIPTION (provided by applicant): Alcohol abuse is common in adolescence, a time of marked neurocircuitry development. Recently, we discovered that NADIA adolescent intermittent ethanol (AIE) treatment of rats increased frontal cortical neuroimmune molecules, blunted frontal cortical cFos responses to ethanol, reduced hippocampal neurogenesis, reduced choline acetyltransferase (ChAT, the enzyme synthesizing acetylcholine), and caused deficits in reversal learning in adulthood. Reduced hippocampal neurogenesis and ChAT are unique to AIE and did not occur after similar ethanol treatment in adulthood. In an important parallel with human studies, we found increased expression of neuroimmune genes and reduced expression of ChAT and other cholinergic neuron markers in the post-mortem brains of alcoholic patients. This is consistent with adolescent alcohol exposure contributing to adult alcoholic neuropathology. This proposal will test multiple hypotheses: 1) that inhibiting AIE-induced neuroimmune signaling will protect against loss of adult neurogenesis and ChAT+ neurons, and reduce reversal learning deficits. 2) That reduced cholinergic signaling contributes to AIE-induced adult neuroimmune gene induction, reduced neurogenesis, reduced adult prefrontal cortical neuronal responses to ethanol, and reversal learning deficits. As well as investigating adolescent rat brain connectivity using resting-state functional Magnetic Resonance Imaging (rsfMRI) for direct comparisons to human studies testing hypothesis 3, i.e. that adolescent alcohol exposure alters neural connectivity in the adult brain through persistent increases in neuroimmune signaling and deficits in ChAT. It is expected that AIE will alter adult functional connectivity through pro-inflammatory gene induction and decreased cholinergic signaling. These studies will link key signaling mechanisms to AIE-induced adult neuropathology and lead to therapies.

描述（适用提供）：在青少年中，酗酒很常见，这是神经循环发展的时代。 Recently, we discovered that NADIA adolescent intermittent ethanol (AIE) treatment of rats increased frontal cortical neuroimmune molecules, blunted frontal cortical cFos responses to ethanol, reduced hippocampal neurogenesis, reduced choline acetyltransferase (ChAT, the enzyme synthesizing acetylcholine), and caused Deficiencies in reverse learning in成年。降低的海马神经发生和聊天是AIE独有的，在成年后类似的乙醇治疗后也没有发生。在与人类研究的重要相似之处中，我们发现在酒精患者后大脑中，神经免疫基因的表达增加，聊天和其他胆碱能神经元标记的表达降低。这与青少年酒精暴露促成成年是一致的。酒精神经病理学。该建议将检验多个假设：1）抑制AIE诱导的神经免疫信号传导将防止成人神经发生和聊天+神经元的丧失，并减少逆转学习缺陷。 2）减少胆碱能信号传导有助于AIE诱导的成年神经免疫性基因诱导，降低神经发生，减少成年前额叶前皮质神经元对乙醇的反应，并定义了逆转学习。以及使用静止状态功能性磁共振成像（RSFMRI）与人类研究测试假设3的直接比较的静息状态功能磁共振成像（RSFMRI）进行研究，即，青少年酒精暴露暴露在成年大脑中的神经元连通性通过神经免疫信号的持久增加改变了成人脑中的神经元连接性，并在聊天中定义了。预计AIE将通过促炎基因诱导和改善的胆碱能信号来改变成人功能连通性。这些研究将将关键信号机制与AIE诱导的成年神经病理学联系起来，并导致疗法。