Behavioral Core

行为核心

• 批准号: 10613956
• 负责人: Elizabeth J Glover
• 金额: $ 21.59万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613956
• 关键词: Abstinence; Acute; Address; Affect; Alcohol consumption; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Animal Model; Anxiety; Attenuated; Automobile Driving; Behavior; Behavioral; Brain; Brain region; Chronic; Cognition; DNA Methylation; Data; Dependence; Development; Diet; Epigenetic Process; Ethanol; Experimental Designs; Funding; Future; Gene Expression; Genes; Glucocorticoid Receptor; Hippocampus; Histone Deacetylase Inhibitor; Hour; Intake; Link; Liquid substance; Measures; Medial; Mental Depression; Modification; Motivation; Negative Reinforcements; Neuroimmune; Neurons; Phenotype; Play; Prefrontal Cortex; Process; Production; Protein Isoforms; Rattus; Recovery; Research Personnel; Research Project Grants; Resources; Rodent; Role; Self Administration; Signal Transduction; Site; Standardization; Symptoms; Testing; Tissues; Treatment Factor; Validation; Ventral Tegmental Area; Vorinostat; Withdrawal; Withdrawal Symptom; Work; addiction; alcohol exposure; alcohol research; alcohol use disorder; brain tissue; cognitive control; drinking; drinking behavior; epigenetic regulation; experimental study; gamma-Aminobutyric Acid; genome analysis; histone deacetylase 2; histone modification; human model; maladaptive behavior; negative affect; neural circuit; neuroadaptation; neurotransmission; new therapeutic target; pre-clinical; receptor expression; relapse prevention; synaptic function; whole genome; willingness

PROJECT SUMMARY Acute withdrawal from chronic alcohol exposure is associated with a number of symptoms including neuronal hyperexcitability, heightened irritability, and a negative affective state. In addition, acute withdrawal is associated with escalated and uncontrolled alcohol consumption, which is thought to occur, at least in part, due to negative reinforcement as drinking alleviates withdrawal symptoms. The brain undergoes significant neuroadaptations during withdrawal from chronic alcohol exposure. These neuroadaptive processes are thought to play an important role in driving maladaptive behaviors including continued alcohol consumption. During the current funding period CARE investigators have uncovered a number of significant, epigenetically regulated changes in gene expression in the brains of rats withdrawn from chronic ethanol exposure. Interestingly, while some withdrawal-induced epigenetic modifications appear to be common throughout the brain, many are brain region- specific. CARE investigators have further demonstrated that reversal of some of these epigenetic alterations attenuates withdrawal symptoms including those associated with negative affect and altered neurotransmission. However, it is not yet known whether withdrawal-induced epigenetic dysregulation promotes escalated alcohol consumption. The proposed Behavioral Core will allow CARE investigators to address this gap by providing the resources necessary to link withdrawal-induced epigenetic changes with alterations in drinking behavior across all four Research Projects of the CARE. The Behavioral Core will provide CARE investigators with oversight of experimental design, implementation, and analysis of standardized behavioral experiments measuring operant ethanol self-administration in control and ethanol withdrawn rats following either systemic or region-specific reversal of withdrawal-induced epigenetic alterations. The Behavioral Core will also facilitate centralized production of brain tissue from control rats and rats withdrawn from chronic ethanol liquid diet for experiments conducted by the Epigenetics Core. The results generated by the Behavioral Core will allow CARE investigators to establish a causal link between epigenetic modifications and escalated alcohol consumption. Together with findings from each Research Project, these data will inform future work aimed at the development of novel drugs targeting epigenetic factors for the treatment of alcohol use disorders.

项目摘要 慢性酒精暴露的急性戒断与许多症状有关，包括神经元 过度兴奋、高度易怒和消极情感状态。此外，急性戒断与 随着酒精消费的升级和不受控制，这被认为是发生的，至少部分是由于消极的， 强化，因为饮酒会减轻戒断症状。大脑经历了重要的神经适应 从长期酒精暴露中戒断这些神经适应过程被认为是 在驱动适应不良行为中起重要作用，包括持续饮酒。于本 CARE研究人员发现了一些重要的，表观遗传调节的变化， 从慢性乙醇暴露中撤出的大鼠大脑中的基因表达。有趣的是，虽然一些 戒断诱导的表观遗传修饰似乎在整个大脑中很常见，许多是大脑区域- 特定. CARE的研究人员进一步证明，逆转这些表观遗传改变， 减轻戒断症状，包括那些与负面影响和改变神经传递有关的症状。 然而，目前还不清楚戒断诱导的表观遗传失调是否会促进酒精浓度的升高 消费拟议的行为核心将允许CARE调查人员通过提供 将戒断引起的表观遗传变化与饮酒行为的改变联系起来所需的资源 这四个研究项目的研究。行为核心将为CARE调查人员提供以下监督 标准化行为实验的实验设计、实施和分析 在全身或区域特异性给药后，对照和乙醇戒断大鼠中的乙醇自我给药 逆转戒断诱导的表观遗传学改变。行为核心还将促进集中化 从对照大鼠和从慢性乙醇液体饮食中取出的大鼠中制备脑组织用于实验 由表观遗传学中心进行行为核心产生的结果将允许CARE调查人员 建立表观遗传修饰和酒精消费量增加之间的因果关系。连同 每个研究项目的发现，这些数据将为未来的新药开发工作提供信息 针对表观遗传因素治疗酒精使用障碍。