Temperament, functional connectivity, and ethanol self-adminstration in monkeys

描述（由申请人提供）：美国的酒精消费分布不均匀，64%的成年人饮酒，但8%符合酒精滥用标准（Grant等人，2004年）。许多导致过量饮酒的风险因素已经被确定， 包括攻击性的气质，这可以在人类和非人类灵长类种群中进行研究。我的实验室的结果将攻击性气质表征为非人灵长类动物中重度乙醇（酒精-这些术语将在整个提案中互换使用）自我给药的预测因子，并发现基线时攻击性行为的程度与开放获取乙醇和水期间乙醇（4% w/v）的平均每日摄入量之间存在正线性关系。重要的是，在人类或非人类灵长类受试者中尚未确定攻击性气质的功能神经相关性，尽管已经确定了与人类攻击性有关的杏仁核和前额叶皮质区的网络。此外，目前还不清楚这个或其他网络中的非典型功能连接是否与未来的乙醇摄入量或慢性乙醇消费的变化有关。这些研究的目的是确定调节攻击性气质的功能性脑网络，以确定进展为重度饮酒的风险的体内神经相关性，并评估长期饮酒后气质和功能连接的变化。 因此，目标1将寻求通过评估攻击性和非攻击性猴子的杏仁核和前额叶皮质区之间的静息状态功能连接来识别攻击性气质的功能神经相关性。分析还将扩展到这个网络之外，以表征可能与攻击性气质相关的调节网络中模块化组织的差异。接下来，猴子将在12个月的时间内自我施用乙醇，并且将消耗3.0 g/kg/d或更多的那些猴子（重度饮酒者）与消耗少于3.0 g/kg/d的乙醇的猴子（非重度饮酒者）进行比较。目标2将评估目标1中确定的相同网络中功能连接的变化，以确定与攻击相关的相同非典型连接是否与大量饮酒相关。最后，目标3将评估在基线评估的相同猴子中长期摄入乙醇后目标1中确定的网络内的攻击行为和功能连接的变化。识别神经机制，有助于积极的气质和发展到大量饮酒是重要的，在进一步了解酗酒的出现和发展，并可能导致改善识别和治疗的风险个人。

DESCRIPTION (provided by applicant): Alcohol consumption in the United States is unevenly distributed, with 64% of adults consuming alcohol but 8% meeting criteria for alcohol abuse (Grant et al., 2004). Many risk factors leading to excessive alcohol drinking have been identified, including an aggressive temperament, which can be studied in both human and non-human primate populations. Results from my laboratory have characterized aggressive temperament as a predictor of heavy ethanol (alcohol - these terms will be used interchangeably throughout the proposal) self- administration in non-human primates, and have found a positive linear relationship between the extent of aggressive behavior at baseline and average daily intake of ethanol (4% w/v) during open access to concurrent ethanol and water. Importantly, the functional neural correlates of an aggressive temperament have not been identified in human or non-human primate subjects, although a network encompassing the amygdala and prefrontal cortical areas has been identified in relation to aggression in humans. Additionally, it is not known whether atypical functional connectivity within this or other networks associate with future ethanol intake or change with chronic ethanol consumption. The goal of these studies is to identify the functional brain network modulating an aggressive temperament, to determine in-vivo neural correlates of risk for progression to heavy drinking, and to assess changes in temperament and functional connectivity following chronic ethanol consumption. Thus, Aim 1 will seek to identify the functional neural correlates of an aggressive temperament by assessing resting state functional connectivity between the amygdala and prefrontal cortical areas in aggressive and non-aggressive monkeys. Analysis will also extend beyond this network to characterize differences in modular organization in regulatory networks that may be associated with aggressive temperament. Next, monkeys will self-administer ethanol over a 12 month period, and those monkeys consuming 3.0 g/kg/d or more (heavy drinkers) will be compared monkeys consuming less than 3.0 g/kg/d of ethanol (non-heavy drinkers). Aim 2 will assess changes in functional connectivity in the same networks identified in Aim 1, to determine whether the same atypical connectivity associated with aggression is associated with heavy drinking. Finally, Aim 3 will assess changes in aggressive behavior and functional connectivity within the networks identified in Aim 1 following chronic intake of ethanol in the same monkeys assessed at baseline. Identification of the neural mechanisms contributing to an aggressive temperament and progression to heavy drinking is important in furthering understanding of the emergence and progression of alcoholism, and could lead to improved identification and treatment of at-risk individuals.