Behavioral Neurobiology of Aggression, Alcohol, GABA, and 5-HT

项目摘要 酒精在至少一半的暴力袭击、家庭暴力和凶杀案中起着关键作用。 和谋杀然而，酒精与神经和行为过程之间的联系， 对暴力的了解仍然很少。这项研究计划的目的是描绘神经机制， 在某些人中，酒精会持续增强实施强烈攻击行为的动机， 个体这些目标是经验追求使用固定间隔（FI）的时间表的操作 回应，这将通过参与侵略性遭遇的机会来加强， 直接量化攻击性动机。在此，促肾上腺皮质激素释放因子（CRF）在 （1）从事攻击行为的动机，（2）攻击行为的表现 将进行定量和定性研究。通过隔离攻击动机， 我们将能够识别与随后的攻击性行为相关的潜在神经机制， 行为。最重要的假设是，升级的侵略，特别是当产生的， 反复暴露于酒精，是一个功能失调的CRF调制的神经回路，即 下丘脑-腹侧被盖区（VTA）和下丘脑-中缝背核（DRN）通路。 这些回路可能是通过多巴胺能和多巴胺能神经调节情绪处理的基础。 电子能系统，分别。在一个特定的个体子集中，我们预测， CRF神经元有助于酒精后寻求攻击机会的动机升级 消费在第一个目标中，我们计划充分描述酒精升级的持久性 攻击性动机作为酒精剂量的函数，并与酒精摄入后的持续时间有关 消费目的二将利用细胞和分子工具研究神经肽能神经元的可塑性 导致反复饮酒后攻击性动机持续升级的机制 摄入这项工作将揭示重叠、交叉或平行的通用报告格式机制的变化， 最终汇聚在多巴胺能和多巴胺能系统上， 处理.我们还将使用转基因技术来确定CRF表达的相对重要性。 下丘脑-VTA和下丘脑-DRN回路中的细胞群。拟议的实验 工作描绘了高度翻译和动物行为学有效的分析物种规范和升级 由酒精引起的攻击性预期治疗干预的新靶点 根据这些研究的结果。

Project Summary Alcohol plays a key role in at least half of all violent assaults, incidents of domestic violence, homicides and murders. However, the neural and behavioral processes underlying the link between alcohol and violence remain poorly understood. This research proposal aims to delineate the neural mechanisms by which alcohol persistently escalates the motivation to commit intense aggressive acts in some individuals. These aims are empirically pursued using a fixed interval (FI) schedule of operant responding which will be reinforced by the opportunity to engage in an aggressive encounter, allowing us to directly quantify aggressive motivation. Here, the role of corticotropin-releasing factor (CRF) in both (1) the motivation to engage in aggressive acts, and (2) the performance of aggressive behaviors will be quantitatively and qualitatively examined. By isolating the motivation to engage in aggression, we will be able to identify the underlying neural mechanisms that relate to subsequent aggressive behaviors. The overarching hypothesis is that escalated aggression, particularly when engendered by repeated exposures to alcohol, is a function of dysregulated CRF-modulated neurocircuits, namely the hypothalamus-ventral tegmental area (VTA) and hypothalamus-dorsal raphé nucleus (DRN) pathways. These circuits may be fundamental to the modulation of emotional processing via dopaminergic and serotonergic systems, respectively. In a specific subset of individuals, we predict that subpopulations of CRF neurons contribute to escalated motivation to seek out aggressive opportunities after alcohol consumption. In the first aim, we plan to fully characterize the enduring nature of alcohol-escalated aggressive motivation as a function of alcohol dose and as it relates to the duration since alcohol consumption. Aim two will use cellular and molecular tools to investigate plasticity in neuropeptidergic mechanisms that contribute to the persistent escalation of aggressive motivation after repeated alcohol intake. This work will reveal changes in overlapping, intersecting or parallel CRF mechanisms that ultimately converge on dopaminergic and serotonergic systems that are critical for emotional processing. We will also use transgenic technology to define the relative importance of CRF-expressing cell populations in hypothalamus-VTA and hypothalamus–DRN circuits. The proposed experimental work portrays highly translational and ethologically valid analyses of species-normative and escalated forms of aggression engendered by alcohol. Novel targets for therapeutic interventions are anticipated based on the results of these studies.