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、家庭暴力事件、杀人案中起着关键作用 还有谋杀案。然而，酒精和酒精之间联系的神经和行为过程 人们对暴力仍然知之甚少。这项研究计划旨在通过以下方式描述神经机制 在某些情况下，酒精会持续增强实施强烈攻击性行为的动机 个人。这些目标是使用固定间隔(FI)的操作员时间表来经验地实现的 这种反应将因有机会参与一场咄咄逼人的比赛而得到加强，允许 让我们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)从事攻击性行为的动机；(2)攻击性行为的表现 将进行定量和定性的检查。通过隔离参与攻击的动机， 我们将能够确定与后续攻击有关的潜在神经机制 行为。最重要的假设是，升级的攻击性，特别是当产生 反复接触酒精是CRF调节的神经回路失调的一种功能，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 分别为5-羟色胺能系统。在特定的个体子集中，我们预测 CRF神经元促进酒精后寻找攻击性机会的动机升级 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质 攻击性动机与饮酒剂量和饮酒时间的关系 消费。目标二将使用细胞和分子工具来研究神经肽能的可塑性 导致反复饮酒后攻击性动机持续升级的机制 入口处。这项工作将揭示重叠、交叉或并行的CRF机制的变化 最终汇聚到对情绪至关重要的多巴胺和5-羟色胺能系统 正在处理。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环路的细胞群。拟议中的实验 作品描述了对物种的高度翻译和行为学上的有效分析--规范的和升级的 由酒精引起的各种形式的攻击。治疗干预的新靶点被期待 基于这些研究的结果。

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.