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

描述(申请人提供)：这项拟议的研究将增加我们对酒精使一些人的攻击性行为升级的神经机制的理解，但对另一些人则不是。暴力爆发是酒精消费最昂贵、最可怕、最具破坏性的后果之一，是公共卫生和刑事司法系统面临的最重大问题之一。最重要的假设是评估不断升级的攻击行为，特别是在酒精影响下，是如何通过躯体树突状细胞自身受体的反馈，以及GABA和谷氨酸能影响，特别是通过来自前额叶皮质的反馈，以及CRF输入，是中缝细胞5-羟色胺能活动失调的一种功能。我们认为，前额叶皮质前额叶前部、边缘下部和眶腹侧的5-羟色胺能神经元反馈控制失调是饮酒后攻击行为升级的特征。具体地说，在小鼠和大鼠身上的实验旨在回答以下问题：(1)在从事不断升级的攻击行为的个体中，从中缝背核(DRN)到前额叶皮质(PFC)的5-羟色胺能投射活动是如何调节的？前额叶皮质5-羟色胺受体亚型的表达在多大程度上对不断升级的攻击行为至关重要？酒精强化攻击的动物前额叶皮质5-HT1和5-HT2受体家族的基因表达是否受到抑制？在高攻击性个体，特别是在饮酒后，PFC终末的突触前受体相对于躯体树突状细胞自身受体和SERT在控制5-羟色胺传递方面分别起着什么作用？(2)谷氨酸和GABA能对DRN中5-羟色胺细胞的影响对于表现出不断升级的攻击行为是关键的，特别是在酒精自我给药后？这些信号是否来自GABA能中间神经元？来自PFC的谷氨酸能反馈有多重要？GABA-A受体中的哪些亚单位是酒精增强攻击性的关键？在酒精自我给药后，NMDA谷氨酸受体亚型是否比AMPA受体更有选择性地调节升级的攻击行为？(3)在从事升级攻击行为的个体中，CRF对PFC的5-羟色胺能投射的调制有多关键？CRF-1和CRF-2受体亚型在酒精强化或减弱攻击行为中的各自作用能被定义吗？5-羟色胺能细胞上的CRF受体是酒精自我给药后攻击行为升级的关键群体吗？实验工作依赖于定量行为学方法来分析物种标准和不断升级的攻击形式、自愿酒精自我给药、实时聚合酶链式反应、原位杂交组织化学、遗传点突变、体内微透析和高效液相色谱，以及脑内微量注射。预期结果将确定治疗干预的目标。与公共健康相关：这项拟议研究的基本原理很容易转化为公共卫生和刑事司法系统最重要的问题之一，即理解为什么酒精会加剧一些人的攻击性行为，而不是另一些人。暴力行为的爆发是酒精消费最昂贵、最可怕、最具破坏性的后果之一。这项拟议的研究将评估不断升级的攻击性，特别是在酒精影响下，是如何通过GABA能、谷氨酸能和CRF调节反馈来调节中缝细胞5-羟色胺能活动的功能。

DESCRIPTION (provided by applicant): The proposed research will increase our understanding of the neural mechanisms via which alcohol escalates aggressive behavior in some individuals but not in others. Violent outbursts are one of the most costly, horrifying and damaging consequences of alcohol consumption, representing one of the most significant problems for the public health and criminal justice systems. The overarching hypothesis is to assess how escalated aggression, particularly under the influence of alcohol, is a function of dysregulation of serotonergic activity in the raphe cells by feedback via somatodendritic autoreceptors and by GABAergic and glutamatergic influences, especially by feedback from the prefrontal cortex, and by CRF input. We propose that the dysregulation of feedback control on serotonergic neurons projecting to prelimbic, infralimbic and orbitoventral regions of the prefrontal cortex characterizes those individuals who engage in escalated aggressive behavior after alcohol consumption. Specifically, experiments in mice and rats are designed to answer the following questions: (1) How is the activity of serotonergic projections from the dorsal raphe n (DRN) to the prefrontal cortex (PFC) regulated in individuals who engage in escalated aggressive behavior? To which extent is the expression of 5-HT receptor subtypes in the prefrontal cortex critical for escalated aggressive behavior? Is gene expression for the 5-HT1 and 5-HT2 receptor families in the prefrontal cortex suppressed in animals that engage in alcohol-heightened aggression? What is the respective role of presynaptic receptors in the PFC terminals relative to somatodendritic autoreceptors and SERT in gating serotonin transmission in highly aggressive individuals, particularly after alcohol consumption? (2) Are glutamatergic and GABAergic influences on the 5-HT cells in the DRN critical for the display of escalated aggressive behavior, particularly after alcohol self-administration? Do these signals originate from GABAergic interneurons? How significant is the glutamatergic feedback from the PFC? Which subunits in GABA-A receptors are essential for the aggression- heightening effects of alcohol? Are NMDA glutamate receptor subtypes more selective in their modulation of escalated aggression after alcohol self-administration than AMPA receptors? (3) How critical is the modulation by CRF of serotonergic projections to the PFC in individuals who engage in escalated aggressive behavior? Can the respective role of CRF 1 and 2 receptor subtypes be defined for the intensification or attenuation of alcohol-heightened aggressive behavior? Are the CRF receptors on serotonergic cells the critical population that is pivotal for escalated aggressive behavior after alcohol self-administration? The experimental work relies on quantitative ethological methodology for the analysis of species-normative and escalated forms of aggression, voluntary alcohol self-administration, real time PCR, in situ hybridization histochemistry, genetic point mutations, in vivo microdialysis and HPLC, and intracerebral microinfusions. The anticipated outcome will identify targets for therapeutic interventions. PUBLIC HEALTH RELEVANCE: The rationale for the proposed research is readily translated to one of the most significant problems for the public health and criminal justice system, namely to understand why alcohol escalates aggressive behavior in some individuals but not in others. Violent outbursts are one of the most costly, horrifying and destructive consequences of alcohol consumption. The proposed research will assess how escalated aggression, particularly under the influence of alcohol, is a function of dysregulation of serotonergic activity in the raphe cells by feedback via GABAergic, glutamatergic and CRF modulation.