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

描述（由申请人提供）：这项拟议的研究将增加我们对酒精使某些个体的攻击行为升级的神经机制的理解，而对另一些个体则没有。暴力爆发是酒精消费造成的最昂贵、最可怕和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。主要的假设是评估攻击性的升级，特别是在酒精的影响下，是如何通过躯体树突自身受体的反馈，gaba能和谷氨酸能的影响，特别是来自前额皮质的反馈，以及CRF输入来调节中颚细胞中血清素能活性失调的功能。我们认为，对投射到前额叶皮层前边缘、边缘下和眶腹区的血清素能神经元的反馈控制失调，是饮酒后攻击性行为升级的个体特征。具体来说，在小鼠和大鼠身上进行的实验旨在回答以下问题：(1)在参与升级攻击行为的个体中，从背中叶n （DRN）到前额叶皮质（PFC）的血清素能投射活动是如何调节的？前额皮质中5-羟色胺受体亚型的表达在多大程度上对升级的攻击行为至关重要？在酒精增强攻击行为的动物中，前额皮质5-HT1和5-HT2受体家族的基因表达是否受到抑制？相对于躯体树突自身受体和SERT， PFC末端突触前受体和SERT在高攻击性个体（尤其是饮酒后）控制血清素传递中的作用是什么？(2)谷氨酸能和氨基丁酸能对DRN中5-HT细胞的影响是否对攻击行为升级的表现至关重要，尤其是在酒精自我给药后？这些信号来自gaba能中间神经元吗？PFC的谷氨酸反馈有多重要？GABA-A受体中的哪些亚基对酒精的攻击性增强作用至关重要？与AMPA受体相比，NMDA谷氨酸受体亚型在酒精自我给药后升级攻击的调节中更具选择性吗？(3)在升级攻击行为个体中，CRF对5 -羟色胺能投射对PFC的调节有多重要？CRF 1和CRF 2受体亚型在酒精增强攻击行为的增强或减弱中各自的作用是否可以确定？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规范和升级形式的攻击，自愿酒精自我给药，实时PCR，原位杂交组织化学，基因点突变，体内微透析和HPLC，以及脑内微输注。预期结果将确定治疗干预的目标。公共卫生相关性：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使某些人的攻击行为升级，而对另一些人却没有。暴力爆发是酒精消费最昂贵、最可怕和最具破坏性的后果之一。拟议的研究将评估攻击性的升级，特别是在酒精的影响下，是如何通过gaba能、谷氨酸能和CRF调节的反馈来调节中颚细胞中血清素能活性失调的功能。

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.