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

描述（由申请人提供）：拟议的研究将增加我们对神经机制的理解，酒精通过该机制在某些个体中升级攻击行为，而在其他个体中则不会。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严重问题之一。首要的假设是评估如何升级的侵略，特别是在酒精的影响下，是一个功能失调的中缝细胞中的多巴胺能活性的反馈通过体树突状细胞的自受体和GABA能和多巴胺能的影响，特别是通过反馈从前额叶皮层，并通过CRF输入。我们认为，投射到前额皮质的前边缘系统、边缘下系统和眶腹侧区域的多巴胺能神经元的反馈控制失调是饮酒后攻击行为升级的特征。具体而言，在小鼠和大鼠中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，从中缝背核（DRN）到前额叶皮层（PFC）的多巴胺能投射的活动是如何调节的？前额叶皮质5-HT受体亚型的表达在多大程度上对攻击行为升级至关重要？在酒精刺激的攻击性动物中，前额叶皮层中5-HT 1和5-HT 2受体家族的基因表达是否受到抑制？在高攻击性个体中，尤其是在饮酒后，PFC末梢的突触前受体相对于体树突自受体和SERT在控制5-羟色胺传递中的作用是什么？(2)多巴胺能和γ-氨基丁酸能对DRN中5-HT细胞的影响是否是升级攻击行为的关键，特别是在自我饮酒后？这些信号来源于GABA能中间神经元吗？来自前额叶皮层的听觉反馈有多重要？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？NMDA谷氨酸受体亚型在酒精自我给药后对攻击升级的调节中比AMPA受体更具选择性吗？(3)在攻击行为升级的个体中，CRF对PFC的多巴胺能投射的调节有多重要？CRF 1和2受体亚型各自的作用是否可以被定义为增强或减弱酒精增强的攻击行为？酒精能细胞上的CRF受体是酒精自我给药后攻击行为升级的关键人群吗？实验工作依赖于定量行为学方法分析物种规范和升级形式的侵略，自愿酒精自我管理，真实的时间PCR，原位杂交组织化学，遗传点突变，在体内微透析和HPLC，和脑内微量输注。预期的结果将确定治疗干预的目标。公共卫生相关性：这项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某些人的攻击性行为，而不是其他人。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。拟议的研究将评估如何升级的侵略，特别是在酒精的影响下，是一个功能失调的多巴胺能活性在中缝细胞的反馈通过GABA能，多巴胺能和CRF调制。

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.