Neural Mechanisms in the Medial Amygdala Underlying Aggression

项目摘要/摘要 攻击性和暴力是许多精神障碍的常见症状，但导致它们表达的潜在机制在很大程度上仍不清楚。杏仁核是参与情绪调节的关键区域，并被认为是精神病理的主要场所。杏仁内侧核(MEA)是杏仁核的一个主要分支，是攻击和暴力的重要调节器。先前的研究表明，对大脑中枢神经元的高频刺激可以在未来的社交活动中增强攻击性，从而产生一种被称为攻击性启动的现象。然而，杏仁内侧核调节攻击的确切机制及其在精神疾病中的作用还需要进一步阐明。这项Prat奖学金提案的目标是定义MEA在侵略中的作用。我的初步结果表明，mea内的谷氨酸能神经元对刺激的反应是频率相关的，并且mea可以在社交互动测试中调节攻击性和暴力的表达。我的中心假设是，大脑中脑中央谷氨酸能突触的增强可以激发攻击性，导致社交互动中攻击性和暴力的增加。首先，我计划确定在社会互动测试中，使用光遗传学的高频光刺激(HFPS)是否可以诱导攻击性启动。我将使用活体电生理学测试HFPS是否在MEA诱导突触增强，以及突触增强是否通过使用低频光刺激消除HFPS后突触的攻击行为负责，低频光刺激是一种已知的诱导突触活性抑制的方案。其次，我将利用光遗传学通过刺激中缝背侧投射来确定5-羟色胺在Mea调节攻击中的作用。中缝背侧投射是5-羟色胺能神经元的主要部位。最后，我将通过对体内5-羟色胺释放机制的遗传修改和专门设计的传感器来检测5-羟色胺在MeA上的结合，从而确认5-羟色胺在MeA调节攻击中的作用。这项提案的成功完成将产生积极的翻译影响，因为根据拟议研究的结果，有可能开发针对MEA的预防性治疗战略，以遏制与精神障碍相关的过度攻击和暴力。

PROJECT SUMMARY/ABSTRACT Aggression and violence are common symptoms of many psychiatric disorders, but the underlying mechanisms that lead to their expression remain largely unknown. The amygdala is a key region involved in the regulation of emotion and has been implicated as a primary locus of psychopathology. The medial amygdala (MeA) is a major subdivision of the amygdala and is an important modulator of aggression and violence. Previous studies have shown that high-frequency stimulation of neurons at the MeA can enhance aggression during future social encounters, producing a phenomenon called aggression priming. The precise mechanism by which the medial amygdala mediates aggression and its role in psychiatric illness, however, requires further elucidation. The goal of this PRAT fellowship proposal is to define the role of the MeA in aggression. My preliminary results show that glutamatergic neurons within the MeA respond to stimulation in a frequency-dependent manner and that the MeA can regulate expressions of aggression and violence during a social interaction test. My central hypothesis is that potentiation of glutamatergic synapses at the MeA can prime aggression, leading to an increase in aggression and violence during social interaction. Firstly, I plan to determine whether high-frequency photostimulation (HFPS) using optogenetics can induce aggression priming during a social interaction test. I will test whether HFPS induces synaptic potentiation at the MeA using in vivo electrophysiology and whether synaptic potentiation is responsible for aggressive behavior by depotentiating synapses after HFPS using low-frequency photostimulation, a known protocol for inducing depression of synaptic activity. Secondly I will determine the role of serotonin in MeA regulated aggression by stimulating dorsal raphe projections, a primary locus of serotonergic neurons, at the MeA using optogenetics. Finally I will confirm the role of serotonin in MeA regulated aggression using genetic modifications to the serotonin releasing machinery in vivo and specialized sensors designed to detect serotonin binding at the MeA. The successful completion of this proposal will have a positive translational impact because preventative therapeutic strategies targeting the MeA can potentially be developed to curb excessive aggression and violence associated with psychiatric disorders based on the findings of the proposed research.