Role of prefrontal cortical dopamine in aggression

前额皮质多巴胺在攻击行为中的作用

• 批准号: 9281915
• 负责人: Wen-Jun Gao
• 金额: $ 19.31万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9281915
• 关键词: Affect; Aggressive behavior; Alpha Cell; Animals; Behavior; Behavioral Mechanisms; Brain; Cells; Charge; Clozapine; Complex; Corpus striatum structure; DRD2 gene; Data; Decision Making; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Emotional; Emotions; Ensure; Exhibits; FOS gene; Goals; Haloperidol; Home environment; Immediate-Early Genes; Individual; Label; Ligands; Literature; Molecular Profiling; Mus; Neurons; Neurotransmitters; Oxides; Pharmacogenetics; Pilot Projects; Play; Prefrontal Cortex; Property; Regulation; Reporting; Rodent; Role; Social Behavior; Social Interaction; Societies; Synapses; Tamoxifen; Testing; Thinking; Time; Transgenic Mice; Ventral Tegmental Area; base; behavioral response; cell type; designer receptors exclusively activated by designer drugs; dopaminergic neuron; male; nerve supply; neural circuit; novel; optogenetics; recombinase; response; segregation; social

Role of prefrontal cortical dopamine in aggression Abstract Aggression is a complex social behavior that may impose a significant toll on society. Although the mechanisms remain elusive, the prefrontal cortex (PFC) exhibits top-down inhibitory control of aggressive behaviors. However, a fundamental question is how neurons in the PFC control aggression versus normal social interaction and how these neurons are regulated by dopamine (DA), a major neurotransmitter for emotional control. One mechanism through which this may occur is activation of neurons with differential DA receptor expression profiles. Recent studies have demonstrated a segregation of D1R- and D2R-expressing neurons in the PFC. Since D2R antagonists are effective in the treatment of aggressive behaviors, we predict that these divergent D1R- or D2R-expressing neurons are likely endowed with different synaptic connectivity and afferent inputs to enable the execution of distinct regulation in social and aggressive behaviors, respectively. Indeed, our preliminary data indicate that both aggression and normal social interaction induced significant increases in levels of c-fos expression compared with asocial groups in the PFC; but interestingly, episodes of attack significantly increased c-fos expression in D2R-expressing neurons, whereas basal social interaction clearly increased c-fos expression in D1R-expressing neurons in the PFC. Based on these observations, we hypothesize that prefrontal DA regulates social behaviors via differential effects on D1R- and D2R-expressing neurons within PFC circuitry. Specifically, DA promotes basal social interaction through activation of D1R-expressing neurons, but triggers aggressive behavior by activating D2R-expressing neurons. We will use Cre-dependent transgenic mice combined with pharmacogenetics to test this hypothesis. In Aim 1, we will identify the roles of D1R- and D2R-containing PFC neurons in social and aggressive behaviors, and then characterize their neuronal and synaptic properties that are differentially affected by social interaction and aggression, respectively. In Aim 2, we will determine whether pharmacogenetically manipulating the functionality of D1R- and D2R-expressing cells within the PFC is capable of promoting social interaction or controlling aggressive behavior. This proposal will determine the role of the PFC in aggression control and dissect the specific effects of DA receptor subtypes on social behaviors in a cell-type specific manner. Our study will bridge a gap in the literature given that we aim to offer causative evidence of the “social neural circuit” containing prefrontal D1R- and D2R-expressing neurons in regular social interaction and escalated aggression.

前额叶皮质多巴胺在侵略性中的作用 抽象的 侵略是一种复杂的社会行为，可能会对社会造成重大损失。虽然 机制仍然难以捉摸，前额叶皮层（PFC）表现出对侵略性的自上而下的抑制作用 行为。但是，一个基本问题是PFC控制中的神经元如何侵略性与正常 社交互动以及这些神经元如何受到多巴胺（DA）的调节，这是一种主要的神经递质 情绪控制。可能发生的一种机制是激活具有差异DA的神经元 受体表达谱。最近的研究表明，表达D1R和D2R的分离 PFC中的神经元。由于D2R拮抗剂可以有效地治疗攻击行为，因此我们预测 这些发散的D1R-或D2R表达神经元可能具有不同的突触连通性 和传入的输入，以使社会和侵略行为中的独特监管执行， 确实，我们的初步数据表明既激进和正常的社会互动都引起了 与PFC中的美学基团相比，C-FOS表达水平显着增加；但有趣的是， 攻击发作显着增加了表达D2R的神经元中的C-FOS表达，而基本的社会 相互作用清楚地增加了PFC中表达D1R的神经元中的C-FOS表达。基于这些 观察结果，我们假设前额叶通过对D1R和D1R-和 PFC电路中表达D2R的神经元。特别是，DA通过 激活D1R表达神经元，但通过激活表达D2R的神经元触发攻击行为。 我们将使用依赖CRE的转基因小鼠与药物遗传学结合来检验该假设。在AIM 1中， 我们将确定含D1R和D2R的PFC神经元在社会和侵略性行为中的作用，以及 然后表征其神经元和突触特性，这些特性受社会互动以及 分别具有侵略性。在AIM 2中，我们将确定药物遗传学是否操纵 PFC中D1R-和D2R表达细胞的功能能够促进社交相互作用或 控制攻击行为。该提案将确定PFC在侵略性控制中的作用和 以细胞类型的特定方式剖析DA受体亚型对社会行为的特定影响。我们的 鉴于我们旨在提供“社会神经循环”的严重证据，研究将弥合文献中的差距 在常规社交互动中包含前额叶D1R和D2R表达神经元，并升级了侵略性。