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攻击性中的作用 摘要 攻击是一种复杂的社会行为，可能会对社会造成重大损失。虽然 尽管这种机制仍然难以捉摸，但前额叶皮层（PFC）表现出自上而下的对攻击性行为的抑制性控制， 行为。然而，一个基本的问题是，与正常人相比，PFC中的神经元如何控制攻击性 社会互动以及这些神经元如何受到多巴胺（DA）的调节，多巴胺是一种主要的神经递质， 情绪控制其中一种机制可能是激活具有差异DA的神经元 受体表达谱。最近的研究表明，D1 R和D2 R表达的分离 由于D2 R拮抗剂在治疗攻击性行为中是有效的，我们预测 这些不同的D1 R或D2 R表达神经元可能具有不同的突触连接性， 和传入输入，使社会和攻击行为的不同调节的执行， 分别事实上，我们的初步数据表明，攻击性和正常的社会交往都会引起 在PFC中与不合群组相比c-fos表达水平显著增加;但有趣的是， 发作显著增加了表达D2 R神经元中c-fos的表达，而基础社交神经元中c-fos的表达显著增加。 相互作用明显增加PFC中D1 R表达神经元中c-fos的表达。 观察，我们假设，前额叶DA调节社会行为，通过对D1 R-和 PFC电路中的D2 R表达神经元。具体来说，DA通过以下方式促进基础的社会互动： D1 R表达神经元的激活，但通过激活D2 R表达神经元触发攻击行为。 我们将使用依赖Cre的转基因小鼠结合药物遗传学来验证这一假设。在目标1中， 我们将确定含有D1 R和D2 R的PFC神经元在社交和攻击行为中的作用， 然后描述他们的神经元和突触特性，这些特性受到社会互动的不同影响， 侵略，分别。在目标2中，我们将确定药物遗传学操作是否 PFC内表达D1 R和D2 R的细胞的功能能够促进社会互动，或 控制攻击性行为该提案将确定PFC在攻击控制中的作用， 以细胞类型特异性方式剖析DA受体亚型对社会行为的特异性影响。我们 这项研究将弥补文献中的空白，因为我们的目标是提供“社会神经回路”的因果证据。 包含前额叶D1 R和D2 R表达神经元在定期的社会互动和升级的侵略。