Role of prefrontal cortical dopamine in aggression

前额叶皮质多巴胺在攻击行为中的作用 摘要 攻击性是一种复杂的社会行为，可能会给社会带来巨大的损失。尽管 机制仍然难以捉摸，前额叶皮质(PFC)表现出自上而下的对攻击性的抑制控制 行为。然而，一个根本的问题是，PFC中的神经元是如何控制攻击性的，而不是正常的 以及这些神经元是如何受多巴胺(DA)调节的，多巴胺是 情绪控制。发生这种情况的一种机制是激活具有不同DA的神经元 受体表达谱。最近的研究表明，D1R和D2R的表达是分离的 前额叶中的神经元。由于D2R拮抗剂在治疗攻击行为方面是有效的，我们预测 这些不同的D1R或D2R表达神经元可能具有不同的突触连接性 以及能够在社交和攻击性行为中执行不同规则的传入输入， 分别进行了分析。事实上，我们的初步数据表明，攻击性和正常的社交互动都会导致 在PFC中，c-fos的表达水平与非社会群体相比显著增加；但有趣的是， 发作次数显著增加D2R表达神经元的c-fos表达，而基础社会 相互作用明显增加PFC中D1R表达神经元的c-fos表达。基于这些 观察到，我们假设前额叶DA通过对D1R-和D1R-的不同影响来调节社会行为 PFC回路内表达D2R的神经元。具体地说，DA通过以下方式促进基础社交 激活D1R表达的神经元，但通过激活D2R表达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相结合来验证这一假设。在目标1中， 我们将确定含有D1R和D2R的PFC神经元在社交和攻击行为中的作用，以及 然后描述他们的神经元和突触属性，这些属性受到社会互动和 分别是攻击性。在目标2中，我们将确定是否通过药物遗传学操纵 PFC内表达D1R和D2R的细胞的功能能够促进社会互动或 控制攻击性行为。这项提议将决定PFC在攻击控制和 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 鉴于我们的目标是提供“社会神经回路”的因果证据，研究将填补文献中的空白。 含有前额叶D1R和D2R表达的神经元，在规则的社交互动和升级的攻击中。

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.