Developmental Origins of Aggressive and Impulsive Behavior

项目摘要。隔-下丘脑神经元活动中枢调节攻击行为，而 单胺类神经递质多巴胺和5-羟色胺的调节作用很强，而且大多是相反的。 然而，相关的电路机制和个体发育在很大程度上是未知的。在赛道上取得进展 机制，我们在小鼠身上发现，从腹侧被盖区到外侧隔的多巴胺输入是 足以促进攻击性，也是建立基线攻击性所必需的。在侧向内 在隔区，多巴胺作用于D2受体，以抑制投射到下丘脑的GABA神经元。这些 研究结果有效地将临床上相关的高多巴胺攻击模型与经典的隔膜- 下丘脑侵袭轴。随着个体发育的进展，我们发现了一种敏感的发育 在青春期，多巴胺转运体的阻断会永久性地增加成人的攻击性， 冲动和行为刺激反应，同时导致多巴胺系统过度活跃。 相反，阻断青春期5-羟色胺转运体可以减少攻击性和行为刺激性 成年期的反应，并同时导致多巴胺系统活性低下。在这里，我们将继续这条线 研究和研究发育DA和5-羟色胺信号调节DA输入的总体假说 进入LS和NAC，以影响成年后与攻击相关的行为。在目标1中，我们调查 伏隔核多巴胺输入在攻击相关行为中的因果作用。攻击性是 在行为上归类为反应性攻击，对感知到的外部威胁做出冲动反应 以及主动的攻击性，这种攻击性是有预谋的，直接受到欲望奖励的驱使。我们 假设伏隔核的输入有助于主动攻击的食欲价值。在目标2中， 我们检验了这样的假设，即外侧隔区的D2受体与性别二型性差异有关。 攻击性行为。我们已经发现D2受体介导了多巴胺促进的雄性小鼠的攻击行为 以及D2受体表达的性别二型性。此外，进入外侧隔的多巴胺是 不足以引发雌性动物的攻击性。在目标3中，我们研究了5-羟色胺输入到脑内的因果作用。 攻击相关行为中的外侧隔核和伏隔核。最后，在目标4中，我们调查是否 对LS和NAC的永久性改变的DA能输入在多巴胺和NAC之后驱动攻击表型 5-羟色胺转运体在发育过程中通过监测发育过程中特定途径的多巴胺能活动而被阻断 行为，配合光基因拯救实验。通过将电路映射到敏感上下文中的行为 发育期干预，我们将推进我们对正常大脑和受损大脑的理解 发展和功能。这些信息将影响对人类适应不良风险因素的理解 攻击性和多巴胺功能障碍。通过新的机械论和翻译洞察力，我们试图告知 开展临床和流行病学研究，改进精神病学的诊断、预防和治疗策略。

Project Summary. Septal-hypothalamic neuronal activity centrally mediates aggressive behavior, while the monoamine neurotransmitters dopamine and serotonin play strong and mostly opposing modulatory roles. However, related circuit mechanisms and ontogeny are largely unknown. Making progress towards circuit mechanism, we found in mice that dopamine input from the ventral tegmental area to the lateral septum is sufficient for promoting aggression and necessary for establishing baseline aggression. Within the lateral septum, dopamine acts on D2 receptors to inhibit GABA neurons that project to the hypothalamus. These findings effectively link the clinically pertinent hyper-dopamine model of aggression with the classic septal- hypothalamic aggression axis. Making progress towards ontogeny, we identified a sensitive developmental window during adolescence where dopamine transporter blockade permanently increases adult aggression, impulsivity, and behavioral stimulant response, and in parallel leads to a hyperactive dopamine system. Conversely, periadolescent serotonin transporter blockade reduces aggression and behavioral stimulant response in adulthood, and in parallel leads to a hypoactive dopamine system. Here we will continue this line of research and study the overarching hypothesis that developmental DA and 5-HT signaling tunes DA input into the LS and NAc to impact aggression-related behaviors in adulthood. In Aim 1, we investigate the causal role of dopamine input into the nucleus accumbens in aggression-related behavior. Aggression is behaviorally classified into reactive aggression which occurs impulsively in response to perceived external threat and proactive aggression that is premeditated and directly motivated by a drive for appetitive reward. We hypothesize that nucleus accumbens input contributes to the appetitive value in proactive aggression. In Aim 2, we test the hypothesis that D2 receptors of the lateral septum contribute to sexual dimorphic differences in aggressive behavior. We already found D2 receptors mediate dopamine-promoted aggression in male mice as well as sexual dimorphism for D2 receptor expression. Furthermore, dopamine input into the lateral septum is not sufficient to trigger aggression in females. In Aim 3, we investigate the causal role of serotonin input into the lateral septum and nucleus accumbens in aggression-related behavior. Finally, in Aim 4, we investigate if permanently altered DAergic input into the LS and NAc drives the aggression phenotypes after dopamine and serotonin transporter blockade during development, by monitoring pathway-specific dopaminergic activity during behavior, paired with optogenetic rescue experiments. By mapping circuits to behavior in the context of sensitive developmental period interference, we will advance our understanding of normal as well as disrupted brain development and function. Such information will impact the understanding of human risk factors for maladaptive aggression and dopamine dysfunction. With the novel mechanistic and translational insight, we seek to inform clinical and epidemiological studies and improve diagnosis, prevention and treatment strategies for in psychiatry.