Developmental Origins of Aggressive and Impulsive Behavior

项目摘要。隔-下丘脑神经元活动中枢介导攻击行为，而 单胺神经递质多巴胺和5-羟色胺起着强烈的且大多相反的调节作用。 然而，相关的电路机制和个体发育在很大程度上是未知的。向巡回赛迈进 机制，我们发现，在小鼠中，多巴胺输入从腹侧被盖区到外侧隔是 足以促进侵略和必要的建立基线侵略。在横向内 隔，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相关的高多巴胺攻击模型与经典的间隔- 下丘脑攻击轴在个体发育方面取得了进展，我们发现了一个敏感的发育 在青春期，多巴胺转运蛋白阻断永久性地增加了成年人的攻击性， 冲动，和行为刺激反应，并在平行导致一个过度活跃的多巴胺系统。 相反，青少年期的5-羟色胺转运体阻滞会降低攻击性和行为刺激性。 反应在成年期，并在平行导致一个功能减退的多巴胺系统。在这里，我们将继续这条线， 研究和研究发育DA和5-HT信号调节DA输入的总体假设 进入LS和NAc以影响成年期的攻击相关行为。在目标1中，我们研究了 多巴胺输入丘脑核在攻击相关行为中的因果作用。侵略是 在行为上被归类为反应性攻击，这种攻击是对感知到的外部威胁的冲动反应 以及有预谋的主动攻击，直接受到欲望奖励的驱使。我们 假设前摄性攻击中丘脑核的输入对食欲值有影响。在目标2中， 我们检验了外侧隔的D2受体对性二形性差异有贡献的假设， 攻击性行为我们已经发现D2受体介导多巴胺促进的雄性小鼠的攻击性， 以及D2受体表达的性别二型性。此外，多巴胺输入到外侧隔， 不足以引发女性的攻击性在目标3中，我们研究了5-羟色胺输入的因果作用， 外侧隔和丘脑外侧核在攻击相关行为中的作用。最后，在目标4中，我们研究，如果 永久改变的DA能输入到LS和NAc驱动多巴胺后的攻击表型， 通过监测发育过程中的途径特异性多巴胺能活性， 行为，与光遗传学拯救实验配对。通过将电路映射到敏感环境中的行为， 发育期的干扰，我们将推进我们对正常和中断的大脑的理解 发展和功能。这些信息将影响对适应不良的人类风险因素的理解 攻击性和多巴胺功能障碍随着新的机械和翻译的见解，我们寻求告知 临床和流行病学研究，并改善精神病学中的诊断、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.