Developmental Origins of Aggressive and Impulsive Behavior

攻击性和冲动行为的发展起源

• 批准号: 10639422
• 负责人: Mark Sascha Ansorge
• 金额: $ 77.81万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639422
• 关键词: Adolescence; Adult; Aggressive behavior; Behavior; Behavioral; Brain; Classification; Clinical; Clinical Research; Coupled; DRD2 gene; Data; Desire for food; Development; Diagnosis; Dopamine; Dopamine D2 Receptor; Dorsal; Estrus; Female; Functional disorder; Genetic; Growth; Human; Hyperactivity; Hypothalamic structure; Impulsive Behavior; Impulsivity; Investigation; Knowledge; Lateral; Link; Maps; Mediating; Meditation; Modeling; Monitor; Mus; Neurons; Neurotransmitters; Nucleus Accumbens; Pathway interactions; Phenotype; Play; Prevention strategy; Psychiatry; Public Health; Research; Resolution; Rewards; Risk Factors; Role; Self Administration; Serotonin; Serotonin Receptor 5-HT2C; Sex Differences; Signal Transduction; Site; Social isolation; Stimulant; Testing; Time; Ventral Tegmental Area; Violence; dopamine system; dopamine transporter; epidemiology study; experimental study; fighting; gamma-Aminobutyric Acid; improved; insight; male; monoamine; mouse model; neural circuit; neuropsychiatric disorder; novel; optogenetics; periadolescent; psychostimulant; receptor expression; response; sensor; serotonin transporter; sex; sexual dimorphism; tool; translational model; treatment strategy

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.

项目摘要。隔膜 - 高丘脑神经元活动中心介导侵略性行为，而 单胺神经递质多巴胺和5-羟色胺起着强大的调节作用。 但是，相关的电路机制和个体发育基本上是未知的。迈向电路 机制，我们在小鼠中发现，从腹侧侧侧区域到外侧隔膜的多巴胺输入为 足以促进攻击性，需要建立基线攻击。在侧面 隔膜，多巴胺作用于D2受体，可抑制向下丘脑投射的GABA神经元。这些 发现有效地将临床上相关的侵略性多巴胺模型与经典的分子联系起来 下丘脑攻击轴。取得了个体发育的进展，我们确定了敏感的发展 青春期多巴胺转运蛋白阻滞永久增加成人侵略性的窗户， 冲动性和行为刺激反应，并并行导致多巴胺系统。 相反，周长5-羟色胺转运蛋白封锁降低了侵略性和行为刺激性 成年后的反应，并并行导致多巴胺系统。在这里，我们将继续这条线 研究和研究发展性DA和5-HT信号调谐DA输入的总体假设 进入LS和NAC，以影响成年后与侵略相关的行为。在AIM 1中，我们调查了 多巴胺在侵略相关行为中输入多巴胺对伏隔核的因果作用。侵略是 行为归类为反应性侵略，这是针对感知到的外部威胁而冲动发生的 和积极主动的侵略，这些侵略是由驱动力奖励的动力而直接激发的。我们 假设伏隔核输入有助于主动攻击中的食欲。在AIM 2中， 我们检验了以下假设，即侧隔隔隔隔隔的D2受体有助于性二态性差异 侵略性行为。我们已经发现D2受体在雄性小鼠中介导多巴胺促进的侵略为 以及D2受体表达的性二态性。此外，多巴胺输入到侧隔隔中 不足以引发女性的侵略。在AIM 3中，我们研究了5-羟色胺输入到该的因果作用 侧隔和伏隔核与攻击相关的行为。最后，在AIM 4中，我们调查是否 永久改变DAERGIC输入到LS中，NAC驱动多巴胺后的侵略表型 在发育过程中，血清素转运蛋白转运蛋白封锁，通过监测途径特异性多巴胺能活性 行为，与光遗传学救援实验配对。通过在敏感的背景下将电路映射到行为 发育时期的干扰，我们将提高对正常和破坏大脑的理解 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 侵略性和多巴胺功能障碍。有了新颖的机械和转化见解，我们试图告知 临床和流行病学研究并改善精神病学的诊断，预防和治疗策略。