Developmental Origins of Aggressive and Impulsive Behavior

攻击性和冲动行为的发展起源

基本信息

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
项目类别：
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

项目摘要

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。间隔下丘脑神经元活动集中介导攻击行为，而单胺类神经递质多巴胺和血清素发挥着强烈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。电路方面取得进展机制，我们发现在小鼠中，从腹侧被盖区到外侧隔膜的多巴胺输入是足以促进攻击性并且对于建立基线攻击性是必要的。侧面内在隔膜中，多巴胺作用于 D2 受体，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进展，我们发现了一个敏感的发育青春期的窗口期，多巴胺转运蛋白阻断永久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，青春期血清素转运蛋白阻断可减少攻击性和行为兴奋成年后的反应，同时导致多巴胺系统活性低下。在这里我们将继续这一行研究和研究发育 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，我们调查了多巴胺输入伏隔核在攻击相关行为中的因果作用。攻击性是行为上分为反应性攻击，是为了应对感知到的外部威胁而冲动发生的主动攻击是有预谋的，并直接受食欲奖励的驱动。我们假设伏隔核输入有助于主动攻击的食欲值。在目标 2 中，我们检验了这样的假设：侧隔膜的 D2 受体有助于性别二态性差异攻击行为。我们已经发现 D2 受体在雄性小鼠中介导多巴胺促进的攻击行为以及 D2 受体表达的性别二态性。此外，输入到侧隔膜的多巴胺是不足以引发雌性的攻击性。在目标 3 中，我们研究了血清素输入到大脑中的因果作用。外侧隔膜和伏隔核在攻击相关行为中的作用。最后，在目标 4 中，我们调查是否永久性改变 LS 和 NAc 的 DAergic 输入在多巴胺和通过监测发育过程中途径特异性多巴胺能活性来阻断发育过程中的血清素转运蛋白行为，与光遗传学救援实验相结合。通过将电路映射到敏感环境中的行为发育期干扰，我们将加深对正常大脑和受损大脑的理解发育和功能。此类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。凭借新颖的机制和转化洞察力，我们寻求告知临床和流行病学研究并改进精神病学的诊断、预防和治疗策略。