CA3-Restricted BDNF Knockout as a Model of Abnormal Traits in Social Behaviors

描述（由申请人提供）：反社会人格障碍（ASPD）是“…一种从童年开始就普遍存在的无视和侵犯他人权利的模式 或青春期早期，并持续到成年。“ASPD在美国成年人口中占1.0%。患有反社会人格障碍的人打破社会规范，反复撒谎，为了自己的利益将他人置于危险之中，并表现出深刻的缺乏悔恨。所谓的精神病或反社会病是ASPD的一种变体，其特征是工具性/主动性攻击和缺乏同理心;同时，没有病理性焦虑，抑郁或认知缺陷。虽然这些行为给人类社会带来了严重的负担，但由于患者的临床管理困难和缺乏干预策略，ASPD被认为是不可治疗的。ASPD是预测在青年与品行障碍（CD）;然而，CD/ASPD的基本机制仍然未知，潜在的治疗策略尚未调查，部分原因是没有良好的动物模型。本研究的目的是验证和研究一种新的ASPD实验动物模型，即海马CA 3区BDNF基因缺失小鼠（KO小鼠）。这些动物具有攻击性，似乎没有类似同情的行为，但有正常的认知，焦虑和抑郁样行为。这种表型让人联想到人类的ASPD症状，并与血清素水平降低和血清素受体3活性增强有关，血清素受体3在海马体内的激活增强了攻击性。令人惊讶的是，这种受体减弱了海马γ振荡。目前尚不清楚海马中BDNF和多巴胺能系统通过何种神经元机制控制攻击性或共情。该提案代表了一项多学科研究，并结合了行为和生化分析，体外切片记录和药物遗传学，以解决以下问题：哪些形式的同情样行为在KO小鼠中受到损害？基因敲除小鼠海马的哪些变化可能与攻击行为的升级有关？药物干预这些变化是否可以减弱升级的攻击性并增加同情样行为？这些研究可以验证BDNF CA 3 KO小鼠作为ASPD模型，并促进ASPD新疗法的开发。

DESCRIPTION (provided by applicant): Antisocial personality disorder (ASPD) is "...a pervasive pattern of disregard for, and violation of, the rights of others that begins in childhood or early adolescence and continues into adulthood." ASPD is found in 1.0 % of the U.S. adult population. People with ASPD break social norms, lie repeatedly, place others at risk for their own benefit, and demonstrate a profound lack of remorse. What is referred to as psychopathy or sociopathy is a variant of ASPD characterized by instrumental/proactive aggression and lack of empathy; at the same time, there is no pathological anxiety, depression or cognitive deficits. While such behaviors impose severe burden on human society, ASPD is considered untreatable because of difficulty in clinical management of the patients and lack of intervention strategies. ASPD is predicted in youth with conduct disorder (CD); however, the fundamental mechanisms of CD/ASPD remain unknown and potential treatment strategies have not been investigated, partly because there is no good animal model. The goal of the proposal is to validate and investigate a novel empirical animal model of ASPD, mice with the deletion of BDNF gene in the hippocampal area CA3 (KO mice). These animals are aggressive and appear to have no empathy-like behaviors, but have normal cognition, anxiety and depression-like behaviors. This phenotype is reminiscent of ASPD symptoms in humans and was associated with reduced levels of serotonin and enhanced activity of serotonin receptor 3, whose activation inside hippocampus enhanced aggression. Surprisingly, this receptor attenuated hippocampal gamma oscillations. It is unclear through which neuronal mechanisms BDNF and serotonergic system in the hippocampus control aggression or empathy. The proposal represents a multidisciplinary study and combines behavioral and biochemical analyses, in vitro slice recording and pharmacogenetics to addresses the following questions: Which forms of empathy-like behaviors are compromised in KO mice? What changes in the hippocampus of KO mice may be relevant to the escalated aggression? Can pharmacological intervention with these changes attenuate escalated aggression and increase empathy-like behaviors? Such studies may validate BDNF CA3 KO mice as a model of ASPD and promote development of novel therapies for ASPD.