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

CA3 限制性 BDNF 敲除作为社会行为异常特征的模型

基本信息

批准号：
8686082
负责人：
Alexei Morozov
金额：
$ 32.4万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686082
关键词：
Address Adult Age Aggressive behavior Alcohols Animal Model Animals Antisocial Personality Disorder Anxiety Area Attenuated BDNF gene Behavior Behavioral Behavioral Model Behavioral Symptoms Biochemical Brain Brain-Derived Neurotrophic Factor Childhood Chronic Clinical Management Cognition Cognitive Cognitive deficits Conduct Disorder DSM-IV Data Development Disease Drug Addiction Empathy Gene Mutation Genotype Goals Hippocampus (Brain)Human Impairment In Vitro Interneurons Intervention Knock-out Mental Depression Modeling Mus Neurons Patients Pattern Pharmaceutical Preparations Pharmacogenetics Phenotype Population Prevention Preventive Intervention Property Rights Risk Serotonin Serotonin Receptors 5-HT-3 Slice Social Behavior Societies Symptoms System Testing Time Variant Youth base conditioned fear critical period early adolescence mouse model multidisciplinary novel postnatal preference psychopathic personality receptor research study social social norm therapeutic target therapy development trait treatment strategy

项目摘要

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.

描述（由申请人提供）：反社会人格障碍（ASPD）是“ ...无视和违反童年开始的他人权利的普遍性模式在美国成年人口的1.0％中发现了ASPD。具有ASPD的人违反了社会规范，反复撒谎，将其带来自己的利益，并表现出深深的re悔。表现出所谓的精神病或社会病是ASPD的ASPD，这是由具有工具/有效的侵略性的变体；焦虑症或认知不足，而这种行为对人类社会施加了严重的负担，因为在患者的临床管理中难以理解，并且没有良好的策略，而不是良好的策略，而不是良好的策略研究ASPD的新型经验动物模型，在海马区域CA3（KO小鼠）中删除了BDNF基因的小鼠。这些动物是侵略性的，似乎没有同理心的行为，但具有正常的认知，焦虑和抑郁症行为。这种表型让人联想到人类的ASPD症状，并且与5-羟色胺水平降低和血清素受体3的活性有关，羟色胺受体3的活性增强了，其在海马体内的激活增强了侵略性。令人惊讶的是，该受体减弱了海马γ振荡。尚不清楚海马控制侵略性或同理心中的哪种神经元机制BDNF和血清素能系统。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来解决以下问题：在KO小鼠中，哪些形式的同理心样行为受到了损害？ KO小鼠海马的哪些变化可能与升级的攻击性有关？这些变化的药理学干预能否减少侵略性升级并增加类似移情的行为？这样的研究可以验证BDNF CA3 KO小鼠作为ASPD模型，并促进ASPD新型疗法的开发。