Genes, Neural Circuits, and Behavior

基因、神经回路和行为

• 批准号: 10406346
• 负责人: Il Hwan Kim
• 金额: $ 38.08万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-18 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406346
• 关键词: Amygdaloid structure; Anxiety; Axon; Behavior; Behavioral; Biological Assay; Brain; Brain imaging; Cells; Characteristics; Communication impairment; Complex; Electrophysiology (science); Foundations; Gene Deletion; Gene Mutation; Genes; Goals; Halorhodopsins; Human; Impairment; Interneurons; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Label; Mental Depression; Mental disorders; Methods; Monitor; Morphology; Mus; Mutant Strains Mice; Names; Neural Pathways; Neurons; Optics; Pathogenicity; Pathway interactions; Pattern; Prefrontal Cortex; Reporting; Research; Research Domain Criteria; Schizophrenia; Series; Social Behavior; Social Controls; Social Interaction; Social Processes; Social support; Synapses; Synaptic Cleft; System; Testing; Therapeutic Intervention; Ventral Tegmental Area; Vertebral column; Work; autism spectrum disorder; base; endophenotype; excitatory neuron; experimental study; genetic approach; genetic manipulation; in vivo; mouse model; mutant; neural circuit; neural network; novel; reconstitution; relating to nervous system; response; restoration; risk variant; selective expression; social; social deficits; social influence

ABSTRACT Impaired social processes are a common feature in diverse psychiatric disorders such as communication disorders, autism-spectrum disorder, depression, and schizophrenia. Despite extensive studies using mouse models and human brain imaging, the mechanisms underlying deficiencies in social processes are obscure. Experiments with ArpC3 or Shank3 mice reveal that homozygous mutants from both strains are deficient in social behavior. We have developed a system where selected genes can be disrupted within a specific neural circuit and have some preliminary results that a prefrontal cortex (PFC) to basolateral amygdala (BLA) circuit can modulate social behavior. The Overall Goal of this proposal is to use this novel circuit-based gene manipulation approach to identify neural circuits in the ArpC3 and Shank3 mutant mice that may regulate social behaviors. Our Central Hypothesis is that disturbances in a PFC-BLA neural circuit produce abnormal social behaviors. In Aim #1 we will determine whether the PFC-BLA circuit is a common neural pathway controlling abnormal social behavior in ArpC3 and Shank3 mice. Aim #2 will analyze the collateral circuit projecting from the PFC to both BLA and VTA, and test the distinctive responses of recipient neurons in the BLA and VTA during social interaction. Aim #3 will focus on identifying additional neural circuits downstream of the PFC-BLA circuit that can modulate social processes.

摘要 社交过程受损是各种精神疾病的共同特征， 障碍、自闭症谱系障碍、抑郁症和精神分裂症。尽管使用小鼠进行了广泛的研究， 尽管社会模型和人类大脑成像的研究成果有限，但社会过程缺陷背后的机制仍然不清楚。 用ArpC 3或Shank 3小鼠进行的实验表明，来自这两个品系的纯合突变体在社会性表达方面都有缺陷。 行为我们已经开发出一种系统，可以在特定的神经回路中破坏选定的基因 并有一些初步的结果，前额叶皮层（PFC）到基底外侧杏仁核（BLA）的回路可以 调节社会行为。这项提案的总体目标是使用这种新的基于电路的基因操作 方法来识别ArpC 3和Shank 3突变小鼠中可能调节社会行为的神经回路。 我们的中心假设是，PFC-BLA神经回路中的干扰产生异常的社会行为。在 目的#1我们将确定PFC-BLA回路是否是控制异常社交的常见神经通路 ArpC 3和Shank 3小鼠的行为。目标#2将分析从PFC投射到两个 BLA和VTA，并测试在社会互动过程中的受体神经元在BLA和VTA的独特反应。 目标#3将专注于识别PFC-BLA回路下游的其他神经回路， 社会进程

项目成果

Neural circuit pathology driven by Shank3 mutation disrupts social behaviors.

• DOI: 10.1016/j.celrep.2022.110906
• 发表时间: 2022-06-07
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Kim, Sunwhi;Kim, Yong-Eun;Song, Inuk;Ujihara, Yusuke;Kim, Namsoo;Jiang, Yong-Hui;Yin, Henry H.;Lee, Tae-Ho;Kim, Il Hwan
• 通讯作者: Kim, Il Hwan