Transgenic Mouse Model for Mental Disorders including schizophrenia

用于精神疾病（包括精神分裂症）的转基因小鼠模型

• 批准号: 7970158
• 负责人: Daniel Weinberger
• 金额: $ 54.34万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7970158
• 关键词: Acute; Affective; Amphetamines; Animal Model; Animals; Antipsychotic Agents; Area; Arousal; Autopsy; Behavior; Biological; Blood specimen; Brain; Brain-Derived Neurotrophic Factor; Breeding; Catechols; Cell Line; Clinical; Cognition; Cognitive; Cognitive deficits; Disease; Dopamine; Drug Delivery Systems; Emotional; Enzyme Stability; Event; Gene Mutation; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glutamine; Human; Human Genetics; Impaired cognition; Knockout Mice; Laboratories; Mediating; Memory impairment; Mental disorders; Methods; Methyltransferase; Methyltransferase Gene; Modeling; Mouse Strains; Mus; Mutation; Neurons; Pain; Pathogenesis; Patients; Performance; Predisposition; Prefrontal Cortex; Process; Protocols documentation; Psychotic Disorders; RNA Interference; Reaction; Regulation; Research; Research Personnel; Reversal Learning; Risk Factors; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Stress; Susceptibility Gene; Symptoms; System; Testing; Transgenes; Transgenic Mice; Transgenic Organisms; Translating; Treatment Efficacy; Validation; Work; base; biological adaptation to stress; cellular development; environmental stressor; enzyme activity; experience; gene interaction; knock-down; lymphoblast; meetings; memory process; memory recognition; mouse model; neuroimaging; neurotransmission; new technology; overexpression; programs; response; valylvaline

We currently are investigating COMT, Dysbindin, BDNF, ARC, NRG, BAD, KCNH2 and the gene-gene interaction of COMT/Dysbindin. We have demonstrated conclusively with genetically altered mice the effect of COMT on psychiatric relevant behaviors, including on cognition, emotional arousal, pain sensitivity and amphetamine response. Increased COMT activity is a risk factor for cortically dependent cognitive dysfunctions but a protective factor in stressful situations, whereas COMT reduction enhances working memory processes but results in exaggerated stress reactivity. The generated COMT transgenic mice (overexpressing a human COMT-val), and compared them with mice containing a null COMT mutation. COMT transgenic and knock-out mice mimicked salient aspects of human behaviors associated with COMT polymorphisms, and established the biologic validation of these associations. Our COMT model reifies that a common genetic factor can be involved in diverse clinical disorders characterized by abnormal cognitive processing and stress reactivity and represents a promising new animal model for testing cognitive and stress related therapies. In this context, the need for an established strategy for biological validation is important. CBDB/GCAP investigators have developed neuroimaging methods to confirm at a biological level clinical evidence of epistatic interactions within genes and between genes and have extended these findings to signaling within lymphoblast cell lines and in animal models involving breeding of genetically altered mouse strains. Our transgenic mice overexpressing human COMT-val (Val-tg) was compared with mice without a functional COMT and normal mice which contain COMT-leu. Increased COMT activity in Val-tg mice resulted in impaired attentional set shifting abilities, and working and recognition memory. There was no change in acquisition or reversal learning. COMT Val-tg mice also showed recognition memory deficits. However, acute treatment with amphetamine, which increases dopamine levels, restored recognition memory performance in COMT Val-tg mice but worsened performance control. Despite the COMT genotype effects on working memory processes, COMT Val-tg mice showed normal performance in tasks involving a regularly repeated sequence of events rather than trial-specific experience. These results highlight the COMT gene as a critical factor in the regulation of executive memory processes. With regards to environmental stressors, COMT null mice ( -/-) were the best performers under low stress conditions, whereas COMT heterozygous mice (+/-) performed best under challenging conditions. It appears that mild uncontrolled stress impairs PFC working memory functions in human and animals. We have demonstrated that increased COMT activity is a risk factor for cortically dependent cognitive dysfunctions but a protective factor when under stress, whereas COMT reduction enhances working memory processes but results in exaggerated stress reactions. The COMT transgenic and knock-out mice show notable aspects of human behaviors associated with COMT mutations and establish biologic validity of these associations. Our COMT mouse model establishes that a common genetic factor can be involved in diverse clinical disorders characterized by abnormal cognitive processing and reaction to stress which represents a promising new animal model for testing cognitive and stress related therapies. Finally, these results demonstrate an intriguing functional trade-off between genetic variation that concurrently results in more efficient cognitive behaviors and less adaptive affective behaviors.

目前，我们正在研究COMT、dybindin、BDNF、ARC、NRG、BAD、KCNH2以及COMT/dybindin的基因-基因相互作用。我们用转基因小鼠确凿地证明了COMT对精神相关行为的影响，包括对认知、情绪唤醒、疼痛敏感性和苯丙胺反应的影响。COMT活性增加是皮质依赖性认知功能障碍的风险因素，但在压力情况下是保护因素，而COMT活性减少会增强工作记忆过程，但会导致夸大的应激反应。产生的COMT转基因小鼠(过表达人COMT-Val)，并将它们与含有零COMT突变的小鼠进行比较。COMT转基因和敲除小鼠模仿了与COMT多态相关的人类行为的显著方面，并建立了这些关联的生物学验证。我们的COMT模型证实了一个共同的遗传因素可以参与以认知加工和应激反应异常为特征的各种临床疾病，并代表了一种很有前途的新动物模型，用于测试认知和应激相关治疗。在这方面，制定生物验证战略的必要性是重要的。CBDB/GCAP的研究人员已经开发出神经成像方法，以在生物学水平上证实基因内部和基因之间存在上位性相互作用的临床证据，并将这些发现扩展到淋巴母细胞系内的信号以及涉及转基因小鼠品系繁殖的动物模型中。 我们的高表达人COMT-Val的转基因小鼠(Val-TG)与没有功能COMT的小鼠和含有COMT-Leu的正常小鼠进行了比较。Val-Tg小鼠COMT活性增加导致注意力定势转移能力、工作记忆和识别记忆受损。在习得或反转学习方面没有变化。COMT Val-Tg小鼠也表现出识别记忆缺陷。然而，安非他明的急性治疗，增加了多巴胺水平，恢复了COMT Val-TG小鼠的识别记忆能力，但恶化了表现控制。尽管COMT基因对工作记忆过程有影响，但COMT Val-TG小鼠在涉及规则重复事件序列的任务中表现出正常的表现，而不是特定于试验的体验。这些结果强调了COMT基因是调节执行记忆过程的关键因素。在环境应激源方面，COMT缺失小鼠(-/-)在低应激条件下表现最好，而COMT杂合子小鼠(+/-)在挑战条件下表现最好。轻微的失控应激似乎会损害人和动物的PFC工作记忆功能。我们已经证明，COMT活性增加是皮质依赖认知功能障碍的风险因素，但在压力下是保护因素，而COMT活性减少会增强工作记忆过程，但会导致夸大的应激反应。COMT转基因和基因敲除小鼠显示了与COMT突变相关的人类行为的显着方面，并建立了这些关联的生物学有效性。我们的COMT小鼠模型建立了一个共同的遗传因素可以参与多种临床疾病，其特征是认知加工和对压力的反应异常，这代表了一个很有希望的新的动物模型，用于测试认知和压力相关的治疗方法。最后，这些结果表明，基因变异同时导致更有效的认知行为和更不适应的情感行为之间存在有趣的功能性权衡。