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.

我们目前正在研究COMT、Dysbindin、BDNF、ARC、NRG、BAD、KCNH 2以及COMT/Dysbindin的基因-基因相互作用。 我们已经用基因改变的小鼠证明了COMT对精神相关行为的影响，包括认知，情绪唤起，疼痛敏感性和安非他明反应。COMT活性增加是皮质依赖性认知功能障碍的危险因素，但在应激情况下是保护因素，而COMT减少增强工作记忆过程，但导致过度的应激反应。产生的COMT转基因小鼠（过表达人COMT-val），并将它们与含有无效COMT突变的小鼠进行比较。COMT转基因和基因敲除小鼠模仿了与COMT多态性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模型具体化了一个共同的遗传因素可以参与以异常认知加工和应激反应为特征的各种临床疾病，并代表了一种有前途的新动物模型，用于测试认知和应激相关疗法。在这种情况下，需要一个既定的生物学验证策略是很重要的。CBDB/GCAP研究人员已经开发出神经影像学方法，以在生物学水平上确认基因内和基因间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传导和涉及遗传改变小鼠品系繁殖的动物模型中。 将我们的过表达人COMT-val（Val-tg）的转基因小鼠与没有功能性COMT的小鼠和含有COMT-leu的正常小鼠进行比较。Val-tg小鼠中COMT活性的增加导致注意力转移能力以及工作记忆和识别记忆受损。习得或反向学习没有变化。COMT Val-tg小鼠也表现出识别记忆缺陷。然而，急性治疗安非他明，增加多巴胺水平，恢复识别记忆性能的COMT Val-tg小鼠，但恶化的性能控制。尽管COMT基因型对工作记忆过程有影响，但COMT Val-tg小鼠在涉及定期重复事件序列的任务中表现正常，而不是试验特定经验。这些结果突出了COMT基因作为一个关键因素在调节执行记忆过程。关于环境应激源，COMT敲除小鼠（-/-）在低应激条件下表现最好，而COMT杂合小鼠（+/-）在挑战条件下表现最好。研究表明，轻度的不可控应激会损害人和动物的PFC工作记忆功能。我们已经证明，COMT活性增加是皮质依赖性认知功能障碍的危险因素，但在压力下是一个保护因素，而COMT减少增强工作记忆过程，但导致夸大的压力反应。COMT转基因和基因敲除小鼠显示出与COMT突变相关的人类行为的显著方面，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各种临床疾病，其特征在于异常的认知处理和应激反应，这代表了一个有前途的新的动物模型，用于测试认知和应激相关的治疗。最后，这些结果证明了一个有趣的功能之间的权衡遗传变异，同时导致更有效的认知行为和适应性较低的情感行为。