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

基本信息

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
项目类别：
财政年份：
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

项目摘要

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，KCNH2和COMT/DYSBINDIN的GENE-GENE相互作用。我们用遗传改变的小鼠最终证明了COMT对精神病相关行为的影响，包括对认知，情绪唤醒，疼痛敏感性和苯丙胺反应的影响。增加的COMT活性是皮层依赖性认知功能障碍的危险因素，但在压力大的情况下是保护因素，而COMT还原会增强工作记忆过程，但导致压力反应性夸大。生成的COMT转基因小鼠（过表达人类COMT-VAL），并将其与含有无效的COMT突变的小鼠进行了比较。 COMT转基因和敲除小鼠模仿了与COMT多态性相关的人类行为的显着方面，并确定了这些关联的生物学验证。我们的COMT模型可以证明一种常见的遗传因素可以参与以异常认知处理和压力反应性为特征的多种临床疾病，并代表了一种有希望的新动物模型，用于测试认知和压力相关的疗法。在这种情况下，对生物学验证的既定战略的需求很重要。 CBDB/GCAP研究者已经开发了神经影像学方法，以在基因内和基因之间的上敏感性相互作用的生物学水平上确认，并将这些发现扩展到淋巴母细胞细胞系中的信号传导以及涉及遗传差异小鼠菌株的繁殖的动物模型中。将过表达人体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的正常小鼠进行了比较。 Val-TG小鼠的COMT活性增加导致注意力设置的转移能力以及工作和识别记忆受损。获取或逆转学习没有变化。 COMT Val-TG小鼠还显示出识别记忆缺陷。然而，使用苯丙胺急性治疗增加了多巴胺水平，恢复了COMT Val-TG小鼠的识别记忆性能，但性能控制恶化。尽管COMT基因型对工作记忆过程的影响，但COMT Val-TG小鼠在涉及定期重复的事件序列而不是特定特定经验的任务中表现出正常的性能。这些结果突出了COMT基因是调节执行记忆过程的关键因素。关于环境压力源，在低应力条件下，COMT无效小鼠（ - / - ）是表现最好的人，而COMT杂合小鼠（+/--）在挑战性的条件下表现最好。似乎轻度的不受控制的应力会损害人类和动物中的PFC工作记忆功能。我们已经证明，增加的COMT活性是皮层依赖性认知功能障碍的危险因素，但是在压力下，保护因素是保护因素，而COMT减少会增强工作记忆过程，但会导致夸张的压力反应。 COMT转基因和敲除小鼠表现出与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小鼠模型确定，一种常见的遗传因素可以参与不同的临床疾病，其特征是具有异常的认知处理和对压力的反应，这代表了一种有希望的新动物模型，用于测试认知和压力相关的疗法。最后，这些结果表明，遗传变异之间的功能权衡很有趣，同时导致更有效的认知行为和较少的适应性情感行为。