Striatal Glutamate Signaling and Cognition in Autism Mouse Models

自闭症小鼠模型中的纹状体谷氨酸信号传导和认知

• 批准号: 9180311
• 负责人: MICHAEL E RAGOZZINO
• 金额: $ 22.56万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180311
• 关键词: Address; Area; Autistic Disorder; BTBR Mouse; Behavior; Behavioral; Biosensor; Brain; Characteristics; Cognition; Cognitive; Cognitive deficits; Compulsive Behavior; Conflict (Psychology); Corpus striatum structure; Dependence; Discrimination; Disease; Dorsal; Exhibits; FDA approved; Feedback; Functional disorder; Glutamates; Goals; Heterogeneity; Impaired cognition; Individual; Knowledge; Lead; Learning; Lifestyle-related condition; Marble; Measurement; Measures; Modeling; Mus; Neurodevelopmental Disorder; Neurotransmitters; Nucleus Accumbens; Outcome; Pattern; Phenotype; Positive Reinforcements; Psychological reinforcement; Reporting; Research Project Grants; Rest; Reversal Learning; Rewards; Severities; Space Perception; Stereotyped Behavior; Stereotyping; Symptoms; Technology; Testing; Time; abstracting; autism spectrum disorder; base; behavior test; cognitive rigidity; cognitive testing; glutamatergic signaling; in vivo; insight; interest; mouse model; neural circuit; neurochemistry; new therapeutic target; repetitive behavior; transmission process

Project Abstract The central goal is to determine whether glutamate signaling is disrupted in different striatal circuits that underlie repetitive behaviors in mouse models of autism. Biosensor technology will be employed concomitantly with behavioral testing to determine real-time glutamate changes in the striatum during learning, reversal learning and marble burying. Restricted and repetitive behaviors are common to autism spectrum disorders (ASD) but have considerable heterogeneity that can vary in severity and type. A varying severity of cognitive impairment may arise from the degree of heightened dependence on positive reinforcement and increased salience to unpredicted non-reinforcement. This can lead to either a learning deficit or inflexible behavior. Developing probabilistic learning tests for mouse models that match those used to test ASD individuals, we have captured some of the cognitive heterogeneity reported in ASD by testing SHANK3+/- and BTBR mice. SHANK3+/- mice exhibit a probabilistic learning deficit while BTBR mice exhibit a selective probabilistic reversal learning deficit. In a complementary way, we found that BTBR and SHANK3+/- mice exhibit elevated marble burying behavior, but BTBR mice have greater levels than SHANK3+/- mice. To date, there are significant gaps in our knowledge of what neural circuitry and neurochemical mechanisms are altered that underlie repetitive behaviors in ASD. Accumulating evidence indicates that abnormal striatal circuits may underlie certain repetitive behaviors. Further, a long-standing hypothesis to explain ASD features, including cognitive deficits, is an imbalance in the brain excitation/inhibition ratio. There are different lines of evidence that support this hypothesis, although at present, there have been no direct real-time glutamate measurements during behavioral expression of the symptoms. The proposed project will for the first time in two different mouse models of ASD directly examine dynamic changes in striatal glutamate signaling during cognitive tests and expression of a stereotyped behavior. Specific Aim 1 will determine whether real-time glutamate signaling in the dorsomedial striatum, dorsolateral striatum or nucleus accumbens of SHANK3+/- and BTBR mice is altered during spatial learning and reversal learning under conditions in which feedback is certain (100% accurate) and feedback is uncertain (80% accurate for correct choice). Specific Aim 2 will determine in SHANK3+/- and BTBR mice whether glutamate signaling differs in striatal subregions during marble burying behavior. Overall, examination of in vivo glutamate transmission during behavioral testing can provide a better mechanistic understanding of ASD pathophysiology and identify novel therapeutic targets in a disorder known to have heterogeneous symptomology.

项目摘要 中心目标是确定谷氨酸信号是否在不同的纹状体回路中被破坏， 是自闭症小鼠模型重复行为的基础。将采用生物传感器技术 伴随着行为测试以确定学习期间纹状体中的实时谷氨酸变化， 逆向学习和大理石埋藏。限制性和重复性行为在自闭症谱系中很常见 ASD是ASD的一种类型，但具有相当大的异质性，其严重程度和类型可能不同。不同程度的 认知障碍可能源于对积极强化的高度依赖， 增加对不可预测的非强化的显著性。这可能导致学习不足或缺乏灵活性 行为为小鼠模型开发与用于测试ASD的模型相匹配的概率学习测试 个体，我们通过测试SHANK3 +/-和 BTBR小鼠。SHANK3 +/-小鼠表现出概率性学习缺陷，而BTBR小鼠表现出选择性学习缺陷。 概率逆向学习缺陷以互补的方式，我们发现BTBR和SHANK3 +/-小鼠 表现出升高的大理石掩埋行为，但BTBR小鼠比SHANK3 +/-小鼠具有更高的水平。到目前为止， 我们对神经回路和神经化学机制发生改变的认识存在很大的差距， 自闭症患者重复行为的基础越来越多的证据表明，异常的纹状体回路可能 是某些重复行为的基础。此外，解释ASD特征的长期假设，包括 认知缺陷，是大脑兴奋/抑制比率的不平衡。有不同的证据 支持这一假设，尽管目前还没有直接的实时谷氨酸测量， 在症状的行为表现中。该项目将首次在两个不同的 ASD小鼠模型直接检测认知测试期间纹状体谷氨酸信号的动态变化 和刻板行为的表现。特异性目标1将决定实时谷氨酸信号传导是否 在SHANK3 +/-和BTBR小鼠的背内侧纹状体、背外侧纹状体或中脑核中， 在空间学习和反向学习过程中，在反馈是确定的条件下（100%）， 准确）和反馈是不确定的（80%的正确选择准确）。具体目标2将确定在 SHANK3 +/-和BTBR小鼠在大理石埋藏过程中纹状体亚区的谷氨酸信号是否不同 行为总体而言，在行为测试期间检查体内谷氨酸传输可以提供更好的 了解ASD病理生理机制，并确定已知疾病的新治疗靶点 具有异质性的生物学。