Striatal Glutamate Signaling and Cognition in Autism Mouse Models

项目摘要 中心目标是确定谷氨酸信号在不同的纹状体回路中是否受到干扰 这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 在进行行为测试以确定学习期间纹状体内谷氨酸的实时变化的同时， 反转学习和大理石埋葬。限制和重复的行为在自闭症谱系中很常见 疾病(ASD)，但具有相当大的异质性，其严重程度和类型可能有所不同。严重程度不一的 认知障碍可能是由于高度依赖积极强化和 对不可预测的非加固的突出程度增加。这可能导致学习缺陷或缺乏灵活性。 行为。为小鼠模型开发概率学习测试，以匹配用于测试ASD的模型 对于个体，我们通过测试SHANK3+/-和SHANK3+/-捕获了ASD中报告的一些认知异质性 BTBR小鼠。SHANK3+/-小鼠表现出概率学习缺陷，而BTBR小鼠表现出选择性学习障碍 概率反转学习缺陷。通过互补的方式，我们发现BTBR和SHANK3+/-小鼠 表现出更高的大理石埋藏行为，但BTBR小鼠的水平高于SHANK3+/-小鼠。到目前为止， 我们对神经回路和神经化学机制被改变的知识有很大的差距。 这是ASD重复行为的基础。越来越多的证据表明，异常纹状体回路可能 是某些重复行为的基础。此外，一个解释ASD特征的长期假说包括 认知缺陷，是大脑兴奋/抑制比率的不平衡。有不同的证据 这支持这一假设，尽管目前还没有直接的实时谷氨酸测量 在症状的行为表现过程中。拟议中的项目将首次在两个不同的 ASD小鼠模型在认知测试中直接检测纹状体谷氨酸信号的动态变化 以及表达一种刻板的行为。特定的目标1将决定实时谷氨酸信号 在SHANK3+/-和BTBR小鼠的背内侧纹状体、背外侧纹状体或伏隔核 在反馈确定的条件下(100%)在空间学习和反转学习过程中发生改变 准确)和反馈不确定(正确选择的准确率为80%)。具体目标2将在 SHANK3+/-和BTBR小鼠在大理石埋藏过程中纹状体亚区谷氨酸信号是否存在差异 行为。总体而言，在行为测试期间检查体内谷氨酸传递可以提供更好的 从机制上理解ASD的病理生理学，并在已知的疾病中确定新的治疗靶点 有不同的症状。

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.