Strengths and weaknesses in learning in mice with ASD risk genes

总结 自闭症谱系障碍（ASD）具有不同的表现，但其核心特征可以是： 重复行为和B）社会沟通缺陷。近几十年来，人们越来越相信， 已确定的遗传差异导致人类ASD，许多高置信度风险基因 被识别。这些风险基因可以在小鼠中进行研究。有希望，趋同表型和 内表型将阐明ASD的关键特征（Hyman，2014）。一个引人注目的电流区域， 在具有ASD风险基因的小鼠中观察到的会聚是旋转杆运动学习功能的获得， 纹状体的多刺投射神经元（SPN）的神经传递改变（Hyman，2014）。 这首先在具有神经配蛋白基因突变的小鼠中观察到（Rothwell等人，2014年，但也 在具有Tsc 1和Tsc 2基因突变的小鼠中观察到（Benthall等人，2021年）。Tsc 2（以及Tsc 1的一些研究 供比较）将是本建议的中心重点。 在这里，我们提出了一个主要的诊断标准，ASD观察TSC患者-限制， 行为的重复模式-是由基底神经节回路活动的变化介导的， 控制适当动作的学习和更新。具体来说，我们假设Tsc 2 单倍不足导致皮质-纹状体突触和SPN活性的变化， 依赖学习，使更新学习更加不灵活。在目标1中，我们将使用 电生理学和结构成像方法来测试Tsc 2 Het中的特定连接是否更强 小鼠比WT。我们基于对背外侧纹状体的研究发现，皮质纹状体与D1 R的联系 表达SPNs（dSPNs）的神经元在背内侧纹状体（DMS）中的表达将增强。目标2将侧重于行为 并在两个不同的任务中测试Tsc 2 Het小鼠的行为能力是否可以通过减少奖励来改善 学习过程中的概率目的3将使用纹状体的体内成像来检查多巴胺和纹状体 在产生行为差异的条件下，Tsc 2小鼠的活性可能不同。 总之，这些数据将告知基础神经生物学，围绕在神经元中观察到的功能表型的会聚增益。 许多ASD模型：纹状体学习功能的获得（旋转棒是最常见的测试）。我们将翻译 这种学习表型转化为更可翻译的行为学习范式-线索引导的行动学习， 寻找这种功能增益的神经关联。最后，我们将测试一个高度可翻译的治疗理念， 在训练过程中使用较低的奖励概率将改善神经差异，并允许更大的 灵活性稍后

Summary Autism spectrum disorder (ASD) has diverse presentation but can be characterized by at core by a) rigid and repetitive behavior and b) social communication deficits. In recent decades, there is increasing confidence that identified genetic differences contribute to ASD in humans and a number of high confidence risk genes have been identified. These risk genes can be studied in mice. There is hope that convergent phenotypes and endophenotypes will illuminate key features of ASD (Hyman, 2014). One striking current area of convergence seen in mice with ASD risk genes is a gain of function in rotarod motor learning and alteration in neurotransmission onto spiny projection neurons (SPNs) of the striatum (Hyman, 2014). This was first observed in mice with neuroligin gene mutations (Rothwell et al., 2014), but has also been observed in mice with Tsc1 and Tsc2 gene mutations (Benthall et al., 2021). Tsc2 (with some studies of Tsc1 for comparison) will be the central focus of this proposal. Here we propose that a major diagnostic criteria for ASD observed in TSC patients - restricted, repetitive patterns of behavior - is mediated by changes in the activity of basal ganglia circuits that control the learning and updating of appropriate actions. Specifically, we hypothesize that Tsc2 haploinsufficiency leads to changes in corticalstriatal synapses and SPN activity that facilities striatal dependent learning and makes updating learning more inflexible. In Aim 1 we will use electrophysiological and structural imaging methods to test if specific connections are stronger in Tsc2 Het mice than WT. We posit based on studies in the dorsolateral striatum that corticostriatal connections onto D1R expressing SPNs (dSPNs) will be enhanced in the dorsomedial striatum (DMS). Aim 2 will focus on behavior and test in two different tasks if behavioral inflexibility in Tsc2 Het mice can be ameliorated by reducing reward probability during learning. Aim 3 will use in vivo imaging in the striatum to examine how dopamine and striatal activity may differ in Tsc2 mice under conditions that produce behavioral differences. In sum, these data will inform basic neurobiology surrounding a convergent gain of function phenotype seen in many ASD models: gain of function in striatal learning (rotarod being the most common test). We will translate this learning phenotype into more translatable behavior learning paradigm--cue guided action learning and seek the neural correlates of this gain of function. Finally, we will test a highly translatable therapeutic idea, the idea that using lower reward probability during training will ameliorate neural differences and allow for greater flexibility later.