Strengths and weaknesses in learning in mice with ASD risk genes

具有 ASD 风险基因的小鼠在学习方面的优势和劣势

• 批准号: 10753864
• 负责人: Linda E Wilbrecht
• 金额: $ 61.71万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753864
• 关键词: Affect; Area; Axon; Basal Ganglia; Basic Science; Behavior; Behavior Therapy; Behavioral; Biological; Calcium; Cognitive; Complex; Corpus striatum structure; Cues; DRD2 gene; Data; Diagnosis; Discrimination; Disease model; Dopamine; Dorsal; Electrophysiology (science); Evaluation; FRAP1 gene; Fiber; Gene Mutation; Genes; Genetic; Genotype; Human; Intervention; Learning; Mediating; Modeling; Mus; Neurobiology; Neurodevelopmental Disorder; Neurons; Neurophysiology - biologic function; Neurosciences; Olfactory Learning; Outcome; Pathway interactions; Patients; Pattern; Phase; Phenotype; Photometry; Preparation; Probability; Psychological reinforcement; Research; Reversal Learning; Rewards; Side; Signal Transduction; Slice; Synapses; System; TSC1 gene; Testing; Therapeutic; Therapeutic Intervention; Training; Translating; Tuberous Sclerosis; Update; Work; arm; autism spectrum disorder; cohort; density; diagnostic criteria; endophenotype; experimental study; flexibility; gain of function; high reward; human subject; imaging modality; in vivo; in vivo imaging; individuals with autism spectrum disorder; interest; learned behavior; loss of function; motor learning; neural; neural correlate; neurotransmission; repetitive behavior; risk variant; sex; social communication; structural imaging; transmission process; tuberous sclerosis patients

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.

摘要 自闭症谱系障碍(ASD)有不同的表现，但其核心特征是a)僵硬和 重复行为和b)社会沟通障碍。近几十年来，人们越来越相信 已发现的遗传差异有助于人类的ASD，许多高可信风险基因 已被确认身份。这些风险基因可以在老鼠身上进行研究。人们希望汇聚的表型和 内表型将阐明ASD的关键特征(Hyman，2014)。一个引人注目的当前区域 在携带ASD风险基因的小鼠中看到的趋同是旋转棒运动学习和功能的获得 纹状体棘投射神经元(SPN)神经传递的改变(Hyman，2014)。 这首先是在神经连接素基因突变的小鼠身上观察到的(Rothwell等人，2014)，但也一直是 在带有TSC1和TSC2基因突变的小鼠中观察到(Benthall等人，2021)。TSC2(与TSC1的一些研究 以供比较)将是这项提案的中心焦点。 在此，我们提出了在TSC患者中观察到的ASD的一个主要诊断标准-限制性、 重复的行为模式-是由基底节环路活动的变化所介导的 控制适当行动的学习和更新。具体来说，我们假设TSC2 单倍体功能不全导致皮质纹状体突触和促进纹状体功能的SPN活性的变化 依赖学习，使更新学习变得更加僵化。在目标1中，我们将使用 电生理和结构成像方法测试TSC2 Het的特异性连接是否更强 小鼠比WT。基于对背外侧纹状体的研究，我们推测皮质纹状体与D1R的联系 SPN(DSPN)在背内侧纹状体(DMS)的表达将增强。目标2将专注于行为 并在两个不同的任务中测试TSC2 Het小鼠的行为不灵活是否可以通过减少奖励来改善 学习过程中的概率。AIM 3将使用纹状体的活体成像来检查多巴胺和纹状体如何 在产生行为差异的条件下，TSC2小鼠的活动可能会有所不同。 总而言之，这些数据将为基础神经生物学提供信息，这些基础神经生物学围绕着在 许多ASD模型：纹状体学习中的功能获得(最常见的测试是Rotarod)。我们会翻译 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和 寻找这种功能获得的神经关联。最后，我们将测试一个高度可翻译的治疗想法， 在训练中使用较低的奖励概率将改善神经差异并允许更大的 以后再灵活处理。