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.

概括 自闭症谱系障碍 (ASD) 有多种表现形式，但其核心特征是：a) 僵化和 重复行为和 b) 社交沟通缺陷。近几十年来，人们越来越有信心 已确定的遗传差异会导致人类自闭症谱系障碍，并且许多高置信度风险基因已被证实 已被识别。这些风险基因可以在小鼠身上进行研究。有希望趋同的表型和 内表型将阐明 ASD 的关键特征（Hyman，2014）。当前一个引人注目的领域 在带有自闭症谱系障碍（ASD）风险基因的小鼠中观察到的趋同性是旋转杆运动学习和功能的增强 纹状体多刺投射神经元 (SPN) 神经传递的改变 (Hyman, 2014)。 这首先是在具有 Neuroligin 基因突变的小鼠中观察到的（Rothwell 等，2014），但也已被证实 在 Tsc1 和 Tsc2 基因突变的小鼠中观察到这一现象（Benthall 等人，2021）。 Tsc2（对 Tsc1 的一些研究 用于比较）将是该提案的中心焦点。 在此，我们提出在 TSC 患者中观察到的 ASD 的主要诊断标准 - 受限、 重复的行为模式 - 由基底神经节回路活动的变化介导， 控制适当行动的学习和更新。具体来说，我们假设 Tsc2 单倍体不足导致皮质纹状体突触和促进纹状体的 SPN 活动的变化 依赖学习并使更新学习变得更加不灵活。在目标 1 中，我们将使用 电生理和结构成像方法来测试 Tsc2 Het 中的特定连接是否更强 小鼠比WT。我们根据背外侧纹状体的研究假设皮质纹状体与 D1R 的连接 背内侧纹状体 (DMS) 中 SPN (dSPN) 的表达将会增强。目标 2 将关注行为 并在两项不同的任务中测试是否可以通过减少奖励来改善 Tsc2 Het 小鼠的行为僵化 学习过程中的概率。目标 3 将使用纹状体体内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 小鼠的活性可能有所不同。 总之，这些数据将为围绕功能表型收敛增益的基础神经生物学提供信息 许多 ASD 模型：纹状体学习功能的获得（旋转是最常见的测试）。我们会翻译 这种学习表型转化为更可转化的行为学习范式——提示引导的行动学习和 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转化的治疗理念， 认为在训练期间使用较低的奖励概率将改善神经差异并允许更大的 以后灵活运用。