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

基本信息

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
项目类别：
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

项目摘要

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）具有多种表现，但可以以a）刚性和重复行为和b）社会沟通不足。近几十年来，人们的信心越来越确定的遗传差异导致人类的ASD，许多高置信度风险基因具有已确定。这些风险基因可以在小鼠中研究。希望收敛的表型和内型型将阐明ASD的关键特征（Hyman，2014年）。一个惊人的当前区域在具有ASD风险基因的小鼠中看到的收敛性是Rotarod运动学习和神经传递对纹状体的刺刺神经元（SPN）的改变（Hyman，2014）。这首先是在具有神经素基因突变的小鼠中观察到的（Rothwell等，2014），但也一直是在具有TSC1和TSC2基因突变的小鼠中观察到（Benthall等，2021）。 TSC2（有一些TSC1的研究进行比较）将是该提案的主要重点。在这里，我们建议在TSC患者中观察到的ASD的主要诊断标准 - 受限制，重复的行为模式 - 是由基底神经节电路活性的变化所介导的控制适当动作的学习和更新。具体而言，我们假设TSC2 单倍不足会导致皮质突触和SPN活性的变化，该活动设施纹状体依赖学习，使更新学习更加僵化。在AIM 1中，我们将使用电生理和结构成像方法测试特定连接在TSC2 HET中是否更强小鼠比wt。我们基于在背外侧纹状体的研究，即皮质纹状体连接到D1R 在背侧纹状体（DMS）中，将增强表达SPN（DSPN）。 AIM 2将集中于行为并在两个不同的任务中进行测试，如果可以通过降低奖励来改善TSC2 HET小鼠的行为僵硬性学习期间的概率。 AIM 3将在纹状体中使用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，TSC2小鼠的活性可能有所不同。总而言之，这些数据将为围绕功能表型的收敛增益提供依据许多ASD模型：纹状体学习中功能的增益（Rotarod是最常见的测试）。我们将翻译这种学习表型变成更翻译的行为学习范式 - 提示指导的行动学习和寻求该功能增长的神经相关性。最后，我们将测试一个高度可翻译的治疗想法，在训练过程中使用较低的奖励概率会改善神经差异并允许更大的想法灵活性以后。