The impact of Tsc-mTOR signaling on basal ganglia function

项目摘要 多发性硬化症是一种神经发育障碍， 编码mTOR复合物1信号传导负调节因子的TSC 1或2基因。TSC与 自闭症谱系障碍（ASD）和其他神经精神疾病的患病率很高， 对病人和护理人员来说都是很虚弱的。尽管它们在TSC中普遍存在， 关于这些表现的神经生物学，包括负责的细胞类型。我们建议 ASD的核心方面，重复的，不灵活的行为模式，是由突触变化引起的， 基底神经节，负责选择和学习适当行动的大脑区域。这里我们 我将在TSC的背景下通过确定Tsc1的突变如何影响细胞内 包括关键基底神经节回路的神经元的生理和行为输出。分离出特定的 细胞类型，我们将使用遗传小鼠模型，其中Tsc 1从定义的细胞中选择性缺失， 人口。目标1中的实验将确定Tsc 1丢失如何影响突触传递， 可塑性的两类纹状体投射神经元，启动主要输出途径的 基底神经节。我们将验证直接通路纹状体的皮质突触驱动增加的想法， 神经元导致学习改变和运动习惯形成倾向增加。纹状体活动是 由多巴胺信号动态调节，对行为施加强大的控制。在目标2中， 将确定选择性地从多巴胺神经元中删除Tsc1如何影响它们的生理和输出。 我们将检验Tsc1缺失导致纹状体多巴胺信号传导功能减退的假设， 在逆向学习任务中认知灵活性受损。这一战略是朝着以下目标迈出的关键一步： 剖析TSC的细胞和电路基础，并最终为TSC的新治疗策略提供信息。 和相关的ASD。

PROJECT SUMMARY Tuberous Sclerosis Complex is a neurodevelopmental disorder caused by mutations in the TSC1 or 2 genes that encode negative regulators of mTOR complex 1 signaling. TSC is associated with a high prevalence of autism spectrum disorder (ASD) and other neuropsychiatric conditions, which are debilitating for patients and caregivers. Despite their prevalence in TSC, relatively little is known about the neurobiology of these manifestations including the cell types responsible. We propose that a core aspect of ASD, repetitive, inflexible patterns of behavior, is caused by synaptic changes in the basal ganglia, a brain region responsible for the selection and learning of appropriate actions. Here we will investigate this in the context of TSC by determining how mutations in Tsc1 affect the cellular physiology and behavioral output of neurons comprising key basal ganglia circuits. To isolate specific cell types, we will use genetic mouse models in which Tsc1 is selectively deleted from defined cell populations. The experiments in Aim 1 will determine how Tsc1 loss affects synaptic transmission and plasticity in the two classes of striatal projection neurons that initiate the primary output pathways of the basal ganglia. We will test the idea that increased cortical synaptic drive of direct pathway striatal neurons leads to altered learning and increased propensity for motor habit formation. Striatal activity is dynamically regulated by dopamine signaling, which exerts powerful control over behavior. In Aim 2, we will determine how selective deletion of Tsc1 from dopamine neurons affect their physiology and output. We will test the hypothesis that loss of Tsc1 causes hypofunctional striatal dopamine signaling leading to impaired cognitive flexibility in reversal learning tasks. This strategy represents a key step towards dissecting the cellular and circuit basis of TSC, and may ultimately inform new therapeutic strategies for this and related ASDs.