The impact of Tsc-mTOR signaling on basal ganglia function

Tsc-mTOR信号对基底神经节功能的影响

• 批准号: 9915987
• 负责人: Helen S. Bateup
• 金额: $ 32.27万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915987
• 关键词: Affect; Basal Ganglia; Behavior; Behavioral; Biological Assay; Brain; Brain region; Caregivers; Cell physiology; Cells; Cognitive; Complex; Corpus striatum structure; Data; Development; Disease; Dopamine; Electrophysiology (science); Epilepsy; FRAP1 gene; Fire - disasters; Genes; Genetic; Habits; High Prevalence; Impaired cognition; Intervention; Knockout Mice; Knowledge; Learning; Lifestyle-related condition; Mental disorders; Midbrain structure; Motor; Mus; Mutation; Neurobiology; Neurodevelopmental Disorder; Neurologic; Neuromodulator; Neurons; Outcome; Output; Pathway interactions; Patients; Pattern; Pharmacology; Phenotype; Physiology; Population; Prevalence; Process; Proteins; Research; Reversal Learning; Role; Signal Transduction; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Syndrome; TSC1 gene; TSC1/2 gene; TSC2 gene; Testing; Therapeutic; Tuberous sclerosis protein complex; Up-Regulation; autism spectrum disorder; base; brain cell; cell growth; cell type; dopaminergic neuron; experimental study; flexibility; habit learning; improved; loss of function mutation; motor learning; mouse model; nervous system disorder; neuropsychiatry; novel therapeutic intervention; prevent; repetitive behavior; synaptic function; transmission process

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.

项目概要 结节性硬化症是一种由基因突变引起的神经发育障碍 TSC1 或 2 基因编码 mTOR 复合物 1 信号传导的负调节因子。 TSC 关联 自闭症谱系障碍（ASD）和其他神经精神疾病的患病率很高， 使患者和护理人员衰弱。尽管它们在 TSC 中很常见，但人们对其知之甚少 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 自闭症谱系障碍（ASD）的核心方面，即重复的、不灵活的行为模式，是由神经元的突触变化引起的。 基底神经节，负责选择和学习适当行动的大脑区域。在这里我们 将通过确定 Tsc1 突变如何影响细胞，在 TSC 的背景下研究这一点 构成关键基底神经节回路的神经元的生理学和行为输出。隔离特定的 细胞类型，我们将使用遗传小鼠模型，其中 Tsc1 从特定细胞中选择性删除 人口。目标 1 中的实验将确定 Tsc1 丢失如何影响突触传递和 启动主要输出通路的两类纹状体投射神经元的可塑性 基底神经节。我们将测试增加直接通路纹状体的皮质突触驱动的想法 神经元会导致学习的改变和运动习惯形成的倾向增加。纹状体活动是 受多巴胺信号动态调节，对行为施加强大的控制。在目标 2 中，我们 将确定从多巴胺神经元中选择性删除 Tsc1 如何影响其生理和输出。 我们将检验以下假设：Tsc1 缺失会导致纹状体多巴胺信号传导功能低下 逆转学习任务中的认知灵活性受损。这一战略代表着迈向的关键一步 剖析 TSC 的细胞和回路基础，并可能最终为 TSC 提供新的治疗策略 这和相关的自闭症谱系障碍（ASD）。