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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要结节性硬化症复合物是由突变引起的神经发育障碍编码MTOR复合物1信号传导的负调节子的TSC1或2个基因。 TSC是关联的自闭症谱系障碍（ASD）和其他神经精神疾病的患病率很高对患者和看护人感到虚弱。尽管它们在TSC中的盛行，但知之甚少关于这些表现形式的神经生物学，包括负责的细胞类型。我们建议 ASD的核心方面，重复性，不灵活的行为模式是由突触变化引起的基底神经节，一个大脑区域，负责选择和学习适当的行动。我们在这里通过确定TSC1中的突变如何影响细胞，将在TSC的背景下进行研究包括关键基底神经节电路的神经元的生理和行为输出。要孤立特定细胞类型，我们将使用遗传鼠标模型，其中TSC1从定义的单元格中选择性删除人群。 AIM 1中的实验将决定TSC1损失如何影响突触传播和启动主要输出途径的两类纹状体投影神经元中的可塑性基底神经节。我们将测试以下想法，即增加直接途径的皮质突触驱动器神经元导致学习习惯形成的学习改变和增加的倾向。纹状体活性是由多巴胺信号动态调节，该信号传导对行为产生强大的控制。在AIM 2中，我们将确定多巴胺神经元中TSC1的选择性缺失如何影响其生理和输出。我们将测试以下假设，即TSC1的丢失会导致低功能纹状体多巴胺信号引导在逆转学习任务中的认知灵活性受损。该策略是迈向的关键一步剖析TSC的细胞和电路基础，并最终可能为新的治疗策略提供信息这个和相关的ASD。