Investigating the role of Tsc1 in neocortical circuit assembly

研究 Tsc1 在新皮质电路组装中的作用

• 批准号: 8893803
• 负责人: Laura Anne DeNardo
• 金额: $ 5.16万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893803
• 关键词: Affect; Autistic Disorder; Behavior; Behavior Control; Behavioral; Behavioral Symptoms; Benign; Brain; Brain region; Cells; Comb animal structure; Complex; DNA Sequence Alteration; Decision Making; Development; Disease; Epilepsy; Equilibrium; Exhibits; Foundations; Future; Genes; Genetic study; Hippocampus (Brain); Intervention; Investigation; Knock-out; Lead; Link; Maps; Medial; Molecular; Mono-S; Motor output; Mus; Mutation; Neocortex; Neurodevelopmental Disorder; Neurons; Pathway interactions; Patients; Pattern; Phenotype; Prefrontal Cortex; Rabies; Rabies virus; Regulation; Research; Role; Sensory; Short-Term Memory; Signal Pathway; Signal Transduction; Social Interaction; Structure; Synapses; System; Techniques; Testing; Tuberous sclerosis protein complex; Tumor Suppressor Genes; Work; base; cell type; in vivo; information processing; knockout gene; mTOR protein; multisensory; neocortical; neural circuit; public health relevance; sensorimotor system; tumor

DESCRIPTION (provided by applicant): The mammalian neocortex is a six-layered structure that creates a representation of the world by integrating sensory information and controls behavior by generating the appropriate motor output. Each layer processes information differently, so understanding how layer-specific neuronal networks are organized will provide a foundation for understanding how different layers function within circuits. The medial prefrontal cortex (mPFC) integrates information from many brain regions and is involved in complex behaviors including social interaction and decision-making. Importantly, mPFC circuits are often disrupted in neurodevelopmental disorders such as autism, but little is known about the fine scale organization of mPFC or how mPFC layers integrate different kinds of information. The Luo lab recently developed a modified rabies-based mono-trans- synaptic tracing technique that allows for detailed analysis of local circuitry in addition to whole brain long- distance mapping. This new rabies technique can be combined with layer-specific Cre driver mouse lines to generate detailed maps of layer-specific circuits in medial prefrontal cortex (mPFC). Cre-dependent rabies tracing will also be combined with cell-type specific gene knockout, so these maps will provide a basis for studying genetic regulation of neocortical connectivity in development and disease with unprecedented precision and scope. To begin to dissect the molecular pathways involved in establishing specific mPFC connectivity, this project will focus on the role of the autism-related gene Tsc1. Recent studies showed that Tsc1 deletion increases excitatory synaptic connectivity and alters the balance of excitation and inhibition, causing hyperexcitability in hippocampal neurons. This phenotype may be related to the role of Tsc1 in Tuberous Sclerosis Complex, a disease in which patients suffer from benign tumors, epilepsy, and autism. Performing Cre-dependent rabies tracing in conditional Tsc1fl/fl mice crossed with layer-specific Cre-drivers will facilitate investigation of the cell-autonomous role o Tsc1 in the development of mPFC connectivity and layer- specific organization. As Tsc1 is a negative regulator of the mammalian target of rapamycin complex, mTORC1, the molecular mechanisms underlying the in vivo function of Tsc1 will also be investigated to elucidate how these signaling pathways regulate brain development. This work will provide a deeper understanding of the molecular and the circuit-level mechanisms that give rise to autism and epilepsy in patients with Tsc1 mutations.

描述（由申请人提供）：哺乳动物新皮层是一种六层结构，通过整合感官信息并通过产生适当的电动机输出来控制世界的行为来创建世界。每个层的处理信息都不同，因此了解如何组织层特异性神经元网络将为了解不同层在电路中的功能提供基础。内侧前额叶皮层（MPFC）整合了许多大脑区域的信息，并参与了复杂的行为，包括社交互动和决策。重要的是，MPFC电路通常会在自闭症等神经发育障碍中受到破坏，但是对于MPFC的精细规模组织或MPFC层如何整合不同种类的信息。 Luo Lab最近开发了一种基于狂犬病的单频型 - 突触跟踪技术，该技术还可以详细分析除整个大脑长距离映射外，还可以详细分析局部电路。这种新的狂犬病技术可以与特定层的CRE驱动器鼠标线相结合，以生成内侧前额叶皮层（MPFC）中层特异性电路的详细图。 CRE依赖性的狂犬病追踪也将与细胞类型的特异性基因敲除，因此这些地图将为研究新皮质连通性在发育和疾病中以前所未有的精度和范围的遗传调节提供基础。为了开始剖析建立特定MPFC连接性的分子途径，该项目将重点关注自闭症相关基因TSC1的作用。最近的研究表明，TSC1缺失会增加兴奋性突触连通性，并改变兴奋和抑制的平衡，从而导致海马神经元的过度兴奋。该表型可能与TSC1在结节性硬化症复合体中的作用有关，该疾病患者患有良性肿瘤，癫痫和自闭症。在有条件的TSC1FL/FL小鼠中，与层特异性CRE驱动器交叉的有条件TSC1FL/FL小鼠进行CRE依赖性狂犬病将有助于研究细胞自主的作用O TSC1在MPFC连接性和层特定组织的发展中。由于TSC1是雷帕霉素复合物的哺乳动物靶标的负调节剂MTORC1，还将研究TSC1体内功能的分子机制，以阐明这些信号通路如何调节脑发育。这项工作将为TSC1突变患者的自闭症和癫痫引起自闭症和癫痫的分子和电路级机制提供更深入的了解。