A Circuit Mechanism for the Development of Cortico-cortical Connectivity

皮质-皮质连接发展的电路机制

基本信息

批准号：
10469418
负责人：
Natalia Vanesa De Marco Garcia
金额：
$ 50.68万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10469418
关键词：
ASD patient Ablation Adolescent Adult Affect Anatomy Angelman Syndrome Area Behavior Behavioral Brain Brain region Calcium Cerebral cortex Child Cognitive Contralateral Defect Development Developmental Process Disease Distant Emergency Situation Environmental Risk Factor Equilibrium Etiology Functional disorder Genes Genetic Genetic Predisposition to Disease Goals Head Image Impairment Interneurons Ipsilateral Knowledge Lead Motor Cortex Mus Mutation Neonatal Neurons Outcome Parietal Lobe Pathway interactions Patients Pattern Perception Phenotype Process Pyramidal Cells Research Role Schizophrenia Sensory Signal Pathway Signal Transduction Somatosensory Cortex Source Stimulus Study models Techniques Testing Vibrissae Virus Work autism spectrum disorder barrel cortex brain abnormalities childhood epilepsy critical period experimental study gamma-Aminobutyric Acid high risk in vivo innovation mutant neonate neuronal circuitry neuropathology pup rabies viral tracing receptor translational impact two-photon

项目摘要

Project Summary In the cerebral cortex, gamma-aminobutyric acid (GABA)ergic interneurons are the major source of inhibition. Interneuron dysfunction is strongly associated with autism and childhood epilepsy. We demonstrated that environmental influences such as electrical activity are fundamental for the maturation of GABAergic circuits. However, the identity of the activity patterns controlling interneuron development remains poorly understood. The long-term goal of this research is to uncover how early interneuron dysfunction leads to lasting neuropathologies. The objective of this proposal is to reveal the signaling pathways underlying activity- dependent development and to assess how perturbations in this process lead to aberrant brain function. To this end, we will use the murine barrel cortex as a well-established model for the study of activity-dependent circuit maturation. We will focus our studies in superficial circuits since our previous work indicates that these circuits are exquisitely sensitive to environmental perturbations in the neonate. In the near term, this proposal is aimed at investigating the role of specific interneuron subtypes in regulating the emergence of long range connectivity (Aim 1). In addition, this project will determine the role of GABAergic inputs for the functional maturation of pyramidal networks. We will study the role of Gabrb3, a gene encoding for the beta3 subunit of GABAA channel. Mutations in this gene are strongly associated with Angelman syndrome and ASD (Aim 2). Finally, we will assess how developmental defects in early GABAergic signaling lead to abnormal brain activity in cortico-cortical pathways during development (Aim 3). With respect to the outcomes, our work is expected to identify basic mechanisms fundamental for the emergency of a healthy E/I balance. In addition, these results are expected to have a significant translational impact because they will expand our mechanistic knowledge on how mutations in the GABRB3 gene may lead to behavioral abnormalities frequently observed in ASD patients.

项目概要在大脑皮层中，γ-氨基丁酸 (GABA) 能中间神经元是抑制的主要来源。中间神经元功能障碍与自闭症和儿童癫痫密切相关。我们证明了电活动等环境影响是 GABA 电路成熟的基础。然而，控制中间神经元发育的活动模式的身份仍然知之甚少。这项研究的长期目标是揭示早期中间神经元功能障碍如何导致持久的神经病理学。该提案的目的是揭示活动背后的信号传导途径 - 依赖性发展并评估该过程中的扰动如何导致异常的大脑功能。为此，我们将使用小鼠桶状皮层作为研究活动依赖性的成熟模型电路成熟。我们将把研究重点放在表面电路上，因为我们之前的工作表明这些新生儿的电路对环境扰动非常敏感。短期内，该提案旨在研究特定中间神经元亚型在调节长程神经元出现中的作用连接性（目标 1）。此外，该项目将确定 GABAergic 输入对于功能性的作用金字塔网络的成熟。我们将研究 Gabrb3 的作用，Gabrb3 是编码 β3 亚基的基因。 GABAA 频道。该基因的突变与天使综合征和 ASD 密切相关（目标 2）。最后，我们将评估早期 GABA 信号的发育缺陷如何导致大脑活动异常发育过程中的皮质-皮质通路（目标 3）。就成果而言，我们的工作预计将确定对实现这一目标至关重要的基本机制。健康 E/I 平衡的紧急情况。此外，这些结果预计将具有重大的转化作用影响，因为它们将扩展我们关于 GABRB3 基因突变如何导致的机制知识自闭症谱系障碍 (ASD) 患者中经常观察到的行为异常。