Imaging Circuit Change in the Motor Cortex of Mouse Model of ALS

ALS 小鼠模型运动皮层的成像电路变化

基本信息

批准号：
8510018
负责人：
GREGORY A. COX
金额：
$ 21.88万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8510018
关键词：
Ablation Affect Amyotrophic Lateral Sclerosis Attention Bilateral Bulla Cephalic Cessation of life Clinical Color Development Diphtheria Toxin Disease Progression Foundations Functional disorder Future Genes Glutamate Transporter Glutamates Goals Human Image Interneurons Label Life Mediator of activation protein Microscopy Monitor Morphology Motor Cortex Motor Neurons Mus Nerve Degeneration Neurodegenerative Disorders Neurons Onset of illness Pathogenesis Patients Play Proteins Role Saline Spinal Cord Staining method Stains Subgroup Symptoms System Testing Time Toxin Transgenic Mice design diphtheria toxin receptor emerging adult excitotoxicity in vivo inhibitor/antagonist innovation motor neuron degeneration mouse model mutant nervous system disorder neuromuscular neuron loss neurophysiology new therapeutic target novel therapeutic intervention novel therapeutics public health relevance tool two-photon

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in both the motor cortex and the spinal cord. Currently, there is no curative therapy. The objective of this project is to characterize the mechanisms of ALS pathogenesis, with the long-term goal of identifying new therapeutic targets. Glutamate-induced excitotoxicity of motor neurons is considered a primary mechanism of ALS pathogenesis. While most previous studies have focused on the lack of glutamate transporter as the primary mediator of excitotoxicity, little attention has been paid to a potential alternative cause of excitotoxicity: dysfunctional inhibitor mechanisms. The "cortical hyperexcitability" hypothesis states that degeneration of cortical inhibitory interneurons (CIIN) causes excessive excitability of cortical motor neurons (CMN) and their ultimate degeneration. Despite the existence of this hypothesis for decades, it remains unclear whether CIIN indeed undergo degeneration in ALS, whether loss of CIIN precedes loss of CMN, and whether loss of CIIN results in CMN death. Using an innovative two-photon microscopy system that we designed for in vivo imaging of neuronal morphology in mice, we aim to test the cortical hyperexcitability hypothesis using two mouse models of ALS. Our preliminary studies in ALS mice demonstrated significant loss of dendritic branches in CIIN and marked dendritic blebbing in CMN in the motor cortex, both occurring prior to disease onset. These findings suggest that both CIIN and CMN undergo degeneration in ALS, consistent with the hyperexcitability hypothesis. We propose to test this hypothesis using in vivo microscopy imaging and in vivo functional tests to elucidate the morphological changes of CIIN and the functional consequences of their degeneration in ALS mice. We will: Aim 1) Determine if CIIN degeneration is an initiating factor in ALS pathogenesis, through in vivo imaging in ALS mouse models; and Aim 2) Determine if ablation of CIIN in the motor cortex causes CMN death and accelerates ALS disease progression. Successful completion of this project will establish a foundation for understanding the role of CIIN in ALS pathogenesis, paving the way for future research targeting CIIN as a novel therapeutic for ALS.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是运动皮层和脊髓中的运动神经元逐渐丧失。目前，尚无治愈方法。该项目的目标是描述 ALS 发病机制的特征，长期目标是确定新的治疗靶点。谷氨酸诱导的运动神经元兴奋性毒性被认为是 ALS 发病机制的主要机制。虽然大多数先前的研究都集中在缺乏谷氨酸转运蛋白作为兴奋性毒性的主要介质，但很少关注兴奋性毒性的潜在替代原因：功能失调的抑制剂机制。 “皮质过度兴奋”假说指出，皮质抑制性中间神经元（CIIN）的退化导致皮质运动神经元（CMN）过度兴奋并最终退化。尽管这一假说已经存在了几十年，但仍不清楚 CIIN 是否确实在 ALS 中发生退化、CIIN 的丧失是否先于 CMN 的丧失以及 CIIN 的丧失是否会导致 CMN 死亡。使用我们为小鼠神经元形态的体内成像而设计的创新双光子显微镜系统，我们的目标是使用两种 ALS 小鼠模型来测试皮质过度兴奋假说。我们对 ALS 小鼠的初步研究表明，运动皮层 CIIN 中的树突分支显着丧失，CMN 中树突起泡明显，这两种情况都发生在疾病发作之前。这些发现表明 CIIN 和 CMN 在 ALS 中都会发生退化，这与过度兴奋假说一致。我们建议使用体内显微镜成像和体内功能测试来检验这一假设，以阐明 ALS 小鼠中 CIIN 的形态变化及其退化的功能后果。我们将：目标 1) 通过 ALS 小鼠模型的体内成像确定 CIIN 变性是否是 ALS 发病机制的起始因素；目标 2) 确定运动皮质中 CIIN 的消融是否会导致 CMN 死亡并加速 ALS 疾病进展。该项目的成功完成将为理解 CIIN 在 ALS 发病机制中的作用奠定基础，为未来以 CIIN 作为 ALS 新型治疗方法的研究铺平道路。