The Effect of Normal and Prolonged Sensory Activity on Neural Circuits

正常和长时间的感觉活动对神经回路的影响

基本信息

批准号：
9261229
负责人：
Noelle D L 'Etoile
金额：
$ 2.47万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9261229
关键词：
Adaptive Behaviors Address Adult Affect Afferent Neurons Animal Model Animals Autistic Disorder Basic Science Behavior Behavioral Assay Benzaldehyde Binding Proteins Brain Cadherins Caenorhabditis elegans Calcium Cell Adhesion Molecules Cells Cellular biology Defect Development Event G-Protein-Coupled Receptors Gene Expression Genes Genetic Genetic Models Genetic Screening Goals Health Human Image Imagery Individual Label Life Measures Mediating Messenger RNA Mission Molecular National Institute of Neurological Disorders and Stroke Nerve Degeneration Nervous system structure Neuraxis Neurons Nucleotides Odors Organism Output Pathway interactions Perception Play Process Proteins Reporter Research Research Support Resolution Role Schizophrenia Sensory Signal Pathway Signal Transduction Signaling Molecule Structure Synapses Synaptic plasticity System Techniques Testing Therapeutic Time Transgenic Organisms Work base brain behavior cell type complement C2a critical period fluorophore functional plasticity gene discovery genetic approach in vivo innovation loss of function mutant nervous system development nervous system disorder neural circuit neuroligin 1 optogenetics postsynaptic reconstitution research study response sensory stimulus synaptic function tool

项目摘要

DESCRIPTION (provided by applicant): The human central nervous system is composed of 100 billion neurons interconnected into precisely regulated circuits to mediate vital functions such as perception, thought, and behavior. Sensory activity has long been known to have important affects on synaptic plasticity. Understanding the molecular underpinnings of these processes may aid in understanding neurological disorders, such as autism and schizophrenia. However, much remains unknown about the molecular mechanisms by which normal activity and long-term activity affect synaptic plasticity. The discovery of molecules required in these pathways may be accelerated by the study of genetic model organisms, in which large-scale gene discovery techniques are feasible. To address this, we propose to take an innovative approach to studying the affects of sensory activity on synaptic plasticity, investigating all leves of the responses within two defined circuits in the genetic model organism C. elegans. We will assay behavioral output at the highest level, cellular-level calcium responses, specific synaptic connections between the neurons utilizing the trans-synaptic split-GFP based marker NLG-1 GRASP, and the individual molecules required for these events. This integrative proposal is relevant to the NINDS mission to support research that aims to reduce the burden of neurological disease by supporting basic research on the biology of the cells of the nervous system, nervous system development, genetics of the brain, behavior, neurodegeneration, brain plasticity, sensory function, synapses, and circuits. Using this approach, we have discovered a Galpha-olf-dependent pathway by which normal sensory activity maintains appropriate synaptic connections, and an EGL-4/PKG dependent pathway by which animals adapt to long-term sensory signaling. Our research will characterize the mechanism by which these pathways affect structural and functional synaptic plasticity. Our specific aims are to: 1) elucidate the molecular pathway by which normal sensory activity affects structural plasticity, and 2) determine the molecular basis for plasticity induced by long-term sensory activity. The robust prior characterization of these two circuits, in combination with the powerful tools we have available to study them, offers the unique potential to discover new and unexpected signaling pathways that mediate sensory activity dependent synaptic plasticity, which can then be explored in other systems.

描述（由申请人提供）：人类中枢神经系统由 1000 亿个神经元组成，这些神经元相互连接成精确调节的电路，以调节感知、思维和行为等重要功能。人们早就知道感觉活动对突触可塑性有重要影响。了解这些过程的分子基础可能有助于了解神经系统疾病，例如自闭症和精神分裂症。然而，关于正常活动和长期活动影响突触可塑性的分子机制仍然未知。对遗传模型生物的研究可能会加速这些途径所需分子的发现，其中大规模基因发现技术是可行的。为了解决这个问题，我们建议采取一种创新方法来研究感觉活动对突触可塑性的影响，研究遗传模型生物秀丽隐杆线虫中两个定义回路内的所有反应水平。我们将利用基于跨突触分裂 GFP 的标记 NLG-1 GRASP 分析最高水平的行为输出、细胞水平的钙反应、神经元之间的特定突触连接，以及这些事件所需的单个分子。这一综合提案与 NINDS 的使命相关，即支持旨在通过支持神经系统细胞生物学、神经系统发育、大脑遗传学、行为、神经变性、大脑的基础研究来减轻神经系统疾病负担的研究。可塑性、感觉功能、突触和电路。使用这种方法，我们发现了正常感觉活动维持适当突触连接的 Galpha-olf 依赖性途径，以及动物适应长期感觉信号传导的 EGL-4/PKG 依赖性途径。我们的研究将描述这些途径影响结构和功能突触可塑性的机制。我们的具体目标是：1）阐明正常感觉活动影响结构可塑性的分子途径，2）确定长期感觉活动诱导可塑性的分子基础。这两个电路的强大先验表征，与我们可用于研究它们的强大工具相结合，提供了发现新的和意想不到的信号通路的独特潜力，这些信号通路介导感觉活动依赖的突触可塑性，然后可以在其他系统中进行探索。