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：
8686580
负责人：
Noelle D L 'Etoile
金额：
$ 34.18万
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/8686580
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 gene discovery 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，与精确调节的电路相互连接，以介导感知，思想和行为等重要功能。长期以来，人们一直对感官活动对突触可塑性产生重要影响。了解这些过程的分子基础可能有助于理解神经系统疾病，例如自闭症和精神分裂症。然而，对于正常活性和长期活性影响突触可塑性的分子机制仍然未知。通过研究遗传模型生物可以加速这些途径中所需的分子的发现，其中大规模的基因发现技术是可行的。为了解决这个问题，我们建议采用一种创新的方法来研究感觉活动对突触可塑性的影响，研究遗传模型有机体中两个定义的电路中的所有响应的所有响应。我们将在最高水平，细胞水平的钙反应，利用基于反触觉的基于基于跨突触的分型GFP的标记NLG-1抓握以及这些事件所需的单个分子之间的特定突触连接分析行为输出。该综合提案与NINDS的任务有关支持研究旨在通过支持有关神经系统细胞的生物学，神经系统发育，大脑，行为，神经变性，脑可塑性，脑塑性，感官功能，突触和电路的基础研究，旨在减轻神经系统疾病的负担。使用这种方法，我们发现了一种依赖Galpha-Fold的途径，正常的感觉活动可以保持适当的突触连接，以及EGL-4/PKG依赖性途径，通过该途径，动物可以适应长期的感觉信号传导。我们的研究将表征这些途径影响结构和功能突触可塑性的机制。我们的具体目的是：1）阐明正常感觉活动会影响结构可塑性的分子途径，2）确定长期感觉活动引起的可塑性的分子基础。这两个电路的强大表征与我们可用于研究它们的强大工具相结合，提供了独特的潜力，可以发现新的和意外的信号传导途径，以介导感官活动依赖于突触可塑性，然后可以在其他系统中探索。