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Mechanisms of striatal structural and functional plasticity.

纹状体结构和功能可塑性的机制。

基本信息

批准号：
10459485
负责人：
YEVGENIA KOZOROVITSKIY
金额：
$ 33.64万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459485
关键词：
Acute Address Age Architecture Basic Science Birth Brain Cell Culture System Cells Communication Complex Corpus striatum structure Cyclic AMP-Dependent Protein Kinases Data Dendrites Dendritic Spines Development Disease Electron Microscopy Evaluation Female Foundations Functional Imaging Functional disorder G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Genetic Glutamates Goals Growth Image Knowledge Lasers Learning Locomotion Maintenance Maps Membrane Molecular Monitor Nature Neuromodulator Neurons Neurotransmitters Organism Peroxidases Phase Presynaptic Terminals Probability Process Property Protein Biosynthesis Receptor Activation Regulation Research Personnel Sex Differences Signal Transduction Slice Synapses System Testing Therapeutic Therapeutic Agents Time Vertebral column Work base cell type experimental study extracellular functional plasticity imaging approach innovation insight male motivated behavior neuroregulation postnatal development postsynaptic presynaptic reconstruction recruit response sex spatiotemporal synaptic function synaptogenesis therapy design tool two photon microscopy two-photon

项目摘要

Dendritic spines are the remarkable, specialized membrane compartments on neurons that house the postsynaptic, receiving end of most excitatory, glutamatergic synapses in the brain. They are highly plastic and change during development, learning, and in disease. This proposal relies on multi-laser 2-photon imaging and photostimulation approaches to generate and evaluate new connections on genetically targeted striatal neurons, dissecting interacting variables of sex, age, and neuromodulatory state. The proposal builds on preliminary observations of sex differences in spinogenesis, which may interact with other convergent signaling cascades to control dendritic spine formation and sensitivity to therapeutic agents. Further, the earliest stages of nascent synapses in striatal neurons will be defined functionally and ultrastructurally, using newly developed molecular tools and imaging approaches to assist this objective. The proposed work would yield valuable insights into new spine and synapse genesis, early-stage function, and stability, impacting basic research relevant to synaptic development and rules that guide plasticity. The resulting platform will help to drive technical innovation that would allow researchers to design therapies to augment reconstruction of neuronal architecture or deconstruct aberrant connectivity.

树突棘是神经元上显著的、特化的膜隔室，突触后，大脑中大多数兴奋性突触的接收端。它们具有高度可塑性，在发育、学习和疾病中的变化。该提议依赖于多激光器双光子成像，光刺激方法在遗传靶向纹状体上产生和评估新的连接神经元，解剖性别，年龄和神经调节状态的相互作用变量。该提案建立在初步观察到棘发生中的性别差异，这可能与其他会聚信号相互作用级联以控制树突棘形成和对治疗剂的敏感性。此外，最早的阶段新生突触的纹状体神经元将被定义功能和超微结构，使用新开发的分子工具和成像方法来帮助实现这一目标。拟议的工作将产生宝贵的深入了解新的脊柱和突触发生，早期功能和稳定性，影响基础研究与突触发育和指导可塑性的规则有关。由此产生的平台将有助于推动技术创新，使研究人员能够设计出增强神经元重建的疗法，架构或解构异常连接。