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：
10242049
负责人：
YEVGENIA KOZOROVITSKIY
金额：
$ 33.68万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242049
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 Structure 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.

树突棘是神经元上非凡的、专门的膜室，它容纳突触后，大脑中大多数兴奋性谷氨酸突触的接收端。它们具有很强的可塑性并且在发育、学习和疾病过程中发生变化。该提案依赖于多激光 2 光子成像和光刺激方法产生和评估基因靶向纹状体的新连接神经元，剖析性别、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脊柱发生中的性别差异，这可能与其他汇聚信号相互作用级联控制树突棘的形成和对治疗药物的敏感性。此外，最早阶段使用新开发的技术，将在功能和超微结构上定义纹状体神经元中的新生突触分子工具和成像方法可以帮助实现这一目标。拟议的工作将产生有价值的成果对新脊柱和突触发生、早期功能和稳定性的见解，影响基础研究与突触发育和指导可塑性的规则相关。由此产生的平台将有助于推动技术创新将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的连接。