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Optogenetic approaches to study post-stroke recovery mechanisms

研究中风后恢复机制的光遗传学方法

基本信息

批准号：
10364739
负责人：
GARY K STEINBERG
金额：
$ 62.87万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364739
关键词：
Address Affect Animals Area Automobile Driving Biological Brain Brain Diseases Brain region Calcium Cause of Death Cell Count Characteristics Cholesterol Clinical Research Corpus striatum structure Data Event Female Frequencies Functional Magnetic Resonance Imaging Future G Protein-Coupled Receptor Signaling Genes Goals Grant High-Throughput RNA Sequencing Image Imaging Techniques Individual Infarction Intervention Location Maps Medical Metabolism Microscope Molecular Molecular Profiling Molecular Target Motor Cortex Mus Neurons Parvalbumins Pathway interactions Population Recovery Recovery of Function Reporting Resolution Role Sex Differences Site Somatosensory Cortex Stains Stroke Techniques Testing Thalamic structure Therapeutic Therapeutic Intervention Time Translating Validation behavior test brain remodeling calmodulin-dependent protein kinase II cell type cholesterol biosynthesis design disability effective therapy functional outcomes imaging system improved insight male multimodality nervous system disorder neural circuit neuroimaging neuroregulation new therapeutic target optogenetics partial recovery portability post stroke promoter relating to nervous system sex stroke outcome stroke recovery tool transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY Stroke is the leading cause of death with very limited treatment options. This devastating neurological disease is increasingly viewed as a disease of brain connectivity as a damaged stroke area can affect both local and connected brain regions, causing disruptions in neuronal activity and metabolism network-wide. Recovery of lost function can occur after stroke and is attributed to brain remodeling in areas adjacent to or connected to the infarct. In this proposal, we aim to investigate the role of key brain circuits in post-stroke recovery at the functional, cellular and molecular level, using optogenetics, advanced live imaging and high throughput RNA sequencing techniques. Previously our lab has demonstrated that selective optogenetic neuronal stimulation in the ipsilesional motor cortex (iM1) can activate plasticity mechanisms and promote recovery. Recently we have employed the optogenetic functional MRI technique to systematically map brain-wide changes in neural circuits after stroke. We have identified key circuits altered by stroke and demonstrated two key circuits restored by iM1 stimulations. Our map data also revealed two candidate circuits that were not restored by iM1 stimulations, suggesting that greater recovery could be achieved if we can rescue these circuits by directly stimulating them. In this proposal we aim to investigate key neural circuits we identified from our activation maps and elucidate their role in post-stroke recovery. In Aim1 we will use circuit-specific optogenetic tools and functional behavior tests to interrogate the role of key circuits in post-stroke recovery. This aim will address whether these circuits have beneficial or maladaptive role during post-stroke recovery. In Aim2 we will examine cellular resolution of real-time neuronal activity dynamics in key circuits after stroke using a portable live calcium imaging system. This will elucidate the neural activity dynamics (excitatory and inhibitory) of key circuits at the cellular level, allowing us to identify the temporal profile and the key neuronal populations altered by stroke, and how iM1 stimulations affect these characteristics to enhance recovery. In Aim3 we will investigate the transcriptome of key circuit areas using RNAseq, in order to identify key molecular targets and pathways altered by stroke and by iM1 stimulations. Preliminary RNAseq analysis revealed distinct pathways altered by iM1 stimulations. We aim to perform RNAseq in multiple regions including iM1 (stimulation site) and ipsilesional thalamus (iM1- connected region) to elucidate whether similar pathways are involved, and if we can identify a common molecular signature that drive recovery. We will also perform RNAseq in both sexes in order to ascertain any sex-specific differences that may be present in post-stroke recovery. Together these results will 1) advance the understanding of neural circuit dynamics during post-stroke recovery; and 2) identify key neural circuits/cell types/molecular targets and optimal time window for designing brain stimulation strategies and other therapeutic interventions in future clinical studies.

项目总结