权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigating cytoskeletal dynamics in astrocyte structure and cocaine seeking behavior

研究星形胶质细胞结构和可卡因寻求行为的细胞骨架动力学

基本信息

批准号：
10721883
负责人：
Janay Franklin
金额：
$ 3.96万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10721883
关键词：
Abstinence Actins Acute Affect Area Astrocytes Automobile Driving Behavior Behavioral Bioinformatics Brain Cessation of life Chronic Cocaine Cocaine Abuse Cocaine use disorder Collaborations Cytoskeletal Proteins Cytoskeleton Data Data Analyses Development Down-Regulation Elements Extinction FDA approved Functional disorder Gene Expression Genes Genetic Heroin Home Immunohistochemistry Impairment Individual Intervention Investigation Knowledge Learning Measures Mediating Messenger RNA MicroRNAs Microinjections Microscopy Molecular Neuroglia Neurons Nucleus Accumbens Pathway Analysis Pharmaceutical Preparations Phosphorylation Property Proteins Public Health Publishing Rattus Relapse Reporting Research Resolution RiboTag Role Saline Scientist Self Administration Structure Surface Synapses Synaptic Transmission Synaptic plasticity Testing Training United States Validation Viral Withdrawal candidate identification cell type cocaine exposure cocaine relapse cocaine seeking cocaine self-administration cocaine use computerized tools confocal imaging differential expression drug of abuse effective therapy experience experimental study ezrin insight long term abstinence mRNA Expression overdose death pre-clinical prolonged abstinence psychostimulant reward circuitry skills stimulant use disorder symposium synaptic function synaptogenesis therapeutic candidate therapeutic target tool transcriptome transcriptome sequencing treatment group treatment strategy virus genetics

项目摘要

ABSTRACT Cocaine abuse presents a significant public health concern across the United States, as the number of cocaine-related deaths in the United States has almost tripled since 2013. Despite an urgent need for intervention, an FDA-approved treatment for Cocaine Use Disorder is lacking. Hence, there is a considerable need for investigations into the mechanisms that drive relapse vulnerability. Recent advances indicate that cocaine-induced structural adaptations in astrocytes may contribute to relapse vulnerability. Astrocytes are the most abundant glial cell in the brain and regulate varied critical functions, including synaptic transmission and plasticity. Research in the Reissner lab has revealed that astrocytes in the nucleus accumbens are significantly structurally impaired following cocaine self-administration and extinction. In addition, preliminary data from our lab indicate that rat long-access (LgA, 6h/day) self-administration followed by prolonged abstinence (45d) leads to a significant ~40% decrease in astrocyte volume, surface area, and synaptic colocalization. However, the mechanisms driving these observations are unknown. I hypothesize that downregulation of astrocyte cytoskeletal dynamics is a major contributor to these effects. Accordingly, this proposal will examine how astrocyte cytoskeletal dynamics are altered following chronic cocaine self-administration and prolonged abstinence, and how manipulation of cytoskeletal proteins can influence cocaine seeking. Of note, phosphorylation of ezrin, an actin-cytoskeleton linker protein that is abundantly and preferentially expressed in astrocytes, is downregulated by acute cocaine exposure. Thus, the overarching hypothesis of this proposal is that cocaine and abstinence-induced astrocyte structural deficits result from alterations in astrocyte cytoskeletal dynamics, which further contribute to cocaine-seeking behaviors that are exacerbated following long-term abstinence. To test this hypothesis, in Aim 1 I will measure the effects of cocaine self-administration and abstinence on cytoskeletal proteins, including ezrin, and I will use an astrocyte-specific AAV to manipulate ezrin expression, to examine its role astrocyte structure and further in cocaine-seeking behaviors. In Aim 2, I will use a RiboTag AAV, to isolate astrocyte-specific mRNAs in conjunction with RNAseq as an unbiased approach to measure cocaine and abstinence-induced changes in the astrocyte transcriptome that may contribute to cocaine-seeking behavior. I will specifically analyze results to measure relative expression profiles of cytoskeletal proteins among these astrocyte mRNAs. These results will provide a greater understanding of how dysfunctions in astrocyte structure actively contribute to cocaine abuse and relapse.

摘要