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Circuit-Selective Astroglial Plasticity During Opioid Relapse

阿片类药物复发期间的电路选择性星形胶质细胞可塑性

基本信息

批准号：
10738654
负责人：
Anna K Kruyer
金额：
$ 17.91万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10738654
关键词：
ADRBK1 gene Abstinence Actin-Binding Protein Animal Model Astrocytes Attenuated Automobile Driving Behavior Behavioral Behavioral Paradigm Brain Cells Chronic Clinical Complement Receptor Confocal Microscopy Corpus striatum structure Cues Data Diffusion Dissection Dopamine Dopamine D1 Receptor Drug Addiction Drug usage Electrophysiology (science)Epigenetic Process Event Exposure to Extinction Fiber G protein coupled receptor kinase Genetic Transcription Glutamate Transporter Glutamates Goals Halorhodopsins Heroin Homeostasis Human Label Link Literature Measures Mediating Membrane Morphology Neurons Nucleus Accumbens Opioid Opsin Outcome Output Pathway interactions Peripheral Pharmaceutical Preparations Phosphorylation Photometry Physiology Population Pre-Clinical Model Process Production Proteins Publishing Rattus Relapse Research Rewards Role Self Administration Shapes Signal Transduction Sucrose Surface Synapses Synaptic Transmission Techniques Time Training Transgenic Organisms Viral Withdrawal Work cell motility cell type drug craving drug relapse drug seeking behavior effective therapy experience experimental study extracellular ezrin glutamatergic signaling heroin use in vivo insight knock-down link protein motivated behavior neural neural circuit neural model neuroadaptation neuropsychiatric disorder neurotransmission novel optogenetics postsynaptic prolonged abstinence protein expression response reward circuitry selective expression sensor small hairpin RNA tool tool development transmission process uptake

项目摘要

Abstract Vulnerability to relapse despite prolonged abstinence is a principal feature of drug addiction. Decades of research have expanded our understanding of the neural basis of relapse, but have yielded few effective treatments that restore top-down control over drug seeking in active and former users. In animal models, repeated drug use, but not repeated exposure to natural rewards, results in excess glutamate transmission within corticofugal projections to the striatum in the presence of reward-associated cues and contexts that drive seeking. This behavioral paradigm has been used to model neural adaptations that trigger relapse, since reactivity to drug-related cues is linked to drug craving in humans. The dysregulation of glutamate transmission after chronic heroin use arises in part from enduring changes in peripheral astrocyte processes that insulate active synapses and express the glutamate transporter GLT-1, consistent with a growing literature that illustrates a prominent role for this cell type in maintaining the integrity of excitatory synaptic transmission. My published data show that astrocytes in the NAcore undergo profound transient morphological plasticity in response to drug- but not sucrose-conditioned cues and that this plasticity serves to attenuate seeking behavior. Heroin-associated cues also stimulate an increase in surface-proximity of GLT-1 on the astroglial membrane, an adaptation expected to limit glutamate spillover during relapse in preclinical models. The goal of this proposal is to explore whether measures of astroglial plasticity that I have discovered are linked to transmitter release from cortical projections within the NAcore and to uncover intracellular signaling events that trigger morphological plasticity in astrocytes during drug-seeking. A final goal of this proposal is to determine whether cue-induced astrocyte adaptations impact different post-synaptic targets, since the two principle neuronal subtypes in the NAcore, D1- and D2-MSNs differentially impact drug seeking behavior. In Aim 1, I will combine confocal microscopy with in vivo fiber photometry in order to identify the time course of astroglial plasticity during a 2-hr reinstatement session. In Aim 2, I will pair optogenetics with confocal microscopy to determine whether glutamate from prelimbic cortical terminals is necessary to drive astrocyte motility and GLT-1 surface diffusion after extinction from heroin self-administration. In Aim 3, I will interfere with the signaling cascade that drives astrocyte process motility during seeking using viral-mediated delivery of shRNAs selectively in astrocytes. Finally, in Aim 4 I will use confocal microscopy in transgenic D1- and D2-Cre rats to determine whether astrocyte processes or surface- proximal GLT-1 are selectively associated with D1- or D2-MSNs during cue-reinstated seeking. These Aims will provide me with comprehensive training in optogenetics as well as with viral tools that will allow me to selectively manipulate protein expression in astrocytes and will link my previous findings with the underlying neural circuitry. The relevance of this work extends beyond relapse to opioids and may have implications for normal synaptic physiology underlying motivated behavior.

摘要