The Role of the Extracellular Matrix in Alcohol Use Disorder

细胞外基质在酒精使用障碍中的作用

基本信息

批准号：
10606097
负责人：
Jake Ryan Valeri
金额：
$ 4.13万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
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：
2023-04-20 至 2026-04-19
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606097
关键词：
Acute Adult Affect Alcohol consumption Alcohol dependence Alcohols Anabolism Area Astrocytes Autopsy Brain Brightfield Microscopy Cells Chondroitin Sulfate Proteoglycan Complex Confocal Microscopy Corpus striatum structure Cue-induced relapse Data Dependence Development Drug Addiction Enzymes Excitatory Synapse Exposure to Extracellular Matrix Extracellular Matrix Degradation Gene Expression Profile Gene Expression Profiling Glycoproteins Hippocampus Human Individual Interleukins Interneurons Intoxication Knock-out Knockout Mice Label Literature MMP9 gene Maintenance Major Depressive Disorder Matrix Metalloproteinases Measures Mediating Memory Methods Microglia Modeling Molecular Mood Disorders Mus Neuroglia Neurons Parvalbumins Pathology Pathway interactions Peptide Hydrolases Persons Pharmaceutical Preparations Phase Prefrontal Cortex Prevalence Process Protease Inhibitor Public Health Recovery Regulation Regulatory Pathway Rewards Rodent Rodent Model Role Sampling Signal Pathway Signal Transduction Substance Use Disorder Synapses Techniques Testing Therapeutic Tissue Sample Tissues Transcription Alteration Transgenic Organisms Work addiction alcohol comorbidity alcohol effect alcohol exposure alcohol memory alcohol reward alcohol use disorder cohort comorbidity conditioned place preference cytokine design drug of abuse effective therapy experience experimental study fear memory high reward human subject mRNA Expression memory acquisition memory consolidation neurotransmission next generation sequencing novel strategies pharmacologic postsynaptic pre-clinical preclinical study preference presynaptic prevent protein expression receptor therapeutic development transcriptome sequencing

项目摘要

Project Summary Exposure to drugs of abuse, such as alcohol, induces plasticity in the brain and creates persistent drug-related memories. These brain changes and persistent activation of drug memories are believed to be central in contributing to drug addiction. A preponderance of literature has studied the tripartite synapse (pre- and postsynaptic cells, and astrocytes) in addiction; however, mounting evidence has implicated the tetrapartite synapse to indicate the additional involvement of extracellular matrix (ECM) molecules in this process. The ECM is comprised of a complex network of glycoproteins, chondroitin sulfate proteoglycans (CSPG), and enzymes, which interact to control underlying cell plasticity and excitability. Glycoproteins and CSPGs aggregate around inhibitory fast-spiking parvalbumin (PVB) interneurons throughout the brain to form perineuronal nets (PNN) which maintain and strengthen synapses. In rodents, PNNs are temporarily degraded after acute exposure to drugs, a process that relies on the activity of glial cells which secrete endogenous proteases that cleave PNN components. After persistent activation of reward memories (i.e., dependence), PNNs numbers are increased, indicating that neuronal ensembles associated with drugs of abuse are enveloped by PNNs. While the findings studying PNNs in preclinical addiction models are compelling, there are currently no data regarding PNNs in humans with alcohol use disorder (AUD) or other substance use disorders. This proposal focuses on alcohol- induced changes in PNNs and the molecules that regulate PNNs in humans, and how modifying neuron- microglia signaling cascades in rodents alters the regulation of contextual alcohol reward memory and the composition of PNNs. In Aim 1, we will evaluate PNN densities in human postmortem hippocampus tissue using quantitative brightfield microscopy together with measures of protein and mRNA expression for several of the endogenous ECM proteases, GABAergic neurons (e.g., PVB), and synaptic markers in tissue samples from the same subject cohort. We predict that individuals with AUD will have increased numerical densities of PNNs and increased PVB expression that coincide with decreased expression of ECM proteases. These findings will delineate how PNNs are impacted in humans with AUD and provide a basis for evaluating whether PNN changes in rodent models of substance use disorders are translatable to humans. In Aim 2, we will use mice to evaluate how knockout of the interleukin-33 receptor, ST2, impacts reward memory using conditioned place preference. Interleukin-33 is secreted by neurons in an experience-dependent manner, where it signals to its obligate ST2 receptor on microglia to mediate the release of several endogenous ECM proteases. We predict that knockout of the interleukin-33 receptor will impede the proteolytic cascades that mediate memory formation and consolidation, thereby curbing alcohol-induced place preference acquisition and consolidation. We believe the proposed studies will inform the use of pharmacologic agents which target the ECM to treat AUD and other substance use disorders, and will confirm and expand on findings from preclinical studies of the ECM in addiction.

项目概要接触滥用药物（例如酒精）会诱发大脑的可塑性，并产生持久的药物相关性回忆。这些大脑变化和药物记忆的持续激活被认为是助长吸毒成瘾。大量文献研究了三方突触（前突触和突触）突触后细胞和星形胶质细胞）成瘾；然而，越来越多的证据表明四方参与突触表明细胞外基质 (ECM) 分子在此过程中的额外参与。细胞外基质由糖蛋白、硫酸软骨素蛋白聚糖 (CSPG) 和酶组成的复杂网络组成，它们相互作用以控制潜在的细胞可塑性和兴奋性。糖蛋白和 CSPG 聚集在抑制性快速尖峰小清蛋白 (PVB) 整个大脑的中间神经元形成神经周围网 (PNN) 维持和加强突触。在啮齿类动物中，PNN 在急性暴露后会暂时降解。药物，这个过程依赖于神经胶质细胞的活性，神经胶质细胞分泌内源性蛋白酶来裂解 PNN 成分。持续激活奖励记忆（即依赖性）后，PNN 数量会增加，表明与滥用药物相关的神经元群被 PNN 包围。虽然调查结果在临床前成瘾模型中研究 PNN 是引人注目的，目前没有关于 PNN 的数据患有酒精使用障碍 (AUD) 或其他物质使用障碍的人。该提案的重点是酒精—— 诱导人类 PNN 和调节 PNN 分子的变化，以及如何修改神经元啮齿动物中的小胶质细胞信号级联改变了背景酒精奖赏记忆的调节 PNN 的组成。在目标 1 中，我们将使用以下方法评估人类死后海马组织中的 PNN 密度定量明场显微镜以及一些蛋白质和 mRNA 表达的测量内源性 ECM 蛋白酶、GABA 能神经元（例如 PVB）和组织样本中的突触标记物同一受试者队列。我们预测患有 AUD 的个体 PNN 和 PNN 的数值密度将会增加 PVB 表达增加与 ECM 蛋白酶表达减少一致。这些发现将描述 PNN 对 AUD 患者的影响，并为评估 PNN 是否发生变化提供基础在啮齿动物模型中，物质使用障碍可以转化为人类。在目标 2 中，我们将使用小鼠来评估敲除白细胞介素 33 受体 ST2 如何利用条件位置偏好影响奖赏记忆。 Interleukin-33 由神经元以依赖于经验的方式分泌，并向其专性 ST2 发出信号小胶质细胞上的受体介导几种内源性 ECM 蛋白酶的释放。我们预测淘汰赛白细胞介素 33 受体的减少将阻碍介导记忆形成的蛋白水解级联反应整合，从而抑制酒精引起的地方偏好的获得和整合。我们相信拟议的研究将告知使用针对 ECM 的药物治疗 AUD 和其他药物物质使用障碍，并将确认和扩展 ECM 成瘾临床前研究的结果。