Identification of novel mechanisms in alcohol-induced cognitive dysfunction

确定酒精引起的认知功能障碍的新机制

基本信息

批准号：
10349431
负责人：
LUIS ALBERTO NATIVIDAD
金额：
$ 24.9万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349431
关键词：
Abstinence Acute Address Affect Alcohol dependence Alcohol withdrawal syndrome Alcoholic Intoxication Alcoholism Alcohols Amino Acids Anatomy Area Behavior Behavioral Behavioral inhibition Binding Binding Proteins Biochemical Brain Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Characteristics Chronic Cocaine Cognitive Cognitive Therapy Consensus Corpus striatum structure Cues Cyclic AMP Cyclic AMP-Dependent Protein Kinases Disease Dorsal Drug Metabolic Detoxication Faculty Functional disorder Glutamate Receptor Glutamates Goals Heavy Drinking Hippocampus (Brain)Impaired cognition Impairment Laboratories Lead Lesion Long-Term Potentiation Medial Mediating Mitogen-Activated Protein Kinases Modeling Molecular N-Methyl-D-Aspartate Receptors Naltrexone Neurologic Neurotransmitters Nucleus Accumbens Pathology Pathway interactions Peptides Permeability Pharmaceutical Preparations Pharmacology Phase Phenotype Phosphorylation Phosphotransferases Positioning Attribute Prefrontal Cortex Procedures Protein Biosynthesis Protein Kinase Proteins Proteome Proteomics Rattus Receptor Signaling Relapse Role Scaffolding Protein Signal Pathway Signal Transduction Signaling Protein Site Synaptic plasticity System Time Training Treatment Efficacy Variant Withdrawal addiction alcohol exposure alcohol relapse alcohol seeking behavior behavior measurement calmodulin-dependent protein kinase II cognitive function cognitive performance craving density drinking drug of abuse experience experimental study flexibility genetic regulatory protein improved inhibitor insight learning extinction neural circuit novel peptidomimetics postsynaptic preservation prevent problem drinker protein protein interaction receptor function recruit response restraint success synaptic function transcription factor upstream kinase

项目摘要

Project Summary Impairments in cognitive function are among the “hallmark” characteristics of addiction. In this regard, alcoholism is associated with dysfunction of multiple cognitive faculties that may underlie the difficulties in reversing alcohol- seeking behaviors during extended periods of abstinence. Repeated cycles of alcohol intoxication and withdrawal dysregulate brain amino acid systems, an effect that is thought to impart a hyperexcitable state. Whereas acute withdrawal mobilizes signaling of the primary excitatory neurotransmitter glutamate, over time these neurological disturbances subside. The emergence of cognitive disruptions during protracted withdrawal suggests an underlying dysfunction in the medial prefrontal cortex (mPFC). In this regard, drugs of abuse mobilize protein kinases that, over the course of repeated exposures, produce long-term changes in synaptic function and molecular signaling networks that coincide with addictive phenotypes. We propose that withdrawal- induced cognitive impairments relate to an undercurrent of dysfunctional kinase signaling pathways that preserve aberrant glutamate receptor signaling in discrete regions of the mPFC. To this end, the K99 phase will involve training in novel proteomic enrichment strategies to broadly evaluate the mPFC proteome, as isolated by dorsal and ventral regions, towards the goal of identifying novel protein signaling targets in alcohol-dependent rats experiencing protracted withdrawal. We will then seek to characterize the molecular and cognitive behavioral relevance of these targets throughout the R00 phase using novel peptidomimetic strategies that target the disruption of specific protein-protein interactions. This study will provide novel insight into distinct signaling pathways that underlie alcohol-induced cognitive dysfunction.

项目摘要认知功能的障碍是成瘾的“标志”特征之一。在这方面，酒精中毒与多个认知能力的功能障碍有关，这些能力可能是逆转酒精的困难的基础在延长的节制期间寻求行为。重复的酒精中毒和戒断失调的脑氨基酸系统，这种作用被认为可以传播过度可观的状态。急性归功于动员一级兴奋性神经递质谷氨酸的信号传导，但随着时间的流逝这些神经系统疾病消退。长时间退出期间认知破坏的出现建议在介质前额叶皮层（MPFC）中存在潜在的功能障碍。在这方面，滥用药物动员蛋白激酶，在重复暴露的过程中，会产生长期的突触变化与添加剂表型一致的功能和分子信号网络。我们建议退出诱导的认知障碍与保留功能失调的激酶信号通路的潜流有关 MPFC离散区域中的异常谷氨酸受体信号传导。为此，K99阶段将涉及通过背面隔离的新型蛋白质组学富集策略的培训，以广泛评估MPFC蛋白质组和腹侧区域，目的是识别依赖酒精依赖大鼠的新蛋白质信号靶标经历受保护的戒断。然后，我们将寻求表征分子和认知行为这些目标在整个R00阶段的相关性使用针对的新型胡椒策略特定蛋白质蛋白相互作用的破坏。这项研究将提供有关不同信号的新见解酒精引起的认知功能障碍的途径。