Identification of novel mechanisms in alcohol-induced cognitive dysfunction

项目摘要 认知功能障碍是成瘾的“标志性”特征之一。在这方面，酗酒 与多种认知功能障碍有关，这可能是逆转酒精的困难的基础- 在长期禁欲期间寻求行为。反复的酒精中毒和 戒断会使大脑氨基酸系统失调，这种作用被认为会导致过度兴奋状态。 然而，随着时间的推移，急性戒断会调动主要兴奋性神经递质谷氨酸的信号传导， 这些神经紊乱就会消退长期戒断期间认知障碍的出现 表明内侧前额叶皮层（mPFC）存在潜在功能障碍。在这方面，药物滥用 动员蛋白激酶，在反复暴露的过程中，产生突触的长期变化， 功能和分子信号网络，符合成瘾表型。我们建议撤回- 诱导的认知障碍与功能失调的激酶信号通路的暗流有关， mPFC的离散区域中异常的谷氨酸受体信号传导。为此，K99阶段将涉及 在新的蛋白质组富集策略的培训，以广泛评估mPFC蛋白质组，作为分离的背 和腹侧区域，以确定酒精依赖大鼠中新的蛋白质信号转导靶点为目标 经历了长期的戒断然后，我们将寻求表征分子和认知行为 这些目标的相关性在整个R 00阶段使用新的拟肽策略，靶向 破坏特定的蛋白质-蛋白质相互作用。这项研究将为不同的信号传导提供新的见解 酒精引起的认知功能障碍的基础途径。

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.