Identification of novel mechanisms in alcohol-induced cognitive dysfunction

项目摘要 认知功能障碍是上瘾的“标志”特征之一。在这方面，酗酒 与多种认知功能障碍有关，这可能是戒酒困难的基础- 在长期禁欲期间寻求行为。反复的酒精中毒循环和 戒断会扰乱大脑氨基酸系统，这种影响被认为会导致过度兴奋的状态。 而随着时间的推移，急性戒断会调动初级兴奋性神经递质谷氨酸的信号 这些神经紊乱会平息下来。长期戒断过程中认知障碍的出现 提示内侧前额叶皮质(MPFC)存在潜在功能障碍。在这方面，滥用药物 在反复暴露的过程中，激活蛋白激酶，从而在突触中产生长期变化 与成瘾表型一致的功能和分子信号网络。我们建议撤回- 诱发的认知障碍与功能失调的激酶信号通路潜流有关 MPFC不连续区域的谷氨酸受体信号异常。为此，K99阶段将包括 训练新的蛋白质组浓缩策略以广泛评估由背部分离的mPFC蛋白质组 和腹侧区域，朝着识别酒精依赖大鼠新的蛋白质信号靶点的目标前进 经历长时间的戒断。然后我们将寻求描述分子和认知行为的特征 在整个R00阶段使用新的靶向靶点的模拟多肽策略的这些靶点的相关性 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递提供新的见解 酒精引起的认知功能障碍的基础路径。

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.