慢性尼古丁暴露调控Pdlim5减轻精神分裂症引起的认知损伤及其分子机制研究

认知损伤被认为是精神分裂症的核心损伤，目前并无有效药物治疗认知损伤。临床研究发现，精神病人群约有50-90%是吸烟患者，这种高吸烟率可能是因为患者通过吸烟来改善认知损伤。本课题组已发表文章显示，尼古丁可显著提高大鼠在T迷宫交替任务中的空间工作记忆。本实验室前期研究显示，MK-801诱导的精神分裂症引起认知损伤并伴有Pdlim5升高及CREB转录共激活因子CRTC1下降，而慢性尼古丁暴露则引起Pdlim5下降及CRTC1升高。因此我们提出假说：慢性尼古丁暴露通过调控Pdlim5从而减轻精神分裂症引起的认知损伤。本项目将采用基因敲除、siRNA干扰及过表达等技术，以Pdlim5/CRTC1为靶点，研究其在减轻精神分裂症引起的认知损伤中的作用，阐明慢性尼古丁暴露减轻精神分裂症引发的认知损伤的分子机制，从而为寻求认知损伤的治疗靶点、治疗策略提供重要的理论依据和指导。

Cognitive impairment is recognized as a core deficit of schizophrenia, and there is no drug to treat cognitive impairment. Clinical studies have found that about 50-90% of all psychiatric patients are smokers, and the high rate of smoking in schizophrenic patients may be due to the fact that patients are self-treating by smoking to improve recognition. Our published results showed that nicotine treatment significantly improves the working memory of rats in the T maze alternate task. Our preliminary data showed that schizophrenia caused cognitive impairment accompanied by Pdlim5 increase and CRTC1(CREB-regulated transcription coactivator1) decrease. Of note, chronic nicotine exposure could significantly decrease Pdlim5 and increase CRTC1. Our hypothesis is that chronic nicotine exposure attenuates schizophrenia-induced cognitive impairment by regulating Pdlim5. In this study, using gene knockout, siRNA interference and overexpression, we will investigate the roles of Pdlim5/CRTC1 in schizophrenia-induced cognitive impairment as well as the effect of chronic nicotine exposure on Pdlim5/CRTC1 expression, so as to provide important theoretical basis and guidance for the treatment of therapeutic target and treatment strategy.