海马Fyn激酶在θ短阵脉冲经颅磁刺激调节帕金森病认知障碍中的作用及机制研究

Cognitive impairments commonly occur in Parkinson’s disease (PD) and severely affect quality of life and treatment compliance. Current treatment approaches in PD are limited. Our previous studies have shown that deficiencies of the hippocampus are related to cognitive impairments in PD. Intermittent theta burst stimulation (iTBS) can regulate the expression of hippocampal Fyn which is an important factor for cognition, suggesting that iTBS might be a novel therapeutic strategy for cognitive impairments in PD by regulating hippocampal Fyn. In this project, we will investigate the effects of iTBS on cognitive behavior in rats with 6-hydroxydopamine lesions of the medial forebrain bundle by using behavioral, molecular biological, electrophysiological, and morphological approaches. We will further observe changes in the effects of iTBS on cognitive behavior, and Fyn-induced downstream responses by downregulating, upregulating and inhibiting of Fyn in the hippocampus, so as to explore the effects and mechanisms of hippocampal Fyn on the treatment of cognitive impairments in PD with iTBS. We hope that these findings will provide experimental evidences that iTBS is feasible for cognitive impairments in PD.

认知障碍是常见的帕金森病（PD）非运动系统症状，严重影响患者的生活质量及治疗依从性，目前其治疗手段有限。我们前期研究发现海马是导致PD认知障碍的关键脑区，而间断θ短阵快速脉冲刺激（iTBS）可上调海马中认知相关因子Fyn激酶的表达，提示iTBS极有可能通过调控海马Fyn激酶改善PD认知功能。本研究拟以成功建立的PD大鼠模型为对象，综合采用行为学、分子生物学和电生理学方法，明确iTBS对PD认知障碍的作用，并通过上调、下调海马Fyn激酶的表达及抑制其功能，观察iTBS对大鼠认知功能及Fyn下游效应作用的变化，揭示iTBS调节PD认知障碍的机制。本研究为探讨iTBS治疗PD认知障碍的可行性提供了实验依据。

认知障碍、抑郁及焦虑是常见的帕金森病（PD）非运动系统症状，严重影响患者的生活质量及治疗依从性，目前其治疗手段有限。间断θ短阵快速脉冲刺激（iTBS）作为非侵入性神经调控模式，对抑郁等情绪障碍及认知行为均具有调控作用，提示iTBS极有可能是PD非运动症状的新治疗模式。为明确iTBS对PD非运动症状的作用及机制，本研究以成功建立的PD大鼠模型为对象，综合采用行为学、分子生物学、电生理学及形态学方法，观察了iTBS对PD认知障碍、抑郁及焦虑的作用，并进一步观察了iTBS对海马、前额叶皮层等相关脑区电活动、c-Fos表达及Fyn激酶表达的影响。研究结果显示：iTBS-1 block可显著改善PD模型大鼠的运动行为、工作记忆，产生抗抑郁样效应，但不能改变PD模型大鼠的焦虑行为；iTBS-1 block不能改变海马Theta节律的峰频率及标准化功率，但iTBS-3 blocks显著降低海马Theta节律的标准化功率，该效应持续约40分钟；iTBS显著增加内侧前额叶皮层PrL及IL分区c-Fos的密度，同时也增加了外侧隔区、侧脑室旁丘脑c-Fos的密度，但并不改变海马c-Fos的密度；iTBS显著上调海马Fyn激酶的表达。上述结果提示：iTBS对PD工作记忆及抑郁症状具有改善作用，这一作用与内侧前额叶皮层及海马的电活动改变及Fyn激酶改变相关。本研究为探讨iTBS治疗PD认知障碍的可行性提供了实验依据。