脑内5-HT通过调控伏隔核内ΔFosB提高运动动机在脑梗死后运动功能恢复中的作用机制研究

Clinical evidence suggested much more improved motor functions were observed in the affected limbs of ischemic stroke patients without depression who were taking selective serotonin reuptake inhibitors, such as fluoxetine, the first-line anti-depression medication, as an adjunctive agent with rehabilitation therapies. The treatment effects are of significant importance, however, the reason is unknown. It is postulated that changes of the concentration of serotonin (5-HT) in the synaptic cleft of certain area in the brain, such as nucleus accumbens (NAc), might be related to the observed treatment effects. ΔFosB in the NAc has been proved to be the biomarker of “increased impulsivity”. It was found to be involved in motivation and reward sensation. It was also found to be involved in planning new motor programs and its initiation. Based on the above clinical evidence and theories, we postulate that the increased 5-HT in the NAc after application of fluoxetine together with wheeling exercise on rats suffered from cerebral infarction would promote the expression of ΔFosB through 5-HT receptor related pathway, for example, 5-HT receptor → phospholipase C (PLC) → cAMP response element-binding protein (CREB); thus, changing the regulatory molecules in the nucleus, regulating the expression of the surface receptors (such as glutaminergic NMDA receptors and AMPA receptors which are related to the formation of the membrane potential) and remodeling the extracellular environment for synaptic growth through SC1; finally, increasing motor impulsivity, enhancing the effects of exercise therapy and helping with the improvement of motor functions in the affected limbs. The study aims at providing a new perspective for post-stroke motor function rehabilitation, as well as a new indication for medication and a new target for treatment.

有研究认为康复训练辅以氟西汀等5-羟色胺（5-HT）再摄取抑制剂可以更显著地改善无抑郁症脑梗死患者的患肢运动功能。该现象意义重大，但机理不明，考虑可能与伏隔核为主的特定脑区神经突触间隙内5-HT的含量和作用有关。伏隔核内ΔFosB是公认的“动机增强”的分子标志，与奖赏性感知和运动机行为有关，参与运动模式的规划和启动。基于上述临床和理论基础，本研究拟在大鼠脑梗死模型中重建转轮运动训练联合氟西汀治疗模式，通过行为学和分子研究观察验证伏隔核内5-HT水平提高，通过特定受体通路（如5-HT受体→磷脂酶C→CREB）促进ΔFosB表达，调控核内转录翻译，改变神经细胞表面受体（细胞膜电位相关的谷氨酸能NMDA受体和AMPA受体）和细胞外基质突触生长环境（SC1）；表现为运动动机增强，运动训练疗效提高，从而改善患肢运动功能。本研究旨在为脑梗死后运动功能康复提供一个新的理念、新的治疗靶点和新的用药指征。

有研究认为康复训练辅以氟西汀等5-羟色胺（5-HT）再摄取抑制剂可以更显著地改善无抑郁症脑梗死患者的患肢运动功能。伏隔核内ΔFosB是公认的“动机增强”的分子标志，与奖赏性感知和运动机行为有关，参与运动模式的规划和启动。本研究探索了大鼠/小鼠脑梗死模型中转轮运动+氟西汀治疗在行为学、组织形态学、相关蛋白分子表达、功能影像学等指标，发现转轮运动+氟西汀可能有助于加快运动功能恢复进程，但实验终点实验组与对照组间无统计学差异；组织形态学上可见转轮运动、氟西汀、转轮运动+氟西汀干预后突触和突触小泡数量明显增加，其中转轮运动+氟西汀突触联系最显著；分子学上，转轮运动+氟西汀有助于恢复双侧伏隔核内5-HT平衡，提高ΔFosB表达，下调5-HT2CR表达，提高海马区5-HT2AR表达，未能明显影响海马区CREB表达；下游信号分子通路还需进一步探索，分子指标变化与行为学联系仍需进一步研究；另外，转轮运动、氟西汀、转轮运动+氟西汀分别对伏隔核内神经递质产生明显影响，其意义还需进一步分析。本研究为脑梗死后运动功能康复提供一个新的理念，目前有部分结果支持该假设，但依据依旧不足以支持临床推广，还需要更深入的研究明确其有效性和机理。