跑步锻炼通过多靶点缩短经典抗抑郁药物起效潜伏期的机制研究

Depression has become a major public health issue. However, there is a delay in the onset of classical antidepressants in the treatment of depression or even worsen symptoms within the first weeks of treatment, such as fluoxetine. Our previous studies have found that the antidepressant onset time of treadmill exercise was earlier than that of fluoxetine. However, whether exercise can shorten the onset latency of classical antidepressants is not clear yet, and the mechanism is unclear. In recent years, the hypothesis of neuroplasticity in depression has drawn much attention. Our previous studies have shown that treadmill exercise could increase the number of dendritic spines and mature oligodendrocytes in hippocampus and the protein expression of myelin related proteins in medial prefrontal cortex (MPFC) of depression. Additionally, there are evidences proven that fluoxetine on these structures slower than running exercise. Therefore, we will further study whether treadmill exercise activates the PPARγ / adiponectin axis to promote neurogenesis in the dentate gyrus and increase the number of dendritic spines and the complexity of dendrites in the MPFC and hippocampus of depression. Moreover, we will study whether treadmill exercise increases the expression of PGC-1α on the mature oligodendrocyte, then activates LXRβ and ultimately promotes myelination in the MPFC and hippocampus of depression. This study is expected to further understand the mechanism of shortening the onset latency of classical antidepressants by running exercise, which is of great significance for the treatment of depression.

抑郁症已成为重大的公共卫生问题，而经典抗抑郁药（如氟西汀）治疗抑郁症存在起效延迟且在治疗初期病情加重的现象。我们的前期研究发现跑步锻炼抗抑郁起效时间早于氟西汀治疗，而跑步锻炼能否缩短经典抗抑郁药的起效潜伏期，尚不明确，其机制也不清楚。近年来抑郁症神经可塑性假说受到关注，我们的前期研究表明跑步锻炼能增加抑郁症海马内树突棘、成熟少突胶质细胞的数量及内侧前额叶皮质（MPFC）内髓鞘相关蛋白的表达，有证据显示氟西汀对这些结构的作用均迟于跑步锻炼。本项目将深入研究跑步锻炼是否通过激活PPARγ/脂联素轴，促进抑郁症海马新生神经元形成，增加MPFC及海马内树突棘数量和树突复杂程度；研究跑步锻炼是否通过增加抑郁症MPFC及海马内成熟少突胶质细胞上的PGC-1α，激活LXRβ，促进髓鞘形成，以缩短经典抗抑郁药的潜伏期。本研究可望进一步认识跑步锻炼缩短经典抗抑郁药起效潜伏期的机制，对抑郁症的治疗有重要意义。

经典抗抑郁药物（如氟西汀）治疗抑郁症存在起效延迟且在治疗初期病情加重的现象。通过运动来改善精神心理疾病，尤其是抑郁症，已经有几十年的历史。然而，运动能否缩短经典抗抑郁药的起效潜伏期，尚不明确，其机制也不清楚。因此，我们对抑郁症慢性不可预知应激模型（CUS）动物给予跑步锻炼和氟西汀治疗，并运用行为学方法、体视学方法与免疫组化、免疫荧光相结合的方法以及腺相关病毒沉默技术、分子生物学方法，研究了跑步锻炼是否通过多种途径协同增强抑郁症海马及内侧前额叶皮质内的神经可塑性以缩短氟西汀的治疗潜伏期。我们主要的研究发现是：跑步锻炼较经典抗抑郁药物氟西汀能更快、更全面地改善CUS模型小鼠的抑郁样行为；跑步锻炼可以促进该模型小鼠海马CA1区少突胶质细胞的分化及髓鞘形成，而氟西汀却不能；跑步锻炼能够促进CUS模型小鼠海马DG内新生神经元的成熟，而氟西汀对于CUS模型小鼠海马DG内新生神经元成熟的作用弱于跑步锻炼；跑步锻炼能够增加CA1、CA3区及DG内的树突棘突触可塑性，而氟西汀对于CUS模型小鼠海马内的树突棘突触可塑性的改善主要集中于DG内而非CA1、CA3区。这些研究结果揭示了跑步锻炼较氟西汀提前产生抗抑郁样行为的可能机制。同时，跑步锻炼能够显著增加CUS模型大鼠海马及内侧前额叶皮质内星形胶质细胞的总数量及其新生，能够显著改善CUS模型大鼠海马内的炎症因子水平及小胶质细胞的数量及其活化状态，能够显著增加CUS模型大鼠内侧前额叶皮质内成熟少突胶质细胞的数量及髓鞘形成。这些结果进一步从胶质细胞可塑性的角度认识了跑步锻炼抗抑郁的细胞机制。此外，还发现跑步运动通过海马PGC-1α对PV+中间神经元的保护作用可能是跑步运动治疗抑郁症的潜在作用机制之一。因此，本项目的研究结果阐明了跑步锻炼通过多脑区、多途径增加抑郁症大脑的神经可塑性的作用和机制，进一步认识了跑步锻炼较经典抗抑郁药物氟西汀能更快起效的机制，对临床上缩短经典抗抑郁药物的起效潜伏期有重要意义。