Castro-Pascual Ivanna C, Ferramola Mariana L, Altamirano Fernando G, Cargnelutti Ethelina, Devia Cristina M, Delgado Silvia M, Lacoste María G, Anzulovich Ana C
Laboratory of Chronobiology, IMIBIO-SL (CONICET-UNSL), Argentina.
Department of Biochemistry, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis (UNSL), San Luis, Argentina; Laboratory of Chronobiology, IMIBIO-SL (CONICET-UNSL), Argentina.
Brain Res. 2024 Dec 15;1845:149195. doi: 10.1016/j.brainres.2024.149195. Epub 2024 Aug 23.
Aging is a major risk factor for cognitive deficits, impaired locomotion, and gait disorders. Although oxidative stress and circadian disruption are involved in both normal aging and the pathogenesis of age-associated diseases, just a very few studies explore the consequences of aging on circadian rhythms in the cerebellum. Here, we investigated age-dependent changes in the circadian organization of the molecular clock, antioxidant defenses and synaptic plasticity-related factors, in the rat cerebellum, and discussed the impact of that altered temporal organization on the cognitive function of this brain area. Particularly, we examined the circadian patterns of Brain and muscle ARNT-like 1 (BMAL1) protein levels, Glutathione peroxidase 4 (GPx4) gene expression, GPx and Catalase (CAT) enzymes activity, reduced glutathione (GSH) levels, and the Brain-derived neurotrophic factor (Bdnf) and its Tyrosine kinase receptor B (TrkB) circadian expression. Endogenously-driven circadian rhythms of BMAL1, GPx4, CAT, GSH, and Bdnf/TrkB factors, were observed in the young rat cerebellum. The rhythms' acrophases show a circadian organization that might be crucial for the daily cerebellar-dependent cognitive functions. Notably, aging disrupted circadian rhythms and the temporal organization of BMAL1, antioxidant defenses, and cognitive Bdnf/TrkB gene expression. Increased oxidative stress and disruption of clock-controlled rhythms during aging, might precede and cause the loss of circadian organization in the aged cerebellum. We expect our results highlight circadian rhythms of the studied factors as new targets for the treatment of age-dependent cerebellar disorders.
衰老 是认知缺陷、运动功能受损和步态障碍的主要风险因素。尽管氧化应激和昼夜节律紊乱与正常衰老以及与年龄相关疾病的发病机制都有关联，但仅有极少数研究探讨衰老对小脑昼夜节律的影响。在此，我们研究了大鼠小脑中分子时钟、抗氧化防御和突触可塑性相关因子的昼夜节律组织随年龄的变化，并讨论了这种改变的时间组织对该脑区认知功能的影响。具体而言，我们检测了脑和肌肉芳香烃受体核转位蛋白样1（BMAL1）蛋白水平、谷胱甘肽过氧化物酶4（GPx4）基因表达、GPx和过氧化氢酶（CAT）活性、还原型谷胱甘肽（GSH）水平以及脑源性神经营养因子（Bdnf）及其酪氨酸激酶受体B（TrkB）的昼夜表达模式。在幼鼠小脑中观察到了BMAL1、GPx4、CAT、GSH和Bdnf/TrkB因子的内源性昼夜节律。这些节律的高峰期呈现出一种昼夜组织形式，这可能对日常依赖小脑的认知功能至关重要。值得注意的是，衰老破坏了昼夜节律以及BMAL1的时间组织、抗氧化防御和认知相关的Bdnf/TrkB基因表达。衰老过程中氧化应激增加和时钟控制节律的破坏，可能先于并导致老年小脑昼夜组织的丧失。我们期望我们的结果将所研究因子的昼夜节律凸显为治疗年龄依赖性小脑疾病的新靶点。
