Chronic colitis exacerbates neuroinflammation, contributing to cognitive impairment during aging, but the mechanism remains unclear. The polarity distribution of astrocytic aquaporin 4 (AQP4) is crucial for the glymphatic system, which is responsible for metabolite clearance in the brain. Physical exercise (PE) improves cognition in the aged. This study aims to investigate the protective mechanism of exercise in colitis-associated cognitive impairment. To establish a chronic colitis model, 18-month-old C57BL/6 J female mice received periodic oral administration of 1% wt/vol dextran sodium sulfate (DSS) in drinking water. The mice in the exercise group received four weeks of voluntary wheel exercise. High-throughput sequencing was conducted to screen for differentially expressed genes. Two-photon imaging was performed to investigate the function of the astrocytic calcium activity and intervention with TRPV4 inhibitor HC-067047. Further, GSK1016790A (GSK1), a TRPV4 agonist, was daily intraperitoneally injected during the exercise period to study the involvement of TRPV4 in PE protection. Colitis pathology was confirmed by histopathology. The novel object recognition (NOR) test, Morris water maze test (MWM), and open field test were performed to measure colitis-induced cognition and anxiety-like behavior. two-photon imaging and imaging of fluorescent CSF tracers to evaluate the function of the glymphatic system. Immunofluorescence staining was used to detect the Aβ deposition, polarity distribution of astrocytic AQP4, and astrocytic phenotype. Serum and brain levels of the inflammatory cytokines were tested by Enzyme-linked immunosorbent assay (ELISA). The brain TUNEL assay was used to assess DNA damage. Expression of critical molecules was detected using Western blotting. Voluntary exercise alleviates cognitive impairment and anxiety-like behavior in aged mice with chronic colitis, providing neuroprotection against neuronal damage and apoptosis. Additionally, voluntary exercise promotes the brain clearance of Aβ increased glymphatic clearance. Mechanistically, exercise-induced beneficial effects may be attributed, in part, to the inhibition of TRPV4 expression and TRPV4-related calcium hyperactivity, subsequent promotion of AQP4 polarization, and modulation of astrocyte phenotype. The present study reveals a novel role of voluntary exercise in alleviating colitis-related cognitive impairment and anxiety disorder, which is mediated by the promotion of AQP4 polarization and glymphatic clearance of Aβ inhibition of TRPV4-induced astrocytic calcium hyperactivity.

中文翻译：

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自愿轮运动通过抑制 TRPV4 诱导的星形胶质细胞钙活性来改善老年小鼠的类淋巴间隙并改善结肠炎相关的认知障碍

慢性结肠炎会加剧神经炎症，导致衰老过程中的认知障碍，但其机制仍不清楚。星形胶质细胞水通道蛋白 4 (AQP4) 的极性分布对于类淋巴系统至关重要，该系统负责大脑中代谢物的清除。体育锻炼（PE）可以改善老年人的认知能力。本研究旨在探讨运动对结肠炎相关认知障碍的保护机制。为了建立慢性结肠炎模型，18 个月大的 C57BL/6 J 雌性小鼠定期口服含 1% wt/vol 葡聚糖硫酸钠 (DSS) 的饮用水。运动组的小鼠接受了四个星期的自愿轮运动。通过高通量测序筛选差异表达基因。采用双光子成像研究星形胶质细胞钙活性的功能以及 TRPV4 抑制剂 HC-067047 的干预。此外，在运动期间每天腹腔注射TRPV4激动剂GSK1016790A（GSK1），以研究TRPV4在PE保护中的作用。结肠炎病理学通过组织病理学证实。进行新物体识别（NOR）测试、莫里斯水迷宫测试（MWM）和旷场测试来测量结肠炎诱发的认知和焦虑样行为。双光子成像和荧光脑脊液示踪剂成像以评估类淋巴系统的功能。免疫荧光染色检测Aβ沉积、星形胶质细胞AQP4的极性分布和星形胶质细胞表型。通过酶联免疫吸附测定（ELISA）检测血清和脑中炎症细胞因子的水平。大脑 TUNEL 检测用于评估 DNA 损伤。使用蛋白质印迹法检测关键分子的表达。自愿运动可以减轻患有慢性结肠炎的老年小鼠的认知障碍和焦虑样行为，从而提供神经保护，防止神经元损伤和细胞凋亡。此外，自愿运动可促进大脑中 Aβ 的清除，从而增加类淋巴系统的清除率。从机制上讲，运动引起的有益效果可能部分归因于 TRPV4 表达的抑制和 TRPV4 相关的钙过度活跃，随后促进 AQP4 极化，以及星形胶质细胞表型的调节。本研究揭示了自愿运动在缓解结肠炎相关认知障碍和焦虑障碍方面的新作用，该作用是通过促进 AQP4 极化和 Aβ 的类淋巴清除抑制 TRPV4 诱导的星形胶质细胞钙过度活跃来介导的。