Abstract: BACKGROUND: Apoptosis and autophagy imbalance in the hippocampal region of perimenopausal depressed rats are closely related to cognitive decline. Whether aerobic exercise can reduce apoptosis by promoting hippocampal autophagy and thus improve the learning and memory abilities of perimenopausal depressed rats is not clear.
OBJECTIVE: To investigate the possible mechanism by which 4-week moderate-intensity treadmill exercise improves learning memory ability in ovariectomized stressed rats. 
METHODS: Forty Sprague-Dawely rats were randomly divided into four groups, namely, sham operation group (n=10), ovariectomized group (n=10), ovariectomized stress group (n=10) and ovariectomized stress exercise group (n=10). Except for the sham operation group, the ovaries were removed in the other three groups to establish a perimenopausal rat model, and then a depressed rat model was established by chronic unpredictable stress in the latter two groups. The rats in the ovariectomized stress exercise group underwent a 4-week moderate-intensity treadmill exercise. Tail suspension test and sucrose preference test were performed to text depression-like behaviors in rats after exercise and stress. The eight-arm maze experiment was used to test the learning and memory behaviors of rats after exercise and stress. Western blot was used to detect the protein levels of AMP-activated protein kinase/UNC-51 like autophagy activating kinase 1/mammalian target of rapamycin (AMPK/mTOR/ULK1), hippocampus apoptotic factor Caspase-3 and the protein expression of autophagy markers LC-3II/Beclin-1 in the hippocampus. 
RESULTS AND CONCLUSION: (1) Compared with the sham operation group, rats in the ovariectomized and ovariectomized stress groups had prolonged resting time in the tail suspension test and decreased sugar-water intake and sugar-water preference in the sucrose preference test. (2) Ovary removal reduced the learning memory capacity of rats, as evidenced behaviorally by a significant increase in the number of working memory errors, the number of reference memory errors, and the completion time, and an even more pronounced increase in the above measures in the ovariectomized stress group. (3) Compared with the ovariectomized group, there was a significant reduction in the number of working memory errors, the number of reference memory errors, and the completion time in the ovariectomized stress group. (4) Compared with the sham operation group, in the ovariectomized and ovariectomized stress groups, the expression of hippocampal apoptotic factor Caspase 3 protein was significantly elevated, the expression of autophagy-related factors proteins Beclin-1 and LC3II, as well as the protein expression of AMPK and ULK1, was decreased, whereas the expression of mTOR protein was elevated. Changes in the above indicators were more significant in the ovariectomized stress group. (5) Compared with the ovariectomized stress group, in the ovariectomized stress exercise group, the protein expression of Caspase 3 was significantly decreased, the protein expression of Beclin-1 and LC3II was significantly increased, the protein expression of AMPK and ULK1 was significantly increased, and the protein expression of mTOR was significantly reduced. To conclude, 4-week moderate-intensity treadmill exercise may promote cellular autophagy and reduce apoptosis through the AMPK/mTOR/ULK1 autophagy signaling pathway, thereby enhancing the learning and memory capacity of rats with ovariectomized depression.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: treadmill exercise, perimenopausal depression, ovariectomized, depression, learning, memory, autophagy, apoptosis