Neurogranin as an important regulator in swimming training to improve the spatial memory dysfunction of mice with chronic cerebral hypoperfusion

Background:Vascular cognitive impairment caused by chronic cerebral hypoperfusion(CCH)has become a hot issue worldwide.Aerobic exercise positively contributes to the preservation or restoration of cognitive abilities;however,the specific mechanism has remained inconclusive.And recent studies found that neurogranin(Ng)is a potential biomarker for cognitive impairment.This study aims to investigate the underlying role of Ng in swimming training to improve cognitive impairment.Methods:To test this hypothesis,the clustered regularly interspaced short palindromic repeats(CRISPR)-associated protein 9(Cas9)system was utilized to construct a strain of Ng conditional knockout(Ng cKO)mice,and bilateral common carotid artery stenosis(BCAS)surgery was performed to prepare the model.In Experiment 1,2-month-old male and female transgenic mice were divided into a control group(wild-type littermate,n=9)and a Ng cKO group(n=9).Then,2-month-old male and female C57BL/6 mice were divided into a sham group(C57BL/6,n=12)and a BCAS group(n=12).In Experiment 2,2-month-old male and female mice were divided into a sham group(wild-type littermate,n=12),BCAS group(n=12),swim group(n=12),BCAS+Ng cKO group(n=12),and swim+Ng cKO group(n=12).Then,7 days after BCAS,mice were given swimming training for 5 weeks(1 week for adaptation and 4 weeks for training,5 days a week,60 min a day).After intervention,laser speckle was used to detect cerebral blood perfusion in the mice,and the T maze and Morris water maze were adopted to test their spatial memory.Furthermore,electrophysiology and Western blotting were conducted to record long-term potential and observe the expressions of Ca^(2+)pathway-related proteins,respectively.Immunohistochemistry was applied to analyze the expression of relevant markers in neuronal damage,inflammation,and white matter injury.Results:The figures showed that spatial memory impairment was detected in Ng cKO mice,and a sharp decline of cerebral blood flow and an impairment of progressive spatial memory were observed in BCAS mice.Regular swimming training improved the spatial memory impairment of BCAS mice.This was achieved by preventing long-term potential damage and reversing the decline of Ca^(2+)signal transduction pathway-related proteins.At the same time,the results suggested that swimming also led to improvements in neuronal death,inflammation,and white matter injury induced by CCH.Further study adopted the use of Ng cKO transgenic mice,and the results indicated that the positive effects of swimming training on cognitive impairments,synaptic plasticity,and related pathological changes caused by CCH could be abolished by the knockout of Ng.Conclusion:Swimming training can mediate the expression of Ng to enhance hippocampal synaptic plasticity and improve related pathological changes induced by CCH,thereby ameliorating the spatial memory impairment of vascular cognitive impairment.

Differences of Matrix Metalloproteinase 2 Expression between Left and Right Ventricles in Response to Nandrolone Decanoate and/or Swimming Training in Mice

Background： Matrix metalloproteinase （MMP）-2 plays an important role in the remodeling of left ventricles （LVs） and right ventricles （RVs）. We investigated the differences of MMP-2 expression between LV and RV in response to nandrolone dccanoate （ND）, swimming training （ST）, and combined ND and ST （NS） in mice, based on their structural, functional, and biochemical characteristics. Methods： Totally 28 male C57B1 mice （6 weeks old; 20-23 g） were divided into four groups, including the control （n = 7）, ND （n = 6）, ST （n = 8）, and NS （n = 7） groups. After respective treatments for 8 weeks, echocardiographic examination was used to assess the cardiac structure and function. Van Gieson stain was used to examine the fibrosis of LV and RV in response to different treatments, and Western blotting analysis was performed to explore different MMP-2 expressions between LV and RV in response to ND and/or ST. Analysis of variance was used for comparing the four groups. Results： At 8 weeks, right ventricular dimension/body weight in the ND group was larger than the other three groups （F = 7.12, P 〈 0.05） according to the echocardiographic examination. Fibrosis induced by ND administration was increased more in RV （2.59%） than that in LV （2.21%）. MMP-2 expression of the ND group in RV was significantly greater than the control and NS groups in RV and the corresponding ND group in LV. Conclusion： The experimental data support the hypothesis that ND administration induces greater MMP-2 expression increase in RV compared to LV, leading to consequent RV dilation.

Detraining after tumor-bearing accelerates tumor growth while continuous training decreases tumor growth in mice

Objective:Previous studies have shown that exercise suppresses tumor growth.However,the effects of exercise with different intensities and exercise detraining after tumor-bearing on tumor progression remain unclear.The purpose of this study was to investigate the effects of continuous and disrupted free and exhausted swimming training after tumor-bearing on tumor progression in melanoma B16-F10-bearing C57BL/6 mice.Methods:C57BL/6 mice were subjected to free or exhausted swimming exercise training for 4 weeks prior to the injection of melanoma B16-F10 cells.Subsequently,the B16-F10-bearing mice were maintained with training consisting of free or exhausted swimming or without exercise for 2 weeks during the tumor challenge.Results:The tumor weight was increased by 42%and 109%in mice with 4-week exhausted swimming prior to B16-F10 tumor cells inoculation followed by 2-week training cessation compared with the tumor-bearing control(P<.05)and continuous training groups(P<.01).Tumor weights in groups with exercise detraining after tumor cell inoculation tended to be increased,while the proliferation of splenic T lymphocytes tended to be decreased compared with the group that maintained exercise intensity.After 6-weeks continuous free or exhausted swimming training,the tumor weight of mice was decreased and the proliferation of splenic T lymphocytes was increased compared with the tumor-bearing control group.The frequency of natural killer cells in tumors was increased in all exercise training groups of mice.Conclusions:These results suggest that maintaining exercise intensity after tumor-bearing slows tumor growth in mice,possibly because of the enhanced proliferative activity of splenic lymphocytes rather than natural killer cell infiltration.However,detraining after tumor-bearing might accelerate tumor progression because of the reduced proliferation of splenic T lymphocytes.