Research reportBehavioural study of the d-galactose induced aging model in C57BL/6J mice
Introduction
Accelerated senescence in rodent induced by d-galactose (d-gal) was first reported by Xu [35], who found remarkable signs of aging in ICR mice after retrobulbar injection of d-gal for 8 weeks. Moreover, altered lipofuscin content, monoamine oxidase-B (MAO-B) activity and Na+–K+-ATPase activity of the brain and liver in d-gal-treated mice were found close to those of 21-month mice [11]. Behavioural impairment of d-gal-treated Kun-ming mice as shown in T-water maze was similar to that of 25-month mice [16]. Since then, d-gal injection has been gradually used to establish an aging model for brain aging or anti-aging pharmacology research. By the end of 2003, over 300 papers in China had adopted this model in their studies (according to the Medical Database of Chinese Bio-medical Database and the Pubmed Database of National Library of Medicine). However, according to these articles, the doses of d-gal used to produce such a rodent aging or behavioural impairment model varied in a large range, e.g. 50 mg/kg [27], 120 mg/kg [36], 200 mg/kg [34], 500 mg/kg [12], and even 1250 mg/kg [25], even though the administration duration of d-gal was about 6–12 weeks. Whether or not there is a dose-dependent effect of d-gal on behavioural impairment remains unknown.
To address this question, we studied the effect of d-gal at doses of 50, 100 and 200 mg/kg (which represented the most-used doses in prior articles) on mouse behaviour after 8-week continuous subcutaneous injection. The Morris water maze (MWM) and object recognition test (ORT) were used to test for learning and memory ability and locomotor activity test (LAT) for neuromuscular function.
C57BL/6 (C57) inbred mouse is one of the most employed strains in genetic [1], [15] and brain aging researches [10], with the intact object [26] and spatial memory [29]. And this strain has been shown an age-dependent behavioural impairment in MWM [19], ORT [32] and LAT [4]; these features made C57 as an ideal strain for aging and learning deficit study. Nevertheless, few of previous researches used this strain to establish the d-gal induced aging model. In this study, we found d-gal could induce remarkable learning and memory impairment and neuromuscular dysfunction in this strain. Dose-dependent increased effect of d-gal induced behavioural impairment was found at the range from 50 to 100 mg/kg, but not in such manner as the dose of 200 mg/kg.
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Subjects
Animal housing and all experimental procedures followed the requirements of the Provisions and General Recommendations of Chinese Experimental Animal Administration Legislation. Twelve-week-old female C57 mice (20 ± 2 g) were purchased from the Experimental Animal Center of Peking University and housed five or six per cage under a 12/12-h dark/light cycle and standard pathogen free condition. During the entire experiment they had free access to food and water. After 1-week acclimatization to the
d-gal induced spatial learning and memory impairment in MWM
The degrees of d-gal induced spatial learning and memory impairment in MWM of C57 mice differed according to doses. Fig. 1A illustrated the group difference in mean escape latencies to platform. Mice showed significantly difference in mean latencies between training days (F(3, 123) = 81.918, P < 0.001), and between treatments (F(3, 41) = 5.547, P < 0.01), but no interaction between the factors of day × treatment (F(9, 123) = 1.267, P > 0.05). Post-hoc analysis revealed the significant
Discussion
This study firstly compared the behavioural manifestations of a mouse aging model induced by d-gal at three most frequently reported doses (50, 100 and 200 mg/kg) in C57 mice. Although the tendencies of behavioural impairment in d-gal-treated mice had been observed at all three doses, the degrees of behavioural impairment were different. d-Gal at the dose of 50 mg/kg could only induce significant behavioural impairment of C57 mice in ORT, and swim speed of MWM; while d-gal at doses of 100 and 200
Acknowledgements
The authors would like to thank Dr. Wen-lin An, from Karolinska Institutet in Sweden, for his helpful suggestion in the preparation of this paper. This study was supported by the National Science Foundation of China (No. 30340090), the National Key Basic Research Foundation of China (No. G2000057010), and the Beijing Municipal Natural Science Foundation (No. 7982006).
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