Aging-Related Behavioral Change In Mice And Its Neural Mechanisms

BackgroundThere is vast evidence that a varity of functions in brain gradually deteriorate during normal aging. Rodents play a vital role in the studies of development of brain aging and its mechanisms. In decades, many aging researchers focused on the mouse models. But so far, few mouse strains have been investaged extensively in age-related behavioral changes, and all these strains belong to inbred strains. In certain studies, outbred stocks may be better than inbred strains. Senescence-accelerated prone mouse 8 (SAMP8, P8) has been proposed as an excellent mouse model in the study of brain aging, but only the age-related deteriorations in learning and memory have been investigated.Objective(1) To investigate whether the Kunming (KM) mouse, most frequently used in Chinese laboratories, can serve as an mouse model in the study of brain aging; (2) to further investgate that the age-related behavioral changes in P8 mouse and their possible mechanism.MethodsThe subjectives consisted of KM mouse and senescence-accelerated mouse (SAM). 47 KM mice were at the ages of 7-8 months and 17-18months. The number of SAM mice was 147, including 74 P8 mice and 73 senescence-accelerated resistant strains 1 (SAMR1, R1) mice, at different ages. The battery used to investigate the pattern of age-related behavioral changes in the KM mice contains 6 tasks, consisting of beam walking, tightrope, open field, radial six-arm water maze (RAWM), novel-object recognition and olfactory discrimination tasks. To characterize the learning and memory abilities (spatial and non-spatial), species-typical behaviors and anxiety in P8 mice at the different ages, the following tasks were employed: RAWM, Morris water maze (MWM), novel-object recognition, burrowing, hoarding, nesting, open field, black-white alley, neophobia and elevated plus maze. The immunofluorescence histochemisty method wasused to quantify the synaptic protein synaptotagmin (Syt) in the different strata of each subfield in the hippocampus of P8 mice. The reverse transcriptase polymerase chain reaction was used to detect the Syt mRNA in the dorsal or ventral hippocampus of P8 mice at the different ages.Results1. The age-related behavioral changes in KM miceDuring beam walking, the older KM mice showed the similar performance to the younger mice. The older females exhibited sensorimotor impairment in the tightrope task and low locomotor activity in the open-field task. Moreover, older mice spent a longer time in the peripheral squares of the open-field than younger ones. The spatial learning and memory ability in the RAWM were lower in older female KM mice relative to younger female mice and older male mice. Consistent with this, in the novel-object recognition task, a non-spatial cognitive task, older female mice but not older male mice had impairment of short-term memory. In olfactory discrimination, another non-spatial task, the older mice retained this ability. Interestingly, female mice performed better than males, especially in the younger group.2. The age-related behavioral changes in SAM miceIn the RAWM, rather than in the MWM, the impairment in spatial learning could be measured in P8 mice as early as 3 months old, and the impairment in spatial learning memory was found in P8 mice aged 5 months.Obversed at multiple-age points (3-, 5-, 8- and 12-month) , the latency to find the hidden platform in spatial version of MWM in 12-month-old P8 mice was obvious longer than that in 5-month-old P8 mice. The best performance was found in 5-month-old mice, rather than 3-month-old mice. In the RAWM, the number of the errors in the learning phase in the P8 mice aged 8- and 12-months was significantly less than that in 3- and 5-month P8 mice, and the latency in the learning phase in the 8-month P8 mice was significantly shorter than that in 3- and 5- month P8 mice. In the memory phase, the number of the errors and the latency in the 8-month mice was significantly less than that in the 5-month mice.The weight hoarded in 3-month-old mice was significantly lower than that in 7- and 11-month-old mice in the both P8 and R1 strian, and there was no significant difference between the 7-month-old mice and 11-month-old mice. In the burrowing, the weightburrowed by the 3-month P8 mice was significantly less than that by the 7- and 11-month ones, and the weight in 7-month P8 mice was lower than that in 11-month ones. In the Rl mice, however, the weight burrowed in the 7-month-old mice was lower compared to 3-and 11-month mice. The nesting ability in the 3-month P8mice was inferior to that in the 7- and 11-mopth ones, but there was no difference between 7-month mice and 11-month mice.In the battery of anxious tasks, the age effect only took place in P8 mice in the black-white alley task, i.e. the latency in the 2- and 10-month mice was significantly shorter than that in the 6-month mice. For the strain effect, in the 2-month mice, the anxiety in the P8 strain in the open field, black-white alley and neophobia tasks was lower compared to the Rl strain; in the 6-month mice, the anxiety in the P8 strain in the open field and black-white alley tasks was lower than that in the Rl strain; but in the 10-month mice, the lower anxiety in the P8 relative to that in the Rl only took place the open field task. Intrestingly, the anxiety in the 10-month P8 mice in the evelated plus maze was higher than that in the Rl mice with the same age. For the sex effect, in the P8 strain, the lower aniety only took place in the open field in the 10-month female mice compared to the 10-month male mice, and in the Rl strain, the time spent in the white alley of the black-white alley in the 10-month female mice was more than that in the 10-month male mice.3. The relationships between tasksIn the KM mice, there was no correlation between the RAWM and the sensorimotor tasks. However, the suspension time in the tightrope test was positively related to the total exploration time in the testing period of novel-object recognition task, and the squares crossed in the open field was positively related to the preferential index for novel object in the testing period of novel-object recognition task and the latency in olfactory discrimination task. There was no relationship among the 3 learning and memory tasks consisting of RAWM, novel-object recognition and olfactory discrimination.In the SAM mice, there was no relationship among the 3 species-typical behavioral tasks, including food hoarding, burrowing and nesting. For the 4 anxious tasks, consisting of open field, black-white alley, plus maze and neophobia, only a positive correlation occurred between the peripheral time in the open field task and the latency in the neophobia test. There was no relationship among the 3 learning and memory tasks consisting of RAWM, MWM and novel-object recognition.4. The change Syt I in the different layers of dorsal hippocampus in P8 miceCompared to the 4~5-month-old P8, the 13-month-old mice had significantly increased Syt I, a presynaptic protein, in each stratum in each subfield of the hippocampus but the inner molecular layer (IML) of the dentate gyms (DG). The 7~9-month-old P8 mice also had significantly increased Syt I in each layer of DG, stratum lacunosum-moleculare (SLM) and stratum radiatum (SR) of CAl subfield. In the Rl strain, however, the Syt I was decreased in the stratum oriens (SO) of CAl, stratum lucidum (SL) of CA3, polymorphic layer (PL) and IML of DG in the 13-month mice compared to the 4~5-month mice. For the Syt I mRNA, there was no age-related change in the both dorsal and ventral hippocampus in P8 and Rl mice.5. The correlations between the learning and memory and the Syt I protein and mRNAIn the RAWM, the number of errors in the learning phase was reversely related to the Syt I protein in each layer in each subfield but not DG-IML in the hippocampus of P8 mice, and the latency in the learning phase was reversely related to the Syt I protein in CA1-SLM, CA3-SR, CA3-SL and DG-PL. The number of errors in the memory phase was reversely related to the Syt I protein in CAl-SO, CA1-SR, CAl- SLM, CA3-SL and DG-PL, and the latency in the memory phase only was reversely related to the Syt I protein in CAl-SLM. In the MWM, the latency to find the hidden plateform in the P8 was positively related to the Syt I protein in CA3-SL, CA3-SR, DG-PL and outer and middle molecular layer (OMML) in the DG. In the novel-object recognition task, the preferential index for novel object in the testing period was not related to the Syt I protein in any layers in each subfield in the hippocampus of the P8 mice. For the Syt I mRNA, only the abundant in the dorsal hippocampus of the P8 mice was positively related to the latency in the MWM, but not in the RAWM and novel-object recognition.Summary1. There is no gross sensorimotor impairment in older KM mice. A mild to moderate sensorimotor impairment could only be detected in the task demanding stronger power and coordination in the older female KM mice. A lower locomotor activity was found in the older females, and an increased anxiety was found in the older female and male KM mice. Both the spatial learning and memory ability in the RAWM task and the non-spatial novel-object recognition ability were decline in the 17-month female KM mice, but there was no change with ages in the olfactory discrimination task. Therefore, the old female KM mice may be an excellent aging model, and a natural model for...