open access

https://doi.org/10.14943/doctoral.r6685

https://hdl.handle.net/2115/39038

Age-related changes in the higher brain functions of Senescence-accelerated mouse prone 6 (SAMP6)

日本語

2009-06-30

Hokkaido University

80p.

The senescence-accelerated mouse (SAM) was developed through selective breeding of the AKR/J strain based on a graded score for senescence, life span, and pathological phenotypes. There are nine senescence-prone (SAMP) strains and three senescence-resistant (SAMR) strains. SAMP strains have a shortened life span and show early manifestations of senescence, such as various skin lesions and increased lordokyphosis, after a period of normal development. Among SAMR strains, SAMR1 is long-lived, showing resistance to early senescence, and is used as a control. Among SAMP strains, SAMP6 is considered to be a model of senile osteoporosis with slow bone loss after 4 months of age. Recently, it was reported that SAMP6 exhibited increased expression of S100β in the brain compared to SAMR1, suggesting that SAMP6 is also useful as a model of age-related diseases related to central nervous system alterations. I performed a battery of behavioral analyses using 1- (juvenile stage), 4.6- (adult stage), and 8.12-month-old (old stage) SAMP6 and age-matched SAMR1 to investigate the age-related changes in behavioral features and the mechanisms involved. The battery of behavioral analyses revealed innate behavioral alterations in SAMP6, including higher motor activity, lower anxiety, increased short-term memory, a motor coordination deficit, and antidepressant activity. The higher motor activity of SAMP6 was observed until the adult stage, and then the motor activity began to decline, and lower motor activity was observed at the old stage, indicating that the motor activity of SAMP6 exhibited the same pattern of age-related changes as seen in the bone mass of SAMP6. The marked motor coordination deficit of SAMP6 was observed at the juvenile and old stages, whereas amelioration in the motor coordination deficit was seen in the adult stage, suggesting that the motor coordination of SAMP6 exhibited a pattern of age-related changes similar to that of the bone mass of SAMP6. On the other hand, the differences in anxiety and antidepressant activity between SAMP6 and SAMR1 decreased gradually with age, indicating that the lower anxiety and antidepressant activity of SAMP6 showed another pattern of age-related change. No apparent age-related change was observed in the increased short-term memory of SAMP6. Accordingly, the behavioral features of SAMP6 were divided into three categories based on the pattern of age-related changes: (1) accelerated-senescence-like behaviors; (2) behaviors with age-related changes; and (3) behaviors with no age-related changes. The expression of tyrosine hydroxylase, an enzyme involved in the biosynthesis of dopamine, and its phosphorylated form was increased in the striatum and nucleus accumbens (NAc) of juvenile SAMP6, suggesting an increase in the concentration of dopamine in the juvenile SAMP6 brain. This was thought to be one of the innate alterations related to the higher motor activity of SAMP6. Increased expression of D1 in the striatum, an over-activated D1 signal cascade, and an increased dopamine concentration in the NAc were seen in adult SAMP6, which seemed to explain the higher activity of adult SAMP6. An apparent decrease in the sensitivity of D1 of old SAMP6 compared to adult SAMP6 was observed, which was thought to be involved in the decreased motor activity of old SAMP6. These results suggest that an age-related alteration in the D1 sensitivity of SAMP6 is one of the mechanisms altering motor activity, one of the accelerated-senescence-like behaviors observed in this strain. On the other hand, the increased D3 expression in the cerebellum of adult SAMP6 was thought to be one of the mechanisms related to the motor coordination deficit, another accelerated-senescence-like behavior observed in this strain. However, further examinations of the D3 expression levels in juvenile and old SAMP6 cerebellum are needed to evaluate whether the altered D3 expression is involved in the accelerated-senescence-like alteration of this behavior. The serotonin system was studied to examine the mechanism of the lower anxiety and antidepressant activity, behaviors with age-related changes, of SAMP6. The expression of tryptophan hydroxylase, a serotonin biosynthesis enzyme, and its phosphorylated form were increased in the brainstem of juvenile SAMP6, suggesting an increase in the serotonin concentration in the juvenile SAMP6 brain. This was thought to be one of the innate mechanisms related to the lower anxiety and antidepressant activity of SAMP6. Serotonin concentrations were increased the cortex and NAc of adult SAMP6, which likely explained these behavioral patterns in adult SAMP6. However, further examination of the serotonin concentration of juvenile and old SAMP6 brains is needed to evaluate whether the altered serotonin concentration is involved in the age-related change of these behaviors. The dopamine and serotonin systems and N-methyl-D-aspartate (NMDA) receptors were studied to examine the mechanisms for increased short-term memory, a behavior with no age-related changes, of SAMP6. As mentioned above, the increased dopamine and serotonin concentrations in the juvenile SAMP6 brain were also thought to be one of the innate changes related to the increased short-term memory of SAMP6. In addition, expression of the NMDA receptor subunit 2B (NR2B) was increased in the forebrain of adult SAMP6, and this appeared to be involved in the increased short-term memory of adult SAMP6. Further examination of the mechanisms involved in this behavioral property of old SAMP6 is needed. In this study, a battery of behavioral analyses using animals at three different ages showed various behavioral alterations with aging. In addition, biochemical and pharmacological approaches revealed the involvement of several different mechanisms in the behavioral alterations. These results suggest that the higher brain functions are controlled by variable thresholds of the respective neurons and complex neuronal networks. Studies using SAMP6 might elucidate the influences of aging on higher brain functions and related mechanisms, resulting in the specification of the signal cascades that activate higher brain function and the development of new drugs that act on these cascades. These could increase the healthy longevity and quality of life of humans.

2009-06-30

乙第6685号

博士(獣医学)

博士論文

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