8-oxo-G在快速老化小鼠SAMP8海马中表达的增龄性变化研究

目的观察8-氧鸟嘌呤核苷(8-oxo-G)在SAMP8品系快速老化小鼠海马不同区域的表达,以探讨其与SAMP8小鼠增龄性变化的关系。方法选用1、4、8、12月龄的快速老化小鼠SAMP8以及同龄抗快速老化小鼠SAMR1(对照组),每组各6只,采用免疫组化方法检测小鼠海马不同区域8-oxo-G的表达。结果8-oxo-G主要在SAM小鼠海马神经元胞浆内表达。对照组SAMR1 1月龄小鼠海马CA1和CA3区8-oxo-G表达显著高于其他月龄组(P<0.05),4、8、12月龄小鼠间其表达差异无统计学意义(P>0.05);SAMP8 12月龄小鼠海马8-oxo-G的表达显著高于1、4、8月龄组(P<0.05);SAMP8和SAMR1小鼠之间比较,1、4月龄间差异无统计学意义(P>0.05),8、12月龄间差异有统计学意义(P<0.05)。结论SAMP8小鼠海马8-oxo-G的表达除1月龄外随月龄增加而增加,提示8-oxo-G的表达增加与SAMP8小鼠的快速老化相关,有可能为增龄,甚至AD的生物学标志。     

快速老化痴呆模型小鼠SAMP8学习记忆能力的增龄性变化

目的对快速老化痴呆模型小鼠SAMP8学习记忆能力的增龄性变化进行较系统的研究,为利用该模型进行其他研究提供实验依据。方法此实验选用1、4、8、12月龄的快速老化痴呆模型小鼠SAMP8,与同龄的正常老化小鼠SAMR1作对照,从老化度评分、避暗实验、Morris水迷宫实验和自主活动实验等方面观察了SAMP8小鼠学习记忆能力的增龄性变化。结果与对照组SAMR1相比,SAMP8小鼠随月龄增加老化度评分呈增高趋势,在8、12月龄的老化度评分值显著高于同龄对照组(P<0.05);避暗实验中,8、12月龄的SAMP8小鼠在电击24h后进入暗箱的潜伏期比同龄SAMR1小鼠显著缩短(P<0.05);Morris水迷宫实验中,1、4月龄SAMP8小鼠找到暗台的潜伏时间与同龄SAMR1小鼠相比差异无显著性,而8、12月龄SAMP8小鼠与同龄对照组相比,潜伏时间显著延长(P<0.05);从自主活动实验看,1、4、8月龄SAMP8小鼠单位时间内自主活动次数与同龄SAMR1小鼠相比无显著变化,而12月龄SAMP8小鼠与同龄对照组相比单位时间内自主活动次数显著减少(P<0.05)。结论SAMP8小鼠随月龄增长学习记忆能力逐渐减退;与同龄对照组相比,8、12月龄SAMP8小鼠出现明显衰老特征,表现出学习记忆能力明显低下,故可作为老化痴呆的动物模型用于痴呆有关研究。     

快速老化小鼠海马神经元电压门控离子通道特点

目的：观察快速老化小鼠（Senescence-accelerated mouse,SAM)海马神经元的基本离子通道特点，并对抗快速老化亚系（SAM－resistance/1,SAMR1)与快速老化亚系（SAM－prone/8,SMAP8)的基本离子通道特点进行了比较，探讨了离子通道变化在衰老中的可能角度，方法：应用全细胞记录方式，观察并比较原代培养SAMR1和SAMP8海马神经元的电压门控离子通道及膜参数。结果：原代培养SAMR1和SAMP8海马神经元电压门控Na^2 通道电流（INa)和电压门控延迟整流K^ 通道电流（IK）的电学特点和幅度基本一致。SAMP8的电压门控Ca^2 通道电流（ICa)和瞬时外向K^ 通道电流（IA）的幅值则大于相同培养天数的SAMR1。经膜电容校正所得的ICa电流密度也表现出增大的变化规律。结论：SAMP8与SAMR1神经元间IA和ICa的差异可能与其神经系统变异而产生的学习记忆功能下降有关。     

8-氧鸟嘌呤脱氧核苷在快速老化小鼠SAMP8海马中表达的增龄性变化研究

目的观察8-氧鸟嘌呤脱氧核苷（8-oxo-7,8-dihydroguanine,8-oxo-dG）在快速老化小鼠SAMP8海马不同区域的表达,探讨其变化与SAMP8增龄的关系。方法选用1、4、8、12月龄快速老化小鼠SAMP8（每组各6只）,对照组为同龄抗快速老化小鼠SAMR1（每组各6只）,用免疫组化法检测海马不同区域内8-oxo—dG的表达水平。结果8-oxo-dG在海马不同区域均有表达,且主要在海马神经细胞胞核内表达。对照组SAMR1小鼠海马各区域8-oxo-dG的吸光度定量结果显示各月龄组间无统计学差异（P〉0．05）;1、4月龄组SAMP8小鼠海马各区域8-oxo-dG的吸光度定量结果与同龄匹配的SAMR1小鼠间无统计学差异（P〉0．05）;8、12月龄组SAMP8小鼠海马各区域8-oxo-dG的吸光度定量结果分别显著高于1月龄和4月龄组（P〈0．05）,也分别显著高于同龄SAMP1对照组（P〈0．05）。结论8-oxo-dG在SAMP8快速老化小鼠海马中的水平随增龄而显著增高。     

快速老化小鼠海马神经元电压门控离子通道特点

目的:观察快速老化小鼠(Senescence-accelerated mouse,SAM)海马神经元的基本离子通道特点,并对抗快速老化亚系(SAM-resistance/1,SAMR1)与快速老化亚系(SAM-prone/8,SAMP8)的基本离子通道特点进行了比较,探讨离子通道变化在衰老中的可能角色.方法:应用全细胞记录方式,观察并比较原代培养SAMR1和SAMP8海马神经元的电压门控离子通道及膜参数.结果:原代培养SAMR1和SAMP8海马神经元电压门控Na+通道电流(INa)和电压门控延迟整流K+通道电流(Ik)的电学特点和幅度基本一致.SAMP8的电压门控Ca2+通道电流(ICa)和瞬时外向K+通道电流(IA)的幅值则大于相同培养天数的SAMR1.经膜电容校正所得的ICa电流密度也表现出增大的变化规律.结论:SAMP8与SAMR1神经元间IA和ICa的差异可能与其神经系统变异而产生的学习记忆功能下降有关.     

增龄性脑血管相关改变对阿尔茨海默病模型小鼠SAMP8认知能力的影响

目的 探讨脑血流量、血脑屏障(BBB)通透性、脑葡萄糖跨膜转运蛋白表达情况随年龄增大对阿尔茨海默病(AD)模型小鼠SAMP8认知能力的影响. 方法 选择SAMP8小鼠及正常同源抗快速老化小鼠R1(SAMR1)各10只进行观察.采用Morris水迷宫测定小鼠的学习记忆能力,激光多普勒仪测定脑血流量,荧光分光光度计法测定BBB通透性,Western blotting测定葡萄糖转运蛋白(GLUT)1和3的表达. 结果 与SAMR1相比,SAMP8的认知能力早在4月龄时即已出现明显损伤,表现为思维僵化、学习过程减慢.随着年龄增大,SAMP8脑血流明显下降,BBB渗漏更为严重,皮层和海马的GLUT1和GLUT3表达也有不同程度地改变.脑血流、BBB完整性、GLUT1和GLUT3表达受年龄和品系影响明显,并与认知能力高度相关. 结论 衰老及缺血引起的血管损伤、能量供给不足是造成AD神经元功能异常及导致认知障碍的主要原因.     

阿尔茨海默病动物模型研究进展

阿尔茨海氏病(Alzheimer`s disease,AD)是老年人常见的痴呆类型,AD动物模型的建立是研究AD的基础,学者们从不同角度探讨了多种制备AD动物模型的方法。以老化为基础的动物模型1.自然衰老认知障碍模型AD是一个年龄相关的疾病,衰老因素在其发病过程中占有重要地位,衰老所特有的病理生理变化及其它病的影响,是用年轻动物制作的动物模型所不能替代的。常见的有灵长类如猴、狒狒[1-2]和鼠的自然衰老模型。2.衰老加速小鼠模型衰老加速小鼠(senescence accelerated mouse,SAM)是一种较理想的衰老模型,SAM分为易快速老化系SAM(senescenceacclerated mouse prone,SAM)和抗快速老化系SAM(senescenceaccelerated mouse resistance,SAM);其中SAMP有9个(P1、P2、P3、P6、P7、P8、P9、P10和P11);其中SAMR有3个(P1、P4、P5);在SAM品系中,SAMP8是以学习记忆功能衰退为特征的加速老化模型,既有自然衰老小鼠的特征,又有类似老年性痴呆的脑部病理及学习记忆功能衰退[3~5]。生后...     

快速老化动物模型SAMP8小鼠及其相关研究进展

SAMP8鼠由日本京都大学竹田俊男教授开发成功，主要以学习记忆功能呈增龄性加速衰退，中枢神经系统如皮质、海马等部位发生病理改变为主，是一种比较理想的研究脑老化和痴呆的模型，亦是目前研究快速衰老的唯一哺乳类模式动物。行为学、形态学、神经生化和分子生物学为此提供了较充足的证据。SAMP8鼠可被广泛应用于阐明年龄相关的学习记忆功能改变及认知缺陷的基本机制，研究老化相关性疾病，评价治疗老化关联疾病和改善学习记忆机能的益智药物。但SAMP8所涉及的相关疾病主要是阿尔茨海默病，能否用于其他衰老相关性疾病如帕金森病仍需进一步研究。     

新型FKBPs配体HD5-6对SAMP8小鼠的抗老化研究

目的观察FKBPs(FK506 blinding proteins)配体噻嗪酰胺衍生物(HD5-6)对SAMP8快速老化小鼠学习记忆能力和海马神经元的影响,以及对SAMP8小鼠海马神经元基因表达谱的影响。方法选用10月龄快速老化的SAMP8小鼠20只,随机分为痴呆组、HD5-6组;另选10月龄正常老化的SAMR1小鼠10只作为正常对照组。各组分别腹腔注射药物35 d,并于29 d采用Morris水迷宫实验评价各组小鼠学习记忆能力的变化。HE染色观察海马区神经元形态;TUNEL观察海马神经元凋亡情况,用基因芯片技术检测HD5-6组和痴呆组小鼠海马神经元基因表达谱的变化差异。结果与正常对照组相比,痴呆组在定位航行实验中表现出明显的学习记忆障碍,逃避潜伏期显著延长(P0.05),HD5-6组自3 d开始逃避潜伏期比痴呆组明显缩短(P0.05);空间探索实验中HD5-6组跨平台次数、原平台象限停留时间明显多于痴呆组(P0.05)。与正常对照组相比,痴呆组海马区神经元数量明显减少,细胞排列紊乱,大量的神经元细胞核固缩,深染、坏死,其神经元凋亡指数(51.73±4.48)%明显高于正常对照组(28.02±11.25)%(P0.05),HD5-6干预的SAMP8小鼠海马区神经元病理改变明显改善,海马神经元凋亡指数(20.47±2.25)%明显降低(P0.01)。HD5-6组与痴呆组海马神经元基因表达谱相比,表达差异在2倍以上的基因有118条,表达上调的为9条,表达下调的为109条。其中有功能的mRNA中,表达上调的有4条,表达下调的有21条。结论 HD5-6能够改善快速老化小鼠SAMP8的学习记忆能力和海马神经元病理改变,并可能通过对基因表达谱产生影响而发挥明显的抗衰老作用。     

快速老化与正常老化小鼠脑内神经干细胞增殖的差异**★

背景：在老化过程中，脑内环境改变可引起脑内神经干细胞增殖能力改变。脑内神经干细胞与衰老和退行性神经病变疾病密切相关，增殖能力与年龄存在负相关，但以快速老化小鼠为衰老模型的相关研究未见报道。 目的：比较快速老化与正常老化小鼠嗅球、海马、皮质神经干细胞增殖的差异。 方法：分别取6只快速老化小鼠(SAMP8)和6只正常老化小鼠(SAMR1)的嗅球、海马、皮质组织，在固定、冰冻切片后，运用Ki-67/Nestin免疫荧光双标检测3个脑区的神经干细胞增殖情况。免疫荧光双标在荧光显微镜下通过Leica Qwin v3采图，在40倍物镜和10倍目镜下采图，每一张切片随机选取5 个相邻视野，通过Image-pro-Plus软件完成图像分析。 结果与结论：正常老化小鼠和快速老化小鼠均有神经干细胞增殖现象，但二者存在差异，其差异主要表现在海马和嗅球两个脑区(P < 0.05)。提示快速老化可能会导致海马、嗅球神经干细胞增殖能力降低。     

Changes in expressions of proinflammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8

The senescence-accelerated mouse (SAM) is known to be a murine model for accelerated aging. The SAMP8 strain shows age-related deterioration of learning and memory at an earlier age than control mice (SAMR1). In the present study, we investigated the changes in expressions of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the brain of SAMP8. In the hippocampus of 10 months old SAMP8, the expression of IL-1 mRNA was significantly elevated in comparison with that of SAMR1. In both strains of SAMs, increases in IL-1beta protein in the brain were observed at 10 months of age compared with 2 and 5 months. The only differences found between the strain in protein levels were at 10 months and were elevations in IL-1beta in the hippocampus and hypothalamus, and in TNF-alpha and IL-6 in the cerebral cortex and the hippocampus in SAMP8 as compared with SAMR1. However, lipopolysaccharide-induced increases in the expression of these cytokines in brain did not differ between SAMP8 and SAMR1. Increases in expression of proinflammatory cytokines in the brain may be involved in the age-related neural dysfunction and/or learning deficiency in SAMP8.     

Deterioration in learning and memory of inferential tasks for evaluation of transitivity and symmetry in aged SAMP8 mice

This study examined age-dependent deficits in the learning and memory of inferential tasks, using an established senescence-accelerated mouse model in age-related brain dysfunction (SAMP8) and its genetically related inbred strain (SAMR1). The mice learned two sets of nonspatial odor-odor pairs by association learning successively (i.e., A-->B, X-->Y, then B-->C, Y-->Z). They were tested in transitive inference (i.e., A-->C, X-->Z) and symmetrical inference (i.e., C-->B, Z-->Y). In the probe test of A-->C, X-->Z transitive inference, 1-month-old SAMP8 and control SAMR1 at the same age significantly chose the alternative based on transitive inference, but 4- and 7-month-old SAMP8 performed at a random chance level, in comparison with unambiguous inference by control SAMR1 at the same ages. During the test of C-->B, Z-->Y symmetrical inference, SAMP8 at 1 month of age made errors as frequently as control SAMR1 at the same age, but SAMP8 at 4 and 7 months of age made more errors than SAMR1 at the same ages. At 4 and 7 months of age, SAMP8 made more errors than 1-month-old SAMP8. Control SAMR1 did not show such an age-related deficient. These results indicate that SAMP8 mice have age-related learning and memory deficits in the ability to perform inferential tasks. Age-related hippocampal dysfunction is suggested to be the cause of these age-related deficits in old SAMP8 mice during the performance of inferential tasks mediated by declarative memory.     

Changes in expressions of proinflammatory cytokines IL-1β, TNF-α and IL-6 in the brain of senescence accelerated mouse (SAM) P8

The senescence-accelerated mouse (SAM) is known to be a murine model for accelerated aging. The SAMP8 strain shows age-related deterioration of learning and memory at an earlier age than control mice (SAMR1). In the present study, we investigated the changes in expressions of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the brain of SAMP8. In the hippocampus of 10 months old SAMP8, the expression of IL-1 mRNA was significantly elevated in comparison with that of SAMR1. In both strains of SAMs, increases in IL-1β protein in the brain were observed at 10 months of age compared with 2 and 5 months. The only differences found between the strain in protein levels were at 10 months and were elevations in IL-1β in the hippocampus and hypothalamus, and in TNF-α and IL-6 in the cerebral cortex and the hippocampus in SAMP8 as compared with SAMR1. However, lipopolysaccharide-induced increases in the expression of these cytokines in brain did not differ between SAMP8 and SAMR1. Increases in expression of proinflammatory cytokines in the brain may be involved in the age-related neural dysfunction and/or learning deficiency in SAMP8.     

Ameliorative effects of lotus seedpod proanthocyanidins on cognitive deficits and oxidative damage in senescence-accelerated mice

We investigated the effects of lotus seedpod proanthocyanidins (LSPC) administration by oral gavage for 3 months on body weight, learning and memory deficits using Y-maze test, oxidative stress and antioxidative enzyme activity in brain and serum of the senescence-accelerated mice (SAMP8) and the senescence-resistant mice (SAMR1). Mice of each group were weighed weekly. Brain was obtained from SAMP8 and SAMR1 (the control mouse for SAMP8) at 6 months of age and serum was available from SAMP8 and SAMR1 at 3, 4, 5 and 6 months of age. The results of body weight showed that 90mg/kg LSPC administration significantly increased body weight at 5.5 and 6 months of age in SAMP8 when compared with control SAMP8 of the same age. Y-maze test indicated that learning and memory abilities of mice were deteriorated significantly at 6 months of age in SAMP8 compared with age-matched SAMR1, but were remarkably improved after LSPC (60, 90, 120mg/kg body weight) administration beginning at 3 months of ages. Malondialdehyde (MDA), nitric oxide (NO) and nitric oxide synthase (NOS) exhibited significant increases mostly at 5 and 6 months of age in SAMP8. Glutathione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities decreased significantly mostly at 5 and 6 months of age in SAMP8. LSPC (60, 90, 120mg/kg body weight) administration beginning at 3 months of ages decreased MDA, NO content and lowered NOS activity in the brain and serum of SAMP8. Furthermore, LSPC significantly increased GSH level and augmented GPx, SOD activity in the brain and serum of SAMP8. These results suggest that an age-related increase in brain tissue vulnerability to oxidation and deterioration in learning and memory abilities in SAM that can be modified by LSPC, most likely through the ability of LSPC to scavenge oxygen free radicals and to stimulate antioxidant enzyme activity.     

Functional relationship between age-related immunodeficiency and learning deterioration

Disordered immune responses are supposed to alter the function of the central nervous system through the neuroendocrine immunomodulation network. In this paper, we studied the influence of the immune function on learning performances from the angle of pharmacology using aged garlic extract (AGE), an immunomodulator. Splenocyte proliferation, induced by concanavalin A or lipopolysaccharide, and the antibody production response were declined in senescence accelerated mouse-prone 8 (SAMP8) aged 12 months compared with age-matched SAMR1 (SAM-resistant 1). Chronic oral administration of AGE-containing food (2%, w/w) significantly enhanced the immune responses of both SAMP8 and SAMR1. Male ddY mice were thymectomized 4 weeks after birth and fed AGE-containing food after the operation until the experiments were finished. Learning performances, brain monoamine content and choline acetyltransferase (ChAT) activity, as well as the immune response were evaluated 10 months after the operation. Thymectomy resulted in not only immunodeficiency, but also deteriorated learning ability. AGE treatment prevented the reduction of the antibody production response induced by thymectomy and improved the thymectomy-induced deterioration of learning behaviours in passive avoidance performance and in a spatial memory task. The contents of hypothalamic noradrenaline, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and the hypothalamic ChAT activity were increased in thymectomized mice compared to those of sham-operated control, while AGE treatment restored them to the control levels. These results suggest that the improvement of immune function is closely related to the amelioration of age-associated deterioration of learning and memory.     

Age-related expression of sigma1 receptors and antidepressant efficacy of a selective agonist in the senescence-accelerated (SAM) mouse

The sigma1 receptor is a unique intracellular receptor whose activation results in an efficient modulation of several neurotransmitter responses. Its role as a target for the rapid nongenomic effects of neuro(active)steroids and the age-related diminutions in steroid levels suggested that targeting the sigma1 receptor might allow alleviation of age-related neuronal dysfunctions. We examined here the expression and behavioral efficacy of sigma1 receptors in the senescence-accelerated (SAM) mouse model. The sigma1 receptor mRNA expression was measured by using comparative RT-PCR in the olfactory bulb, hippocampus, hypothalamus, cortex, or cerebellum of senescence-prone SAMP/8 and senescence-resistant SAMR/1 control animals. No difference was observed between substrains in 6-, 9-, and 12-month-old (m.o.) mice. The sigma1 protein expression was analyzed by using immunohistochemical techniques. Labeling was intense in the olfactory bulb, hippocampus, hypothalamus, and midbrain of both SAMR/1 and SAMP/8 mice, and the distribution appeared unchanged in 6-, 9-, and 12-m.o. animals. The receptor's in vivo availability was examined by using in vivo [3H](+)-SKF-10,047 binding. No age-related difference was observed in the olfactory bulb, hippocampus, hypothalamus, cortex, cerebellum, and brainstem of 6- or 12-m.o. SAMR/1 or SAMP/8 mice. The antidepressant efficacy of the selective agonist igmesine was examined in the forced-swimming test. The compound decreased significantly the immobility duration at 60 mg/kg in 6- and 12-m.o. SAMR/1 and in 6-m.o. SAMP/8 mice. In 12-m.o. SAMP/8 mice, the drug efficacy was facilitated; a significant effect was measured at 30 mg/kg. Decreased neurosteroid levels, particularly of progesterone, were seen in 12-m.o. SAMP/8 mice that might explain the enhanced efficacy of igmesine. Preserved sigma1 receptor expression and enhanced behavioral efficacy of sigma1 agonists were measured in SAM animals, confirming the therapeutic opportunities for selective ligands against age-related mood disorders.     

Increased Expression of Cathepsins E and D in Reactive Microglial Cells Associated with Spongiform Degeneration in the Brain Stem of Senescence-Accelerated Mouse

Senescence-accelerated mouse (SAM) P8 and P10 exhibit a spongy degeneration, especially in the brain stem, and a brain atrophy mainly in the frontal portion of the cerebral cortex, respectively, with advancing age. In an attempt to clarify the role of two distinct intracellular aspartic proteinases, cathepsins E (CE) and D (CD), in these age-related pathological changes, accumulation and localization of these enzymes were investigated in the brain stem and the cerebral cortex of SAMP8 and P10 and in the senescence-resistant control SAMR1 with four different age groups (1 week and 2, 6, and 12 months). In the brain stem of SAMP8, a marked spongy degeneration was observed at more than 2 months of age. The same degree of spongy degeneration was also observed in the brain stem of age-matched SAMP10 but not SAMR1. The nonlysosomal enzyme CE was barely detectable in the brain stem of all three strains at 1 week of age, but it was markedly accumulated in the brain stem of SAMP8 and P10 at 2 months of age. The lysosomal enzyme CD was found in relatively high concentration in the brain stem of all three strains at 1 week of age. At 2 months of age, CD contents were significantly increased in the brain stem of SAMP8 and P10 compared with those of age-matched SAMR1. At the light-microscopic level, increased immunoreactivities for CE in the brain stem of 2-month-old SAMP8 and P10 were found in reactive microglial cells clustered at the spongy areas but not in microglial cells with resting or ramified morphology and astrocytes. The increased immunoreactivity for CD was observed mainly in reactive astrocytes and partially in reactive microglial cells. Immunoblotting analyses revealed that CE in the brain stem of 2-month-old SAMP10 consisted of only the mature form of 42 kDa, whereas CD in this tissue is composed of mainly the mature form of 44 kDa and partially its degradation products. On the other hand, there was a marked brain atrophy mainly in the frontal portion of the cerebral cortex of 6-month-old SAMP10 but not in age-matched SAMP8 or SAMR1. Although CE was not detectable even in the atrophied cortical area of SAMP10, CD contents in the cerebral cortex slightly increased with senescence in all three strains. These results strongly suggest that CE and CD are upregulated in reactive glial cells and are closely linked with the progression of the spongiform degeneration in the brain stem of SAMP8 and P10, but not in the atrophy developed in the cerebral cortex of SAMP10.     

Spatial memory performance and hippocampal neuron number in osteoporotic SAMP6 mice

The senescence-accelerated mouse strain P6 (SAMP6) is an inbred mouse that represents a clinically relevant model of senile osteoporosis. However, whether osteoporotic SAMP6 mice have cognitive deficits remains largely unexplored. Here, we used Morris water maze to assess reference memory and working memory performance in SAMP6 mice and SAMR1 controls, at 4 and 8 months of age. In addition, unbiased stereological techniques were used to estimate total neuron number in hippocampal CA1 subfield of the mice used in the behavioral study. Morris water maze test revealed impairments in working memory but not in reference memory of the 4- and 8-month-old SAMP6 mice compared with the SAMR1 mice at the same age. However, there were no significant differences in the total numbers of neurons in hippocampal CA1 subfield when comparing 4-month-old SAMR1 and 4-month-old SAMP6 and 8-month-old SAMR1 and 8-month-old SAMP6, which indicate that, in SAMP6 mice, the structural correlates of working memory deficits are to be found in parameters other than the number of neurons in hippocampal CA1 subfield. These findings suggest that SAMP6 mice exhibit selective cognitive deficits and highlight the importance of this mouse model for studying the brain alterations associated with osteoporosis.     

Expression of neurotrophin genes in the brain of senescence-accelerated mouse (SAM) during postnatal development

We compared the expression patterns of neurotrophin genes in the brain of senescence-accelerated mouse (SAMP8) which shows age-related impairment of learning behavior, with SAMR1 control which shows normal aging. By Northern blot analysis, NT-3 mRNA levels in the cortex were higher in SAMP8 than in SAMR1 mice during development, whereas in the midbrain, hippocampus and forebrain, NT-3 expression levels in SAMP8 were lower than those in SAMR1. At early stages, although NGF mRNA levels in SAMP8 were lower than those in SAMR1, BDNF mRNA levels were almost equivalent in both strains. By in situ hybridization analysis, NT-3 mRNA signals in the CA1 and CA2 regions in SAMP8 were shown to be reduced at early stages. However, BDNF mRNA signals were almost equivalent in both SAMR1 and SAMP8.