Effects of aging on the hippocampal formation in a naturally occurring animal model of mild cognitive impairment

Gallagher, Michela; Bizon, Jennifer L.; Hoyt, Eileen C.; Helm, Katherine A.; Lund, P. Kay

doi:10.1016/s0531-5565(02)00159-6

Cited by 90 publications

(59 citation statements)

References 34 publications

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“…The outcome of behavioral testing was consistent with many previous investigations using the same study population (reviewed in Gallagher et al, 2003), and only a brief description is provided. As a group, aged rats displayed significant spatial learning deficits relative to young adults, as measured by both search error on the training trials (repeated measures ANOVA, main effect of age F(1, 63) = 18.3, p < 0.0001) and spatial learning index ( Fig.…”

Section: Spatial Memorysupporting

confidence: 81%

“…Search patterns were recorded throughout training by a videotracking system with custom-developed software (HVS Imaging, Hampton, UK). Standardized measures of spatial learning and memory, validated in many previous studies (reviewed in Gallagher et al, 2003), included: (1) cumulative search error, calculated from subjects' proximity to the escape platform during training trials, and (2) a spatial learning index, reflecting the degree of spatial bias for the escape location during the interpolated probe trials. Accurate search focused on the escape location results in low values for the latter measure.…”

Section: Behavioral Testingmentioning

confidence: 99%

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Age-related spatial learning impairment is unrelated to spinophilin immunoreactive spine number and protein levels in rat hippocampus

Calhoun

Fletcher

et al. 2008

Neurobiology of Aging

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Age-related impairments in hippocampus-dependent learning and memory tasks are not associated with a loss of hippocampal neurons, but may be related to alterations in synaptic integrity. Here we used stereological techniques to estimate spine number in hippocampal subfields using immunostaining for the spine-associated protein, spinophilin, as a marker. Quantification of the immunoreactive profiles was performed using the optical disector/fractionator technique. Aging was associated with a modest increase in spine number in the molecular layer of the dentate gyrus and CA1 stratum lacunosum-moleculare. By comparison, spinophilin protein levels in the hippocampus, measured by Western blot analysis, failed to differ as a function of age. Neither the morphological nor the protein level data were correlated with spatial learning ability across individual aged rats. The results extend current evidence on synaptic integrity in the aged brain, indicating that a substantial loss of dendritic spines and spinophilin protein in the hippocampus are unlikely to contribute to agerelated impairment in spatial learning.

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Section: Spatial Memorysupporting

confidence: 81%

Section: Behavioral Testingmentioning

confidence: 99%

Age-related spatial learning impairment is unrelated to spinophilin immunoreactive spine number and protein levels in rat hippocampus

Calhoun

Fletcher

et al. 2008

Neurobiology of Aging

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“…It is tempting to speculate that the neural substrates for social recognition are relatively more resistant to changes associated with the aging process than those that underlie performance on tasks that require spatial navigation (which does show marked age-related declines [36,37]). Some studies may support this interpretation [35,36], but continued work in this area is necessary. This is the first time that the performance of aged male rats on the social discrimination procedure has been tested, and the social recognition memory of aged female rats has never before been evaluated using any procedure.…”

Section: Methodsmentioning

confidence: 99%

Social recognition memory: Influence of age, sex, and ovarian hormonal status

Markham

Juraska

2007

Physiology & Behavior

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Social recognition memory underlies many forms of rodent interaction and can be easily tested in the laboratory. Sex differences in aspects of this memory have been reported among young adults, and some studies indicate an age-related decline among male rats. In contrast, neither the impact of natural fluctuations in ovarian hormones nor the performance of aged female rats on social recognition memory has been previously evaluated. In experiments 1 and 2, the social recognition memory of young adult female Long-Evans rats (age 3-5 mos.) was compared during proestrus and estrus, and performance was found to be stable across estrous cycle phases. In experiment 3, the social recognition memory of young adults as compared to aged (16.5-19.5 mos.) rats was tested using the social discrimination procedure, following delays of 15, 45, 90 or 120 minutes. The estropausal status of aged female rats was tracked during the experiment but was not found to influence memory ability. Males of both ages investigated juveniles (both novel and familiar) more than did females, although despite this difference, both sexes demonstrated robust memory. Interestingly, only young adult females were capable of demonstrating memory following the longest delay. Collectively, our findings indicate that the pattern of age-related changes in social recognition memory is subtle and that aging does not greatly alter the behavioral sex differences observed among young adults.

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“…Aged learning-impaired rats were compared with aged unimpaired (and young) rats, a strategy that enhances power and reduces confounding effects of general aging (Markowska et al, 1989;Olton et al, 1991;Gallagher et al, 2003;Rowe et al, 2003). We chose the Morris water maze task to screen the aged animals because (1) it represents a (dorsal) hippocampal-dependent task (Moser and Moser, 1998) and (2) we and others have consistently found that there is considerable individual variability on this task, with some aged animals demonstrating the same proficiency as young animals and others exhibiting severe learning deficits (Yau et al, 2002;Gallagher et al, 2003;Rowe et al, 2003;Tombaugh et al, 2005). Together, the results provide an integrative overview of multiple novel and previously reported processes that selectively associate with aging-related cognitive impairment.…”

Section: Introductionmentioning

confidence: 99%

Hippocampal Expression Analyses Reveal Selective Association of Immediate-Early, Neuroenergetic, and Myelinogenic Pathways with Cognitive Impairment in Aged Rats

Rowe¹,

Blalock²,

Chen³

et al. 2007

J. Neurosci.

201

215

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Although expression of some genes is known to change during neuronal activity or plasticity, the overall relationship of gene expression changes to memory or memory disorders is not well understood. Here, we combined extensive statistical microarray analyses with behavioral testing to comprehensively identify genes and pathways associated with aging and cognitive dysfunction. Aged rats were separated into cognitively unimpaired (AU) or impaired (AI) groups based on their Morris water maze performance relative to youngadult (Y) animals. Hippocampal gene expression was assessed in Y, AU, and AI on the fifth (last) day of maze training (5T) or 21 d posttraining (21PT) and in nontrained animals (eight groups total, one array per animal; n ϭ 78 arrays). ANOVA and linear contrasts identified genes that differed from Y generally with aging (differed in both AU and AI) or selectively, with cognitive status (differed only in AI or AU). Altered pathways/processes were identified by overrepresentation analyses of changed genes. With general aging, there was downregulation of axonal growth, cytoskeletal assembly/transport, signaling, and lipogenic/uptake pathways, concomitant with upregulation in immune/inflammatory, lysosomal, lipid/protein degradation, cholesterol transport, transforming growth factor, and cAMP signaling pathways, primarily independent of training condition. Selectively, in AI, there was downregulation at 5T of immediate-early gene, Wnt (wingless integration site), insulin, and G-protein signaling, lipogenesis, and glucose utilization pathways, whereas Notch2 (oligodendrocyte development) and myelination pathways were upregulated, particularly at 21PT. In AU, receptor/signal transduction genes were upregulated, perhaps as compensatory responses. Immunohistochemistry confirmed and extended selected microarray results. Together, the findings suggest a new model, in which deficient neuroenergetics leads to downregulated neuronal signaling and increased glial activation, resulting in aging-related cognitive dysfunction.

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Effects of aging on the hippocampal formation in a naturally occurring animal model of mild cognitive impairment

Cited by 90 publications

References 34 publications

Age-related spatial learning impairment is unrelated to spinophilin immunoreactive spine number and protein levels in rat hippocampus

Age-related spatial learning impairment is unrelated to spinophilin immunoreactive spine number and protein levels in rat hippocampus

Social recognition memory: Influence of age, sex, and ovarian hormonal status

Hippocampal Expression Analyses Reveal Selective Association of Immediate-Early, Neuroenergetic, and Myelinogenic Pathways with Cognitive Impairment in Aged Rats

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