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Impaired structural correlates of memory in Alzheimer's disease mice.

Badhwar A, Lerch JP, Hamel E, Sled JG - Neuroimage Clin (2013)

Bottom Line: The healthy adult brain demonstrates robust learning-induced neuroanatomical plasticity.Using high-resolution post-mortem MRI and deformation-based morphometry, we demonstrate spatial learning and memory-induced focal volume increase in the hippocampus of wild-type mice, an effect that was severely attenuated in APP mice, consistent with their unsuccessful performance in the spatial Morris water maze.Pioglitazone-treatment in APP mice completely rescued functional hyperemia and exerted beneficial effects on spatial learning and memory-recall, but it did not improve hippocampal plasticity.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.

ABSTRACT
The healthy adult brain demonstrates robust learning-induced neuroanatomical plasticity. While altered neuroanatomical plasticity is suspected to be a factor mitigating the progressive cognitive decline in Alzheimer's disease (AD), it is not known to what extent this plasticity is affected by AD. We evaluated whether spatial learning and memory-induced neuroanatomical plasticity are diminished in an adult mouse model of AD (APP mice) featuring amyloid beta-driven cognitive and cerebrovascular dysfunction. We also evaluated the effect of early, long-term pioglitazone-treatment on functional hyperemia, spatial learning and memory, and associated neuroanatomical plasticity. Using high-resolution post-mortem MRI and deformation-based morphometry, we demonstrate spatial learning and memory-induced focal volume increase in the hippocampus of wild-type mice, an effect that was severely attenuated in APP mice, consistent with their unsuccessful performance in the spatial Morris water maze. These findings implicate impaired neuroanatomical plasticity as an important contributing factor to cognitive deficits in the APP mouse model of AD. Pioglitazone-treatment in APP mice completely rescued functional hyperemia and exerted beneficial effects on spatial learning and memory-recall, but it did not improve hippocampal plasticity.

No MeSH data available.


Related in: MedlinePlus

Spatial learning and memory deficits in APP mice. (A) All mice undergoing non-spatial Morris water maze performed equally well at the end of training. (B) In contrast, 6-month-old APP mice () were impaired in the spatial Morris water maze, featuring significantly longer escape latencies in finding the hidden platform relative to WT controls (). Pioglitazone slightly, but not significantly, improved learning performance in treated APP mice (). (C) Compared to WT mice, learning capacity while impaired in APP mice was similar in pioglitazone-treated APP mice. (D) A decrease in the average distance swam per training day was observed in pioglitazone-treated APP mice compared to untreated APP mice, reaching significance on day 5. (E) In the probe trial, the number of crossings was slightly higher in pioglitazone-treated APP mice compared to APP mice, but still significantly different from WT mice. (F) Compared to WT mice, distance travelled in the correct quadrant was significantly lower in APP, but not in pioglitazone-treated APP mice. (G) Representative swim paths ( start,  end) and percent distance travelled in each quadrant. Pioglitazone-treated APP mice showed mild improvement in the swim strategy used to locate the hidden platform. Overall, all groups displayed comparable swim speeds ruling out motor disabilities. Statistical analysis used was a two-way ANOVA. p < .05 compared to APP, p < .05, p < .01, and p < .001 compared to WT. Pioglitazone-treated WT mice (), error bars: SEM, pio: pioglitazone, WT: wild-type.
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f0010: Spatial learning and memory deficits in APP mice. (A) All mice undergoing non-spatial Morris water maze performed equally well at the end of training. (B) In contrast, 6-month-old APP mice () were impaired in the spatial Morris water maze, featuring significantly longer escape latencies in finding the hidden platform relative to WT controls (). Pioglitazone slightly, but not significantly, improved learning performance in treated APP mice (). (C) Compared to WT mice, learning capacity while impaired in APP mice was similar in pioglitazone-treated APP mice. (D) A decrease in the average distance swam per training day was observed in pioglitazone-treated APP mice compared to untreated APP mice, reaching significance on day 5. (E) In the probe trial, the number of crossings was slightly higher in pioglitazone-treated APP mice compared to APP mice, but still significantly different from WT mice. (F) Compared to WT mice, distance travelled in the correct quadrant was significantly lower in APP, but not in pioglitazone-treated APP mice. (G) Representative swim paths ( start, end) and percent distance travelled in each quadrant. Pioglitazone-treated APP mice showed mild improvement in the swim strategy used to locate the hidden platform. Overall, all groups displayed comparable swim speeds ruling out motor disabilities. Statistical analysis used was a two-way ANOVA. p < .05 compared to APP, p < .05, p < .01, and p < .001 compared to WT. Pioglitazone-treated WT mice (), error bars: SEM, pio: pioglitazone, WT: wild-type.

Mentions: In the non-spatial MWM task (visible platform, Fig. 2A), aside from small but significant punctual differences at days 1 and 4, the progressive decrease in escape latency over the five-day training period was comparable between WT and APP mice, thus ruling out overt visual, motor, and motivational deficits in APP mice. Mice displayed shorter escape latency in the non-spatial MWM compared to the spatial MWM (Fig. 2B), confirming the challenging nature of the latter despite similar sensorimotor and motivational requirements in both versions of the MWM (Lerch et al., 2011a). In the spatial MWM task, progressive decrease in escape latency (Fig. 2B), and distance swam prior to locating the hidden platform (Fig. 2D) over the five-day training period were significantly different (p < 0.01) between the two genotypes, indicating that APP mice have difficulty learning the spatial task. This was further evidenced by significantly (p < 0.05) diminished learning capacity in these mice over the five-day training period (slope = − 1.82 ± 1.23) compared to WT mice (slope = − 5.02 ± 0.69) (Fig. 2C). Moreover, in the probe trial, crossings at the target location (Fig. 2E), and the percent distance travelled in the target quadrant (Fig. 2F) by APP mice were significantly less (p < 0.01 and p < 0.05, respectively) than WT controls, consistent with reported deficits in memory retrieval and precision in these mice. These findings were not due to differences in swim speed, which was comparable amongst all groups (data not shown).


Impaired structural correlates of memory in Alzheimer's disease mice.

Badhwar A, Lerch JP, Hamel E, Sled JG - Neuroimage Clin (2013)

Spatial learning and memory deficits in APP mice. (A) All mice undergoing non-spatial Morris water maze performed equally well at the end of training. (B) In contrast, 6-month-old APP mice () were impaired in the spatial Morris water maze, featuring significantly longer escape latencies in finding the hidden platform relative to WT controls (). Pioglitazone slightly, but not significantly, improved learning performance in treated APP mice (). (C) Compared to WT mice, learning capacity while impaired in APP mice was similar in pioglitazone-treated APP mice. (D) A decrease in the average distance swam per training day was observed in pioglitazone-treated APP mice compared to untreated APP mice, reaching significance on day 5. (E) In the probe trial, the number of crossings was slightly higher in pioglitazone-treated APP mice compared to APP mice, but still significantly different from WT mice. (F) Compared to WT mice, distance travelled in the correct quadrant was significantly lower in APP, but not in pioglitazone-treated APP mice. (G) Representative swim paths ( start,  end) and percent distance travelled in each quadrant. Pioglitazone-treated APP mice showed mild improvement in the swim strategy used to locate the hidden platform. Overall, all groups displayed comparable swim speeds ruling out motor disabilities. Statistical analysis used was a two-way ANOVA. p < .05 compared to APP, p < .05, p < .01, and p < .001 compared to WT. Pioglitazone-treated WT mice (), error bars: SEM, pio: pioglitazone, WT: wild-type.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3814975&req=5

f0010: Spatial learning and memory deficits in APP mice. (A) All mice undergoing non-spatial Morris water maze performed equally well at the end of training. (B) In contrast, 6-month-old APP mice () were impaired in the spatial Morris water maze, featuring significantly longer escape latencies in finding the hidden platform relative to WT controls (). Pioglitazone slightly, but not significantly, improved learning performance in treated APP mice (). (C) Compared to WT mice, learning capacity while impaired in APP mice was similar in pioglitazone-treated APP mice. (D) A decrease in the average distance swam per training day was observed in pioglitazone-treated APP mice compared to untreated APP mice, reaching significance on day 5. (E) In the probe trial, the number of crossings was slightly higher in pioglitazone-treated APP mice compared to APP mice, but still significantly different from WT mice. (F) Compared to WT mice, distance travelled in the correct quadrant was significantly lower in APP, but not in pioglitazone-treated APP mice. (G) Representative swim paths ( start, end) and percent distance travelled in each quadrant. Pioglitazone-treated APP mice showed mild improvement in the swim strategy used to locate the hidden platform. Overall, all groups displayed comparable swim speeds ruling out motor disabilities. Statistical analysis used was a two-way ANOVA. p < .05 compared to APP, p < .05, p < .01, and p < .001 compared to WT. Pioglitazone-treated WT mice (), error bars: SEM, pio: pioglitazone, WT: wild-type.
Mentions: In the non-spatial MWM task (visible platform, Fig. 2A), aside from small but significant punctual differences at days 1 and 4, the progressive decrease in escape latency over the five-day training period was comparable between WT and APP mice, thus ruling out overt visual, motor, and motivational deficits in APP mice. Mice displayed shorter escape latency in the non-spatial MWM compared to the spatial MWM (Fig. 2B), confirming the challenging nature of the latter despite similar sensorimotor and motivational requirements in both versions of the MWM (Lerch et al., 2011a). In the spatial MWM task, progressive decrease in escape latency (Fig. 2B), and distance swam prior to locating the hidden platform (Fig. 2D) over the five-day training period were significantly different (p < 0.01) between the two genotypes, indicating that APP mice have difficulty learning the spatial task. This was further evidenced by significantly (p < 0.05) diminished learning capacity in these mice over the five-day training period (slope = − 1.82 ± 1.23) compared to WT mice (slope = − 5.02 ± 0.69) (Fig. 2C). Moreover, in the probe trial, crossings at the target location (Fig. 2E), and the percent distance travelled in the target quadrant (Fig. 2F) by APP mice were significantly less (p < 0.01 and p < 0.05, respectively) than WT controls, consistent with reported deficits in memory retrieval and precision in these mice. These findings were not due to differences in swim speed, which was comparable amongst all groups (data not shown).

Bottom Line: The healthy adult brain demonstrates robust learning-induced neuroanatomical plasticity.Using high-resolution post-mortem MRI and deformation-based morphometry, we demonstrate spatial learning and memory-induced focal volume increase in the hippocampus of wild-type mice, an effect that was severely attenuated in APP mice, consistent with their unsuccessful performance in the spatial Morris water maze.Pioglitazone-treatment in APP mice completely rescued functional hyperemia and exerted beneficial effects on spatial learning and memory-recall, but it did not improve hippocampal plasticity.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.

ABSTRACT
The healthy adult brain demonstrates robust learning-induced neuroanatomical plasticity. While altered neuroanatomical plasticity is suspected to be a factor mitigating the progressive cognitive decline in Alzheimer's disease (AD), it is not known to what extent this plasticity is affected by AD. We evaluated whether spatial learning and memory-induced neuroanatomical plasticity are diminished in an adult mouse model of AD (APP mice) featuring amyloid beta-driven cognitive and cerebrovascular dysfunction. We also evaluated the effect of early, long-term pioglitazone-treatment on functional hyperemia, spatial learning and memory, and associated neuroanatomical plasticity. Using high-resolution post-mortem MRI and deformation-based morphometry, we demonstrate spatial learning and memory-induced focal volume increase in the hippocampus of wild-type mice, an effect that was severely attenuated in APP mice, consistent with their unsuccessful performance in the spatial Morris water maze. These findings implicate impaired neuroanatomical plasticity as an important contributing factor to cognitive deficits in the APP mouse model of AD. Pioglitazone-treatment in APP mice completely rescued functional hyperemia and exerted beneficial effects on spatial learning and memory-recall, but it did not improve hippocampal plasticity.

No MeSH data available.


Related in: MedlinePlus