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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

Focal hippocampal volume increase associated with spatial learning and memory in WT mice is attenuated in APP mice. (A) Location of the five MRI slices shown in reference to the 3D brain. (B) Population-specific 3D MRI brain atlas. (C) Effect of genotype on local brain volume. Warm colors correspond to regions where APP brains were larger than WT whereas cool colors indicate regions that were smaller. The expansion/contraction map is masked based on statistical significance at a false discovery rate (FDR) of 10%. Cross-hairs 1 and 2 point to specific areas that are smaller in APP brains compared to WT, namely, the corpus callosum/cingulum bundle and the midline-adjacent CA1 regions, respectively. Cross-hair 3 points to an area of no change, specifically, the lateral CA1 region. (D) Expansion/contraction associated with spatial vs. non-spatial learning and memory in WT mice (masked at 10% FDR). Cross-hair 4 points to volume increase in the CA1/CA2 boundary region. (E) Expansion/contraction associated with spatial vs. non-spatial learning and memory in APP mice (same significance mask as in (D)). Compared to WT mice, APP mice display attenuated hippocampal volume increase following spatial Morris Water Maze performance. (F) The bar graphs show mean and standard error for the expansion/contraction factor associated with each selected voxel (cross-hairs c1–3 and d4). The genotype plots (1–3) have been normalized such that the WT homecage controls have a factor of 1.0. The training effect plots (4) have been normalized such that the homecage controls for respective genotypes have a factor of 1.0. WT: wild-type.
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f0020: Focal hippocampal volume increase associated with spatial learning and memory in WT mice is attenuated in APP mice. (A) Location of the five MRI slices shown in reference to the 3D brain. (B) Population-specific 3D MRI brain atlas. (C) Effect of genotype on local brain volume. Warm colors correspond to regions where APP brains were larger than WT whereas cool colors indicate regions that were smaller. The expansion/contraction map is masked based on statistical significance at a false discovery rate (FDR) of 10%. Cross-hairs 1 and 2 point to specific areas that are smaller in APP brains compared to WT, namely, the corpus callosum/cingulum bundle and the midline-adjacent CA1 regions, respectively. Cross-hair 3 points to an area of no change, specifically, the lateral CA1 region. (D) Expansion/contraction associated with spatial vs. non-spatial learning and memory in WT mice (masked at 10% FDR). Cross-hair 4 points to volume increase in the CA1/CA2 boundary region. (E) Expansion/contraction associated with spatial vs. non-spatial learning and memory in APP mice (same significance mask as in (D)). Compared to WT mice, APP mice display attenuated hippocampal volume increase following spatial Morris Water Maze performance. (F) The bar graphs show mean and standard error for the expansion/contraction factor associated with each selected voxel (cross-hairs c1–3 and d4). The genotype plots (1–3) have been normalized such that the WT homecage controls have a factor of 1.0. The training effect plots (4) have been normalized such that the homecage controls for respective genotypes have a factor of 1.0. WT: wild-type.

Mentions: Voxel-wise analysis provides a measure of local volumetric expansion (> 0) or contraction (< 0) relative to the reference space. A key feature of this approach is that it can detect small focal volume differences that may not be picked up in brain substructure-based approaches. Fig. 4C illustrates the differences found between APP and WT mice, with the red color scale indicating degrees of volume expansion, and the blue scale indicating degrees of volume contraction. Broad areas of volume expansion can be seen, in line with the overall larger brains seen in the APP mice. Focal regions of volume contraction in APP relative to WT were found in corpus callosum and cingulum bundle, hippocampus (in particular, CA1 region adjacent to the midline, and CA3) and cerebellar cortex. It should be noted that while volume decrease in CA1 spanned almost the entire hippocampal septotemporal axis, in CA3 it was limited to the intermediate portion. Volume contraction in the corpus callosum and hippocampal CA1 subfield in APP mice was further validated using voxel plots (Fig. 4F). In order to understand the cellular basis of the volume differences in the hippocampus, we performed histology on sections of the CA1 subfield.


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

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

Focal hippocampal volume increase associated with spatial learning and memory in WT mice is attenuated in APP mice. (A) Location of the five MRI slices shown in reference to the 3D brain. (B) Population-specific 3D MRI brain atlas. (C) Effect of genotype on local brain volume. Warm colors correspond to regions where APP brains were larger than WT whereas cool colors indicate regions that were smaller. The expansion/contraction map is masked based on statistical significance at a false discovery rate (FDR) of 10%. Cross-hairs 1 and 2 point to specific areas that are smaller in APP brains compared to WT, namely, the corpus callosum/cingulum bundle and the midline-adjacent CA1 regions, respectively. Cross-hair 3 points to an area of no change, specifically, the lateral CA1 region. (D) Expansion/contraction associated with spatial vs. non-spatial learning and memory in WT mice (masked at 10% FDR). Cross-hair 4 points to volume increase in the CA1/CA2 boundary region. (E) Expansion/contraction associated with spatial vs. non-spatial learning and memory in APP mice (same significance mask as in (D)). Compared to WT mice, APP mice display attenuated hippocampal volume increase following spatial Morris Water Maze performance. (F) The bar graphs show mean and standard error for the expansion/contraction factor associated with each selected voxel (cross-hairs c1–3 and d4). The genotype plots (1–3) have been normalized such that the WT homecage controls have a factor of 1.0. The training effect plots (4) have been normalized such that the homecage controls for respective genotypes have a factor of 1.0. WT: wild-type.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f0020: Focal hippocampal volume increase associated with spatial learning and memory in WT mice is attenuated in APP mice. (A) Location of the five MRI slices shown in reference to the 3D brain. (B) Population-specific 3D MRI brain atlas. (C) Effect of genotype on local brain volume. Warm colors correspond to regions where APP brains were larger than WT whereas cool colors indicate regions that were smaller. The expansion/contraction map is masked based on statistical significance at a false discovery rate (FDR) of 10%. Cross-hairs 1 and 2 point to specific areas that are smaller in APP brains compared to WT, namely, the corpus callosum/cingulum bundle and the midline-adjacent CA1 regions, respectively. Cross-hair 3 points to an area of no change, specifically, the lateral CA1 region. (D) Expansion/contraction associated with spatial vs. non-spatial learning and memory in WT mice (masked at 10% FDR). Cross-hair 4 points to volume increase in the CA1/CA2 boundary region. (E) Expansion/contraction associated with spatial vs. non-spatial learning and memory in APP mice (same significance mask as in (D)). Compared to WT mice, APP mice display attenuated hippocampal volume increase following spatial Morris Water Maze performance. (F) The bar graphs show mean and standard error for the expansion/contraction factor associated with each selected voxel (cross-hairs c1–3 and d4). The genotype plots (1–3) have been normalized such that the WT homecage controls have a factor of 1.0. The training effect plots (4) have been normalized such that the homecage controls for respective genotypes have a factor of 1.0. WT: wild-type.
Mentions: Voxel-wise analysis provides a measure of local volumetric expansion (> 0) or contraction (< 0) relative to the reference space. A key feature of this approach is that it can detect small focal volume differences that may not be picked up in brain substructure-based approaches. Fig. 4C illustrates the differences found between APP and WT mice, with the red color scale indicating degrees of volume expansion, and the blue scale indicating degrees of volume contraction. Broad areas of volume expansion can be seen, in line with the overall larger brains seen in the APP mice. Focal regions of volume contraction in APP relative to WT were found in corpus callosum and cingulum bundle, hippocampus (in particular, CA1 region adjacent to the midline, and CA3) and cerebellar cortex. It should be noted that while volume decrease in CA1 spanned almost the entire hippocampal septotemporal axis, in CA3 it was limited to the intermediate portion. Volume contraction in the corpus callosum and hippocampal CA1 subfield in APP mice was further validated using voxel plots (Fig. 4F). In order to understand the cellular basis of the volume differences in the hippocampus, we performed histology on sections of the CA1 subfield.

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