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Short-term recognition memory impairment is associated with decreased expression of FK506 binding protein 51 in the aged mouse brain.

Soontornniyomkij V, Risbrough VB, Young JW, Wallace CK, Soontornniyomkij B, Jeste DV, Achim CL - Age (Dordr) (2010)

Bottom Line: Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age.In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (r (s) = 0.68, p = 0.002, Spearman rank correlation).These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.

View Article: PubMed Central - PubMed

Affiliation: Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, La Jolla, CA 92093-0603, USA. vsoontor@ucsd.edu

ABSTRACT
Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age. We hypothesized that alterations in GR signaling pathway molecules, FK506 binding protein (FKBP) 51 and FKBP52, were associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice, and employed quantitative immunohistochemistry to assess cellular expression of those three proteins in the frontal cortex, hippocampal CA1, and dentate gyrus. Values of the discrimination ratio (DR, a measure of novelty preference) in aged mice were significantly lower than those in young mice (mean 0.54 vs. 0.67, p = 0.003, t test). Aged mice with DR below 0.54 were considered impaired (n = 9). In the three neuroanatomic regions studied, the immunoreactivity normalized to the area measured (IRn) for GR was significantly increased in aged mice regardless of their task performance compared to young mice (p < 0.005), as was the FKBP52 IRn (p < 0.007, U test). In the frontal cortex and CA1, the FKBP51 IRn was significantly lower in impaired aged mice than in unimpaired aged mice (p < 0.01 and <0.05, respectively) and in young mice (p < 0.05 and <0.01, respectively, Dunn's post hoc test). In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (r (s) = 0.68, p = 0.002, Spearman rank correlation). These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.

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a–c Outlines of the frontal cortex (FC), dorsal hippocampal CA1 (CA), and granule cell layer of the dorsal dentate gyrus (DG), respectively, are digitally drawn (green) with the Image-Pro Plus version 4.5 software (Media Cybernetics, Bethesda, MD, USA) in accordance with the neuroanatomic landmarks (Valverde 1998). Immunoreactive signals (brown) for the glucocorticoid receptor (GR) are shown within each of the three neuroanatomic regions. d–f With the Image-Pro Plus software, the histogram-based RGB color segmentation is set to best select the specific immunoreactive signals (red) while ignoring the nonspecific background. Note that right hemi-brain sections immunostained for GR and FK506 binding protein (FKBP) 52 are of one of the young mice, and that for FKBP51 is of one of the impaired aged mice (original magnification, ×100 in a–f)
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Fig1: a–c Outlines of the frontal cortex (FC), dorsal hippocampal CA1 (CA), and granule cell layer of the dorsal dentate gyrus (DG), respectively, are digitally drawn (green) with the Image-Pro Plus version 4.5 software (Media Cybernetics, Bethesda, MD, USA) in accordance with the neuroanatomic landmarks (Valverde 1998). Immunoreactive signals (brown) for the glucocorticoid receptor (GR) are shown within each of the three neuroanatomic regions. d–f With the Image-Pro Plus software, the histogram-based RGB color segmentation is set to best select the specific immunoreactive signals (red) while ignoring the nonspecific background. Note that right hemi-brain sections immunostained for GR and FK506 binding protein (FKBP) 52 are of one of the young mice, and that for FKBP51 is of one of the impaired aged mice (original magnification, ×100 in a–f)

Mentions: On each image of the entire parasagittal hemi-brain section, the outline of the area of interest (AOI; i.e., the frontal cortex, dorsal hippocampal CA1, and granule cell layer of the dorsal dentate gyrus) was digitally drawn with the Image-Pro Plus software in accordance with the neuroanatomic landmarks (Valverde 1998; Fig. 1a–c, respectively). The first superficial layer of the frontal cortex was excluded to avoid staining artifacts, as were large vascular spaces and areas of tissue folding. To measure immunoreactive signals within AOI, histogram-based RGB color segmentation was set to best select the specific signal while ignoring the nonspecific background (Fig. 1d–f). For each pair of the three proteins and three neuroanatomic regions studied, the same setting of color segmentation was applied to all the hemi-brains. The values of three Image-Pro Plus measurement statistics including area (=area of object), integrated optical density (=[area] × [average optical density of object]) and per-area (=[area]/[AOI]) were recorded for each AOI and exported to a Microsoft Excel spreadsheet. The value of AOI (in micrometer squared) was calculated by dividing the mean of area values by the mean of per-area values. The value of immunoreactivity normalized to the AOI (IRn) calculated by dividing the sum of integrated optical density values by the AOI value was used for subsequent statistical analysis.Fig. 1


Short-term recognition memory impairment is associated with decreased expression of FK506 binding protein 51 in the aged mouse brain.

Soontornniyomkij V, Risbrough VB, Young JW, Wallace CK, Soontornniyomkij B, Jeste DV, Achim CL - Age (Dordr) (2010)

a–c Outlines of the frontal cortex (FC), dorsal hippocampal CA1 (CA), and granule cell layer of the dorsal dentate gyrus (DG), respectively, are digitally drawn (green) with the Image-Pro Plus version 4.5 software (Media Cybernetics, Bethesda, MD, USA) in accordance with the neuroanatomic landmarks (Valverde 1998). Immunoreactive signals (brown) for the glucocorticoid receptor (GR) are shown within each of the three neuroanatomic regions. d–f With the Image-Pro Plus software, the histogram-based RGB color segmentation is set to best select the specific immunoreactive signals (red) while ignoring the nonspecific background. Note that right hemi-brain sections immunostained for GR and FK506 binding protein (FKBP) 52 are of one of the young mice, and that for FKBP51 is of one of the impaired aged mice (original magnification, ×100 in a–f)
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2926850&req=5

Fig1: a–c Outlines of the frontal cortex (FC), dorsal hippocampal CA1 (CA), and granule cell layer of the dorsal dentate gyrus (DG), respectively, are digitally drawn (green) with the Image-Pro Plus version 4.5 software (Media Cybernetics, Bethesda, MD, USA) in accordance with the neuroanatomic landmarks (Valverde 1998). Immunoreactive signals (brown) for the glucocorticoid receptor (GR) are shown within each of the three neuroanatomic regions. d–f With the Image-Pro Plus software, the histogram-based RGB color segmentation is set to best select the specific immunoreactive signals (red) while ignoring the nonspecific background. Note that right hemi-brain sections immunostained for GR and FK506 binding protein (FKBP) 52 are of one of the young mice, and that for FKBP51 is of one of the impaired aged mice (original magnification, ×100 in a–f)
Mentions: On each image of the entire parasagittal hemi-brain section, the outline of the area of interest (AOI; i.e., the frontal cortex, dorsal hippocampal CA1, and granule cell layer of the dorsal dentate gyrus) was digitally drawn with the Image-Pro Plus software in accordance with the neuroanatomic landmarks (Valverde 1998; Fig. 1a–c, respectively). The first superficial layer of the frontal cortex was excluded to avoid staining artifacts, as were large vascular spaces and areas of tissue folding. To measure immunoreactive signals within AOI, histogram-based RGB color segmentation was set to best select the specific signal while ignoring the nonspecific background (Fig. 1d–f). For each pair of the three proteins and three neuroanatomic regions studied, the same setting of color segmentation was applied to all the hemi-brains. The values of three Image-Pro Plus measurement statistics including area (=area of object), integrated optical density (=[area] × [average optical density of object]) and per-area (=[area]/[AOI]) were recorded for each AOI and exported to a Microsoft Excel spreadsheet. The value of AOI (in micrometer squared) was calculated by dividing the mean of area values by the mean of per-area values. The value of immunoreactivity normalized to the AOI (IRn) calculated by dividing the sum of integrated optical density values by the AOI value was used for subsequent statistical analysis.Fig. 1

Bottom Line: Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age.In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (r (s) = 0.68, p = 0.002, Spearman rank correlation).These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.

View Article: PubMed Central - PubMed

Affiliation: Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, La Jolla, CA 92093-0603, USA. vsoontor@ucsd.edu

ABSTRACT
Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age. We hypothesized that alterations in GR signaling pathway molecules, FK506 binding protein (FKBP) 51 and FKBP52, were associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice, and employed quantitative immunohistochemistry to assess cellular expression of those three proteins in the frontal cortex, hippocampal CA1, and dentate gyrus. Values of the discrimination ratio (DR, a measure of novelty preference) in aged mice were significantly lower than those in young mice (mean 0.54 vs. 0.67, p = 0.003, t test). Aged mice with DR below 0.54 were considered impaired (n = 9). In the three neuroanatomic regions studied, the immunoreactivity normalized to the area measured (IRn) for GR was significantly increased in aged mice regardless of their task performance compared to young mice (p < 0.005), as was the FKBP52 IRn (p < 0.007, U test). In the frontal cortex and CA1, the FKBP51 IRn was significantly lower in impaired aged mice than in unimpaired aged mice (p < 0.01 and <0.05, respectively) and in young mice (p < 0.05 and <0.01, respectively, Dunn's post hoc test). In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (r (s) = 0.68, p = 0.002, Spearman rank correlation). These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.

Show MeSH
Related in: MedlinePlus