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. 2013 Apr 1:242:17-24.
doi: 10.1016/j.bbr.2012.12.032. Epub 2012 Dec 27.

Effects of minocycline on spatial learning, hippocampal neurogenesis and microglia in aged and adult mice

Rachel A Kohman  1 , Tushar K Bhattacharya, Chessa Kilby, Paula Bucko, Justin S Rhodes
Affiliations

Effects of minocycline on spatial learning, hippocampal neurogenesis and microglia in aged and adult mice

Rachel A Kohman et al. Behav Brain Res. .

Abstract

Age-related priming of microglia and release of inflammatory cytokines, such as interleukin-1β (IL-1β) and interleuekin-6 (IL-6) have been associated with deficits in cognitive function. The present study assessed whether treatment with minocycline could improve spatial cognition in aged mice, and whether these improvements in behavior were associated with reduced microglia activation and an enhancement in hippocampal neurogenesis. Adult (3 months) and aged (22 months) male BALB/c mice received minocycline in their drinking water or control mice received distilled water for 20 days. Mice received BrdU to label dividing cells on days 8-17. Spatial learning was measured using the water maze. Immunohistochemistry was conducted to measure number of BrdU positive neurons and number and size of microglia by detection of Iba-1 in the dentate gyrus molecular layer. Further, hippocampal samples were collected to measure changes in IL-1β, IL-6, and CD74 expression. The data show that aged mice have increased hippocampal expression of IL-1β, IL-6, and CD74 relative to adults. Minocycline treatment significantly improved acquisition of the water maze in aged mice but not adults. Minocycline reduced the average size of Iba-1 positive cells and total Iba-1 counts, but did not affect hippocampal cytokine gene expression. Minocycline increased neurogenesis in adults but not aged mice. Collectively, the data indicate that treatment with minocycline may recover some aspects of cognitive decline associated with aging, but the effect appears to be unrelated to adult hippocampal neurogenesis.

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Conflict of interest statement

Conflicts of interests: All authors declare that there are no conflicts of interest

Figures

Figure 1
Figure 1
Body weight and consumption. Aged mice weighed more than adult mice (A). Minocycline treatment had no effect on body weight (A). Regardless of treatment, aged mice drank less than adult mice (B). Minocycline-treated adults drank significantly more than adult controls (B). * indicates a significant difference from age-matched control group. + indicates a significant difference from treatment-matched adult mice. Bars represent means ± standard error of the means (SEMs).
Figure 2
Figure 2
Spatial learning. Overall all adults had a shorter path length than aged mice, but aged mice treated with minocycline showed a significantly shorter path to the platform compared to aged controls on day 2 (A). Minocycline treatment had no effect on swim speed in aged mice, but increased swim speed in adult mice on day 1 (B). During the probe trial, adult mice crossed the original location of the platform more often than aged mice, but no effect of minocycline treatment was observed (C). * indicates a significant difference from age-matched control group. + indicates a significant difference from treatment-matched adult mice. Bars represent means ± SEMs.
Figure 3
Figure 3
Hippocampal neurogenesis. Aged mice showed decrease new cell survival as indicated by reduction in the number of BrdU positive cells in the granular layer compared to adults. Minocycline treatment had no effect on the number of BrdU positive cells in adult or aged mice (A). Representative hippocampal sections double labeled with antibodies against NeuN (mature neuron; red) and BrdU (new cell; blue) from adult and aged mice (B). Minocycline treatment increased neuronal differentiation in adult mice, but had no effect in aged mice (C). + indicates a significant difference from treatment-matched adult mice. * indicates a significant difference from age-matched control group. Bars represent mean number of cell ± SEMs.
Figure 4
Figure 4
Iba-1 positive cells. (A) Regardless of age minocycline treatment significantly reduced the average size of Iba-1 positive cells. (B) Sample images of Iba-1 labeled cells in the molecular layer of the dentate gyrus of aged control and minocycline-treated mice. (C) Minocycline treatment significantly reduced the number of Iba-1 positive cells counted in the molecular layer of the hippocampus. + indicates a significant difference from treatment-matched adult mice. * indicates a significant difference from aged-matched control mice. Bars represent means ± SEMs.
Figure 5
Figure 5
Hippocampal gene expression. Regardless of treatment condition aged mice showed higher expression of IL-1β (A), IL-6 (B) and CD74 (C) in the hippocampus compared to adult mice. + indicates a significant difference from treatment-matched adult mice. Bars represent means ± SEMs.
Figure 6
Figure 6
Correlation between the overall average path length across the 5 days of water maze testing and Iba-1 staining. There are significant positive correlations between path length in the water maze and total Iba-1 staining (A) and Iba-1 cell counts (B) in aged mice. Path length did not correlate with Iba-1 staining (C) or Iba-1 cell counts (D) in adult mice. Individual graphs list the Pearson’s correlation coefficient (i.e., r value) and p value.
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