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. 2005 Jan 19;25(3):723-31.
doi: 10.1523/JNEUROSCI.4469-04.2005.

Neuroinflammation alters the hippocampal pattern of behaviorally induced Arc expression

Susanna Rosi  1 , Victor Ramirez-Amaya, Almira Vazdarjanova, Paul F Worley, Carol A Barnes, Gary L Wenk
Affiliations

Neuroinflammation alters the hippocampal pattern of behaviorally induced Arc expression

Susanna Rosi et al. J Neurosci. .

Abstract

Neuroinflammation is associated with a variety of neurological and pathological diseases, such as Alzheimer's disease (AD), and is reliably detected by the presence of activated microglia. In early AD, the highest degree of activated microglia is observed in brain regions involved in learning and memory. To investigate whether neuroinflammation alters the pattern of rapid de novo gene expression associated with learning and memory, we studied the expression of the activity-induced immediate early gene Arc in the hippocampus of rats with experimental neuroinflammation. Rats were chronically infused with lipopolysaccharide (LPS) (0.25 mug/h) into the fourth ventricle for 28 d. On day 29, the rats explored twice a novel environment for 5 min, separated by 45 or 90 min. In the dentate gyrus and CA3 regions of LPS-infused rats, Arc and OX-6 (specific for major histocompatibility complex class II antigens) immunolabeling and Arc fluorescence in situ hybridization revealed both activated microglia (OX-6 immunoreactivity) and elevated exploration-induced Arc expression compared with control-infused rats. In contrast, in the CA1 of LPS-infused rats, where there was no OX-6 immunostaining, exploration-induced Arc mRNA and protein remained similar in both LPS- and control-infused rats. LPS-induced neuroinflammation did not affect basal levels of Arc expression. Behaviorally induced Arc expression was altered only within the regions showing activated microglia (OX-6 immunoreactivity), suggesting that neuroinflammation may alter the coupling of neural activity with macromolecular synthesis implicated in learning and plasticity. This activity-related alteration in Arc expression induced by neuroinflammation may contribute to the cognitive deficits found in diseases associated with inflammation, such as AD.

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Figures

Figure 5.
Figure 5.
A-G, Double-immunohistochemical staining for Arc protein (red) and activated microglia (OX-6 positive; blue) within the hippocampus of aCSF rats (A, D, F) and LPS-infused rats (B, C, E, G) that explored a novel environment. Note the dramatic increase in Arc protein-positive neurons above that of aCSF controls only in regions with activated microglia. Nuclei are counterstained in green. Scale bars, 100 μm.
Figure 4.
Figure 4.
A, Examples of Arc mRNA expression (red) after behavioral exploration within the aCSF-infused (left) and LPS-infused (right) rats. Unlike aCSF-infused rats, the granule cells of LPS-infused rats contain numerous bright cytoplasmic Arc-positive neurons. Similarly, in CA3 of LPS-infused rats, there are more neurons with Arc intra nuclear foci compared with aCSF-infused rats. In CA1, both groups show similar Arc expression patterns after behavioral exploration. Nuclei are counterstained in green. B, Percentage increase in Arc-positive neurons above the mean of aCSF-infused rats for the CA3, CA1, and upper blade of the DG. Scale bars, 100 μm.
Figure 1.
Figure 1.
Reconstruction of a 20 μm coronal section from the dorsal hippocampus (at approximately -3.6 mm from bregma) from a young rat with chronic LPS infusion into the fourth ventricle. A, Single immunofluorescence staining revealed activated microglia (red, OX-6-immunoreactive cells) particularly elevated within the granule cell layer and the hilar region of the DG as well as inside and immediately around the CA3 molecular layer. No immunopositive staining was found in CA1. B, Activated microglia showed the characteristic bushy morphology with contracted and ramified processes. Nuclei are counterstained in green. Scale bars: A, 100 μm; B, 2.5 μm. C, Bivariate scattergram quantifying the number of OX-6-immunoreactive cells per square millimeter within each of the three areas of interest: DG, CA3, and CA1 indicated in A by dashed lines. Open circles, aCSF-infused rats; filled circles, LPS-infused rats.
Figure 2.
Figure 2.
Percentage of DG neurons expressing Arc mRNA and Arc protein after spatial exploration of a novel environment in groups of aCSF or LPS chronically infused rats: A, Arc mRNA intranuclear foci; B, cytoplasmic Arc mRNA; C, Arc cytoplasmic protein. Each rat (n = 6/group) was exposed to a novel environment twice for 5 min and kept in its home cage between exposures from either 45 or 90 min. The percentage of neurons expressing Arc mRNA in the nuclear compartment and cytoplasm (A, B) was significantly increased after exploration in the upper but not the lower blade of aCSF-infused rats compared with their caged controls (open bars). LPS-infused rats (filled bars) that underwent the same behavioral treatment also showed an increased percentage of neurons expressing Arc mRNA. This increase, however, was significantly greater compared with the respective aCSF-infused rats in both the upper and lower blades. C, The pattern of Arc protein induction was similar to those of the Arc mRNA in aCSF-infused rats. In contrast, in LPS-infused rats, the 90 min time point showed greater expression than the 45 min time point. *p < 0.0001, significant versus the respective cage control group; †p < 0.0001, significant versus the aCSF group in the same behavioral exposure condition; #p < 0.0001, significant versus the LPS 45 min group.
Figure 3.
Figure 3.
A, B, Percentage of neurons with Arc mRNA intranuclear foci (Arc+ neurons) after spatial exploration of a novel environment in hippocampal CA3 and CA1 of aCSF- or LPS-infused rats. After behavioral exploration of a novel environment, the percentage of Arc+ neurons was significantly higher in both CA3 (A) and CA1 (B) of aCSF-infused rats (open bars) compared with their caged controls. In LPS-infused rats (filled bars), the percentage of Arc+ neurons in both CA3 and CA1 was also higher than that of control rats. In addition, only in CA3 but not in CA1, the exploration-induced increase in Arc+ neurons was significantly higher than that of aCSF rats. C, D, Percentage of neurons with Arc protein across the CA3 and CA1 regions of the same rats. Similar to the results for Arc mRNA, the percentage of neurons that were positive for Arc protein was higher in the aCSF (open bars) exploration groups (both 45 and 90 min) compared with that of the caged controls in CA3 (C) and in CA1 (D). Also similar to the Arc mRNA pattern, in both CA3 and CA1 of LPS-infused rats (filled bars) from the exploration groups, the percentage of neurons positive for Arc protein was significantly higher compared with the LPS caged controls. Again, only in CA3 was this increase above caged controls and also significantly higher than the respective aCSF groups. In both CA3 and CA1 of aCSF and LPS exploration groups, the percentage of neurons positive for Arc protein was highest in the 45 min group. *p < 0.0001, significant versus the respective cage control group; †p < 0.0001, significant versus the aCSF group in the same behavioral exposure condition.
Figure 6.
Figure 6.
Significant correlation between the number of activated microglia and the percentage increase in exploration-induced Arc in LPS-treated rats, above that of aCSF-infused rats, for all three regions.
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