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Neuroinflammation alters the hippocampal pattern of behaviorally induced Arc expression
Susanna Rosi1, Victor Ramirez-Amaya, Almira Vazdarjanova
1Department of Neuroscience and Neurology, Johns Hopkins University, Baltimore, Maryland 21218, USA.
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.
Insights
Neuroinflammation alters gene expression in brain regions critical for learning and memory. This disruption in Arc gene expression, linked to activated microglia, may contribute to cognitive deficits in diseases like Alzheimer's disease.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Neuroinflammation, characterized by activated microglia, is implicated in neurological diseases like Alzheimer's disease (AD).
- Activated microglia are concentrated in learning and memory regions in early AD.
- The activity-induced immediate early gene Arc is crucial for learning and memory plasticity.
Purpose of the Study:
- To investigate if neuroinflammation affects the expression pattern of the Arc gene in response to learning experiences.
- To determine the relationship between activated microglia and altered Arc gene expression in the hippocampus.
Main Methods:
- Experimental neuroinflammation was induced in rats via chronic lipopolysaccharide (LPS) infusion.
- Rats were exposed to a novel environment to elicit exploration-induced gene expression.
- Arc gene and OX-6 (microglia activation marker) expression were analyzed using immunolabeling and in situ hybridization in hippocampal subregions.
Main Results:
- LPS-induced neuroinflammation led to activated microglia (OX-6 positive) and elevated exploration-induced Arc expression in the dentate gyrus and CA3 regions.
- In contrast, the CA1 region, lacking OX-6 staining, showed no alteration in exploration-induced Arc expression.
- Basal Arc expression levels were unaffected by LPS-induced neuroinflammation.
Conclusions:
- Neuroinflammation alters behaviorally induced Arc expression specifically in brain areas with activated microglia.
- This suggests neuroinflammation disrupts the link between neural activity and the macromolecular synthesis required for learning and plasticity.
- Altered Arc expression due to neuroinflammation may underlie cognitive impairments observed in inflammatory neurological diseases such as AD.
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