Abstract
An enriched environment has previously been described as enhancing natural killer cell activity of recognizing and killing virally infected cells. However, the effects of environmental enrichment on behavioral changes in relation to virus clearance and the neuropathology of encephalitis have not been studied in detail. We tested the hypothesis that environmental enrichment leads to less CNS neuroinvasion and/or more rapid viral clearance in association with T cells without neuronal damage. Stereology-based estimates of activated microglia perineuronal nets and neurons in CA3 were correlated with behavioral changes in the Piry rhabdovirus model of encephalitis in the albino Swiss mouse. Two-month-old female mice maintained in impoverished (IE) or enriched environments (EE) for 3 months were behaviorally tested. After the tests, an equal volume of Piry virus (IEPy, EEPy)-infected or normal brain homogenates were nasally instilled. Eight days post-instillation (dpi), when behavioral changes became apparent, brains were fixed and processed to detect viral antigens, activated microglia, perineuronal nets, and T lymphocytes by immuno- or histochemical reactions. At 20 or 40 dpi, the remaining animals were behaviorally tested and processed for the same markers. In IEPy mice, burrowing activity decreased and recovered earlier (8–10 dpi) than open field (20–40 dpi) but remained unaltered in the EEPy group. EEPy mice presented higher T-cell infiltration, less CNS cell infection by the virus and/or faster virus clearance, less microgliosis, and less damage to the extracellular matrix than IEPy. In both EEPy and IEPy animals, CA3 neuronal number remained unaltered. The results suggest that an enriched environment promotes a more effective immune response to clear CNS virus and not at the cost of CNS damage.
Highlights
Sublethal encephalitis following viral infections is known to affect behavior and the immune response, and viral diseases of the central nervous system (CNS) represent a significant proportion of neurological disabilities, in poor countries [1]
Because our previous work had revealed that Piry virus neuroinvasion targets a variety of brain areas including hippocampal CA3 fields inducing apoptosis and picknosis [19] in that region, we decided to estimate the number of activated microglia, perineuronal nets and neurons of CA3
Conditions, we induced viral encephalitis by intranasal inoculation of Piry virus–infected brain homogenate and correlated neuropathological features quantified using a stereologically based unbiased method with behavioral changes, comparing the outcomes with those of animals inoculated with uninfected brain homogenate
Summary
Sublethal encephalitis following viral infections is known to affect behavior and the immune response, and viral diseases of the central nervous system (CNS) represent a significant proportion of neurological disabilities, in poor countries [1]. Emerging virus infections of the CNS are mainly associated with RNA viruses and many that cause neurologic disease [2]. The rhabdoviruses are part of the broad group of negative-strand RNA viruses, a group that includes a number of medically relevant viruses such as avian influenza, measles, Ebola, and vesicular stomatitis virus (VSV) [3]. An enriched environment (EE) was previously described as enhancing natural killer (NK) cell activity, including their recognition and killing of virally infected cells [6]. Rats reared under EE conditions present immune cell recruitment with a higher number of activated microglia than control rats, and these ramified microglial cells resemble the neuroprotective phenotype of microglia activated by T-cell–derived cytokines [8]
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