Because septal damage mimics the effects of both dorsal and ventral hippocampal lesions, we selected ventral and dorsal hippocampal-dependent tasks to investigate behavioral changes. Performances on all of these tasks are altered after hippocampal damage. Burrowing changes started at 8 dpi and recovered to control levels at 13 dpi. Open-field tests presented significant differences between IEPy and IE control mice at 20 dpi and remained altered after 40 dpi. In contrast, animals housed under EE conditions had no significant differences in these tests. Assuming that the open field detected possible anxiety-like behavior associated with ventral Reversine Aurora Kinase inhibitor hippocampus damage, that burrowing activity detects selective damage of the dorsal hippocampus, and that there was no apparent virus immunolabeling in the dorsal hippocampus, burrowing changes may be associated with septal damage. In the murine model of VSV encephalitis, reactive astrocytosis and microglial activation occur relatively early in the disease. As the disease progresses, these non-neuronal cells proliferate with an increasing effect on the extracellular matrix. In the present report, microgliosis and a reduction in type I PNs in CA3 of IE mice were significantly correlated at 8 and 20 dpi, suggesting that the inflammatory response may be related to extracellular matrix damage. As soon as KRX-0401 microglia activation was reduced during the disease recovery process, type I PNs started to recover up to control levels. Because the integrity of the extracellular matrix is important for long-term potentiation in the hippocampus, it may be possible that the observed type I perineuronal losses correlated, at least in part, with the transient behavioral changes observed with Piry virus encephalitis. We report for the first time that an EE induces less intense behavioral changes, a lesser degree of microgliosis, a smaller reduction in the number of PNs, a higher degree of T cell infiltration, and faster virus clearance and disease resolution when compared to animals exposed to impoverished housing. We also demonstrated that nasal instillation of Piry-infected brain homogenate into adult albino Swiss mice induces encephalitis with neuroinvasion, mainly of the olfactory pathways, septum, amygdala, and ventral hippocampus; and that the infection leads to an increase in CA3 microglial number and reduction of the PNs at 8 dpi when behavioral changes first appear, without changes in the number of neurons. The mechanisms of neuronal protection that are activated during the faster clearance of the viruses from the brains of EE animals remain to be investigated.