Limbic system activation is affected by prenatal predator exposure and postnatal environmental enrichment and further moderated by dam and sex

Abstract

Epilepsy is a relatively common and chronic neurological condition, affecting 1–2% of the population. However, understanding of the underlying pathophysiology remains incomplete. To identify potential factors in the early environment that may increase the risk for experiencing seizures, maternal stress and environmental enrichment (EE) were utilized. Pregnant Long-Evans rats were exposed to an ethologically relevant predator stress (PS) and maternal glucocorticoid (GC) response was assessed across the exposure period. At birth, litters were divided into standard care (SC) and EE groups until postnatal day 14 (PD14) when a model of febrile convulsions was used to determine seizure susceptibility of the various groups. Pup brains were then processed for immunohistochemical detection of FosB from several structures in the limbic system as a measure of neuronal activation. Maternal PS-induced GC levels were elevated early in the exposure period, and pup birth weights, in both sexes, were lower in litters from dams exposed to PS. Seizure scores at PD14 were highly individualized and litter dependent, suggesting a dam-dependent and variable effect of controlled pre- and postnatal environmental factors. Further, analysis of FosB-immunoreactive (-ir) patterns revealed an activity dependent distribution, reflecting individual seizure susceptibility. EE had a varying effect on FosB-ir that was dependent on region. In the hippocampus FosB-ir levels were greater in the EE groups while extra-hippocampal regions showed lower levels of FosB-ir. Our results support the concept that pre- and postnatal environmental influences affect fetal programming and neurodevelopment of processes that could underlie seizure susceptibility, but that the magnitude of these effects appears to be dam- or litter-dependent.