Poly (I:C)-induced maternal immune activation modifies ventral hippocampal regulation of stress reactivity: prevention by environmental enrichment

Abstract

Environmental enrichment (EE) has been successfully implemented in human rehabilitation settings, including demonstrated benefits for children with autism. However, the mechanisms underlying its success are not understood. Incorporating components of EE protocols into our animal models allows for the exploration of these mechanisms and their role in mitigation. Using a mouse model of maternal immune activation (MIA), the present study explored disruptions in social behavior and associated hypothalamic pituitary adrenal (HPA) axis functioning, and whether a supportive environment could prevent these effects. We show that prenatal immune activation of toll-like receptor 3, by the viral mimetic polyinosinic-polycytidylic acid (poly(I:C)), led to disrupted maternal care in that dams built nests of poorer quality, an effect corrected by EE housing. Standard housed male and female MIA mice engaged in higher rates of repetitive rearing and had lower levels of social interaction, alongside sex-specific expression of several ventral hippocampal neural stress markers (e.g., corticotropin releasing hormone (Crh) and Crh receptor 1, glucocorticoid receptor, oxytocin receptor, protein kinase C and Camk2a mRNA). Moreover, MIA males had delayed recovery of plasma corticosterone in response to a novel social encounter. Enrichment housing, likely mediated by improved maternal care, protected against these MIA-induced effects. We also evaluated c-Fos immunoreactivity associated with the novel social experience and found MIA to decrease neural activation in the dentate gyrus. Activation in the hypothalamus, including the suprammamillary nucleus (an important region for social novelty) was blunted in EE housed animals, suggesting that the putative circuits modulating social behaviors may be different between standard and complex housing environments. Gestational poly (I:C) and EE also altered gene expression of stress and synaptic plasticity markers in the prefrontal cortex and hypothalamus. These data demonstrate that augmentation of the environment supports parental care and offspring safety/security, which can offset effects of early health adversity by buffering HPA dysregulation.Highlights- Environmental enrichment (EE) protocols are used clinically to promote rehabilitation- Use of EE in animal models may identify mechanisms underlying clinical successes- Maternal immune activation (MIA) decreased social engagement; this effect was blocked by EE- MIA reduced c-Fos activation in the dentate gyrus, while EE reduced activation in the hypothalamus, in response to social stimuli- EE inhibited MIA-induced HPA dysregulation in ventral hippocampus