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

Brain Behav Immun. 2021 Jul:95:203-215. doi: 10.1016/j.bbi.2021.03.018. Epub 2021 Mar 23.


Environmental enrichment (EE) has been successfully implemented in human rehabilitation settings. 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 poorer quality nests, 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. 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 was blunted in EE housed animals, suggesting that the putative circuits modulating social behaviors may be different between standard and complex housing environments. 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 axis dysregulation. Our findings provide further evidence for the viability of EE interventions in maternal and pediatric settings.

Keywords: Autism; CamkIIa, Protein Kinase; Corticotropin releasing factor; Corticotropin releasing hormone receptor; Fetal programming; Glucocorticoid receptor; Hippocampus; Inflammation; Maternal behavior; Maternal care; Oxytocin; Poly I:C; Prefrontal cortex; Schizophrenia; Sex difference; Social approach; Social vigilance; Suprammamillary nucleus; Synaptic plasticity; Vasopressin; cFos.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Child
  • Female
  • Hippocampus
  • Humans
  • Hypothalamo-Hypophyseal System*
  • Male
  • Pituitary-Adrenal System
  • Poly I-C
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Social Behavior


  • Poly I-C