Interactive effects of compounding multidimensional stressors on maternal and male and female rat offspring outcomes

Horm Behav. 2021 Aug:134:105013. doi: 10.1016/j.yhbeh.2021.105013. Epub 2021 Jun 23.


Exposure to adverse childhood experiences (ACEs) is a risk factor for the development of psychiatric disorders in addition to cardiovascular associated diseases. This risk is elevated when the cumulative burden of ACEs is increased. Laboratory animals can be used to model the changes (as well as the underlying mechanisms) that result in response to adverse events. In this study, using male and female Sprague Dawley rats, we examined the impact of increasing stress burden, utilizing both two adverse early life experiences (parental/offspring high fat diet + limited bedding exposure) and three adverse early life experiences (parental/offspring high fat diet + limited bedding exposure + neonatal inflammation), on maternal care quality and offspring behavior. Additionally, we measured hormones and hippocampal gene expression related to stress. We found that the adverse perinatal environment led to a compensatory increase in maternal care. Moreover, these dams had reduced maternal expression of oxytocin receptor, compared to standard housed dams, in response to acute stress on postnatal day (P)22. In offspring, the two-hit and three-hit models resulted in a hyperlocomotor phenotype and increased body weights. Plasma leptin and hippocampal gene expression of corticotropin releasing hormone (Chrh)1 and Crhr2 were elevated (males) while expression of oxytocin was reduced (females) following acute stress. On some measures (e.g., hyperlocomotion, leptin), the magnitude of change was lower in the three-hit compared to the two-hit model. This suggests that multiple early adverse events can have interactive, and often unpredictable, impacts, highlighting the importance of modeling complex interactions amongst stressors during development.

Keywords: Early life stress; Inflammation; Intergenerational; Leptin; Limited bedding; Lipopolysaccharide; Maternal care; Oxytocin; Resilience; Western diet.

Publication types

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

MeSH terms

  • Animals
  • Corticotropin-Releasing Hormone* / genetics
  • Corticotropin-Releasing Hormone* / metabolism
  • Diet, High-Fat
  • Female
  • Hippocampus / metabolism
  • Male
  • Oxytocin
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Rats
  • Rats, Sprague-Dawley


  • Oxytocin
  • Corticotropin-Releasing Hormone