Using a Murine Model of Psychosocial Stress in Pregnancy as a Translationally Relevant Paradigm for Psychiatric Disorders in Mothers and Infants

Summary

The chronic psychosocial stress (CGS) paradigm employs clinically relevant stressors during pregnancy in mice to model psychiatric disorders of mothers and infants. Here, we provide a step-by-step procedure of applying the CGS paradigm and downstream assessments to validate this model.

Abstract

The peripartum period is considered a sensitive period where adverse maternal exposures can result in long-term negative consequences for both mother and offspring, including the development of neuropsychiatric disorders. Risk factors linked to the emergence of affective dysregulation in the maternal-infant dyad have been extensively studied. Exposure to psychosocial stress during pregnancy has consistently emerged as one of the strongest predictors. Several rodent models have been created to explore this association; however, these models rely on the use of physical stressors or a limited number of psychosocial stressors presented in a repetitive fashion, which do not accurately capture the type, intensity, and frequency of stressors experienced by women. To overcome these limitations, a chronic psychosocial stress (CGS) paradigm was generated that employs various psychosocial insults of different intensity presented in an unpredictable fashion. The manuscript describes this novel CGS paradigm where pregnant female mice, from gestational day 6.5 to 17.5, are exposed to various stressors during the day and overnight. Day stressors, two per day separated by a 2 h break, range from exposure to foreign objects or predator odor to frequent changes in bedding, removal of bedding, and cage tilting. Overnight stressors include continuous light exposure, changing cage mates, or wetting bedding. We have previously shown that exposure to CGS results in the development of maternal neuroendocrine and behavioral abnormalities, including increased stress reactivity, the emergence of fragmented maternal care patterns, anhedonia, and anxiety-related behaviors, core features of women suffering from perinatal mood and anxiety disorders. This CGS model, therefore, becomes a unique tool that can be used to elucidate molecular defects underlying maternal affective dysregulation, as well as trans-placental mechanisms that impact fetal neurodevelopment and result in negative long-term behavioral consequences in the offspring.

Introduction

The mechanisms underlying increased susceptibility to neuropsychiatric disorders in mothers and infants following adverse maternal exposures in the peripartum period remain largely unknown. Substantial maternal physiological alterations occur during pregnancy and the transition to the postpartum period, including several neuroendocrine adaptations that are hypothesized to be critical not only for healthy offspring neurodevelopment but also for preserving maternal mental health^1,2. At the level of the maternal hypothalamic pituitary adrenal (HPA) axis, adaptions in both circadian and stress-induced levels of gl....

Protocol

All animal experiments described were approved by the Animal Care and Use Committee at Cincinnati Children's Medical Center and were in accordance with the National Institutes of Health guidelines. Ad libitum access to standard rodent chow and water was provided at all times to mice, including during the CGS paradigm. Mice were housed on a 14 h/10 h light-dark cycle (lights on 06:00 h) unless otherwise specified (i.e., exposure to lights overnight).

1. Preparing for timed matings

1. At least 2 weeks prior to setting up timed matings, house the adult female mice together in a standard mouse cage (18.4 cm x 29.2 cm x 12.....

Results

Exposing the pregnant female mice to CGS results in changes in chronic stress-relevant parameters, including a reduction in body weight gain during pregnancy (Figure 2A) and increased adrenal gland weights in the early postpartum period (Figure 2B)¹⁹. Importantly, exposure to CGS results in postpartum abnormalities in maternal neuroendocrine function. CGS dams exhibit a hyperactive HPA axis as evidenced by the increased serum corticostero.......

Discussion

Exposing the pregnant mice to CGS perturbs postpartum maternal neuroendocrine function, including HPA axis response to novel stressors, and is associated with various behavioral abnormalities relevant to perinatal mood and anxiety disorders. Given that the model employs utilization of an environmental risk factor, higher phenotypic variation is expected than otherwise observed in genetic models²². Nevertheless, results obtained from application of the CGS paradigm can be consistent across research.......

Materials

Name	Company	Catalog Number	Comments
Animal lancet	Braintree Scientific Inc.	GR4MM
Blunt end probe	Fine Science Tools	10088-15	Used to check for copulatory plugs
Bottles for SPT	Braintree Scientific Inc.	WTRBTL S-BL	100 mL glass water bottle with stopper and sipper ball point tube, graduted by 1 mL.
Conical tubes (50 mL)	Corning Inc.	352098	Used for restraining mice to measure HPA axis response to acute stress. Make sure conical tube has small opening at the end for ventilation.
Legos	Amazon	-
Marbles	Amazon	-
Mouse Corticosterone ELISA kit	Biovendor	RTC002R
Mouse EZM	TSE Systems	-
Reciprocal laboratory shaker	Labnet international	S2030-RC-B
Serum separator tubes	Becton Dickinson	365967
Static cage- bottom	Alternative Design Manufacturing and Supply Inc.	RC71D-PC
Static cage - filtered ventilated tops	Alternative Design Manufacturing and Supply Inc.	FT71H-PC