During the perinatal period, the human maternal brain undergoes extensive structural and functional changes (Dufford et al., 2019; Hoekzema et al., 2017; Hoekzema et al., 2022; Kim, 2016; Kim et al., 2010; Paternina-Die et al., 2024; Pritschet et al., 2024). These changes are theorized in part to support behavioral and physiological processes associated with caregiving toward the infant (Brunton and Russell, 2008; Spalek et al., 2024). In particular, changes in hypothalamic volume are observed across studies and may correlate with maternal-infant bonding in humans (Kim et al., 2010; Spalek et al., 2024). Stress during this perinatal period disrupts these brain adaptations (Kim, 2021), with consequences for caregiving as well as mood and emotional regulation in the caregiver, including susceptibility to postpartum mental disorders such as depression and anxiety (Barba-Muller et al., 2019; Pawluski et al., 2017; Raver and Leadbeater, 1999; Simpson and Catling, 2016; Singer et al., 1999).

Adaptations in brain structure and function can also be observed in animal models during the transition to parenting (Lonstein et al., 2015; Numan and Insel, 2003). Recently, studies in laboratory mice have revealed structural, cellular, and molecular mechanisms involved in the functional plasticity in the female mouse brain that promote infant care during the postpartum period (Ammari et al., 2023; Barriere et al., 2021; Celik et al., 2022; Chaker et al., 2023). Furthermore, the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes in mice and humans are anatomically and physiologically comparable (Kaprara and Huhtaniemi, 2018; Keller et al., 2019; Kohl et al., 2017; Packard et al., 2016; Plant, 2015; Russell and Lightman, 2019; Sheng et al., 2020). With respect to the impact of chronic stress, mice show behavioral, neurophysiological, and endocrine responses that are analogous to those in humans, including peripartum stress-induced changes in neural circuitry and infant-directed behaviors (Baram et al., 2012; Hillerer et al., 2012; Klampfl and Bosch, 2019; Slattery and Hillerer, 2016; Zoubovsky et al., 2020). However, relatively few studies have examined the effects of peripartum stressors on maternal caregiving behavior in mice in a systematic manner (Orso et al., 2019; Zoubovsky et al., 2020). Among studies that report infant-directed behavior, the evidence is conflicting on the impact of chronic stress on caregiving measures such as contact with pups, pup retrieval latency, and nest-building (Orso et al., 2019). This variability in outcomes could be attributed to the timing and severity of the stress, the variability in methods for measuring maternal caregiving, differences in susceptibility to stress among mouse strains and/or individual mice, or other factors. In our lab, we have previously observed that caregiving in C57/BL6J mouse dams is unaffected by chronic restraint stress, chronic social stress, and chronic variable stress in the postpartum period (Abdelmesih et al., 2023). This lack of effect may be attributed to HPA axis hyporesponsivity during the perinatal period (Douglas et al., 2003). We wondered if applying stress starting during pregnancy may reveal impacts of chronic stress on maternal caregiving.

In the present study, we observed the effects of two models of perinatal stress on mouse dam caregiving behavior. We used chronic variable stress (CVS) from gestational day 11 (GD11) to post-partum day 4 (PP4) as an unpredictable, ethologically relevant stress. Additionally, we used chronic corticosterone administration (C-CORT, 20 mg/kg s.c.) for the same peripartum period (GD11-PP4) in a separate cohort to upregulate stress hormones in a controlled manner. We found distinct impacts of these stressors on exploratory behavior, but appetitive maternal behavior was resistant to both. Perinatal C-CORT, but not CVS, led to reduced average pup weight at birth, which normalized by PP2. Dams with CVS did not show differences in circulating corticosterone levels, while C-CORT-treated dams showed reduced circulating corticosterone levels compared to control dams. Both stressors reduced activity in PVHCRF neurons, while only C-CORT treatment significantly increased PeFAucn3 neuron activity after pup interaction. Overall, these results demonstrate that perinatal CVS and perinatal C-CORT affect maternal mood-related behavior, while appetitive maternal behavior is resistant to these stressors.