Premature birth, maternal care and anxiety risk: insights from a cross-fostering mice model

• In Event: New insights into the role of environmental factors in the development of individuals born preterm

Abstract

Premature birth confers high risk for neurodevelopmental impairments and psychiatric conditions, including anxiety disorders (Fitzallen et al., 2021). These risks can be moderated by parental caregiving, which can enhance or reduce infants’ initial risk conditions (Gueron-Sela et al., 2015). However, human studies exploring the impact of prematurity are correlational, limiting the ability to infer causal conclusions and explore biological mechanisms. To address this void in the literature, we applied a mouse model in which we manipulated preterm birth and maternal care. We examined whether preterm birth is associated with increased risk for behavioral and biological manifestations of anxiety and whether this risk can be reduced by nurturing maternal behaviors.

Pregnant mice (ICR strain) at day 17 of gestation (full gestation is typically 19.5-20 days) were injected with either 150 μg of the anti-progesterone RU486, which caused preterm parturition at day 18, or with a placebo (saline) injection which was followed by normal term parturition. Preterm-born (PTB) and term-born (TB) mice were then cross-fostered and raised by either BALB/c dams (inbred mouse strain whose females typically show low-quality maternal care; PTB: n=16, TB: n=15) or C57BL/6 dams (inbred mouse strain whose females typically show high-quality maternal care; PTB: n=17, TB: n=12).
During the infancy period (postnatal day 1-12), we observed maternal caregiving behaviors (i.e., pup retrieval, natural observations). During the childhood period (postnatal day 28-34), we assessed offsprings’ anxiety-like behavior using the Open Field and Light-Dark tests. Finally, we collected offsprings’ amygdala tissues, and using rt-PCR we measured several biological indicators that have been linked to anxiety behaviors in mice models (i.e., BDNF, TrkB.FL, TrkB.T1 and CRH expression levels).

In line with previous cross-fostering studies (Priebe et al., 2005), BALB/c dams demonstrated poorer maternal behavior compared to C57BL/6. There were no significant main effects for birth type. However, there were significant interactions between birth type and maternal care in predicting behavioral and biological outcomes. Specifically, PTB mice raised by high-caregiving dams (C57BL/6) demonstrated significantly less anxiety-like behaviors in comparison to PTB mice raised by low-caregiving dams BALB/c, and did not differ from TB mice (Figure 1). Biological examination of the amygdala showed that among mice raised by low-caregiving dams, PTB had higher expression of TrkB.FL compared to TB mice, indicating increased amygdala activity. An opposite pattern of results was revealed among mice raised by high-caregiving dams: PTB had lower BDNF expression and lower CRH expression in comparison to TB mice, suggesting lower amygdala activity (Figure 2).

Results provide initial support for the notion that high-quality caregiving can attenuate the developmental risk associated with preterm birth. In the context of a poor caregiving environment, prematurity increased anxiety-like behaviors and anxiety-related biological indices in the amygdala, whereas in the context of a high-quality caregiving environment PTB mice were no different than their TB counterparts. Findings will be discussed from the perspective of the differential susceptibility hypothesis to inform interventions for infants born at high neonatal risk.

Authors

• Motty Franko
  Presenting Author

• Ravid Doron

• Noa Gueron-Sela, Ben Gurion University of the Negev