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Abstract
Animal models can help elucidate the mechanisms through which early-life stress (ELS) has pathophysiological effects on the developing brain. One model that has been developed for rodents consists of limiting the amount of bedding and nesting material during the first postnatal weeks of pup life. This ELS environment has been shown to induce “abusive” behaviors by rat dams towards pups, while mouse dams have been hypothesized to display “fragmented care”. Here, as part of an ongoing study of gene-environment interactions that impact brain development, we analyzed long observation periods of wild-type C57Bl/6J dams caring for wild-type and Met heterozygous pups. Met encodes for the MET receptor tyrosine kinase, which is involved in cortical and hippocampal synaptogenesis. Dams with limited resources from postnatal day (P)2 to P9 preserved regular long on-nest periods, and instead increased the number of discrete dam-pup interactions during regular off-nest periods. Immediately after dams entered the nest during off-nest periods in this ELS environment, pups responded to these qualitatively different interactions with an increased number of ultrasonic vocalizations (USV) and audible vocalizations (AV), communication signals that have been associated with aversive and painful stimuli. After returning to control conditions, nest entry behaviors normalized, and dams did not show altered anxiety-like or contextual fear learning behaviors after pup weaning. Furthermore, female mice that had undergone ELS as pups did not show atypical nest entry behaviors in control conditions in adulthood, suggesting that these specific maternal behaviors are not learned during the ELS period. The results suggest that atypical responses of both mother and pups during exposure to this ELS environment likely contribute to long-term negative outcomes in mice, and that these responses more closely resemble the effects of limited bedding on rat dams and pups than was previously suggested. Discerning how different early-life stressors mediate changes in maternal-pup interactions can help elucidate the mechanisms of ELS on brain development and behavior.
Highlights
Accumulating evidence from both prospective and retrospective clinical studies has demonstrated a significant relation between early adverse experiences, noted as early-life stress (ELS) or toxic stress, and later risk for cognitive, emotional and physical health problems (Shonkoff and Levitt, 2010; Shonkoff, 2012; Moffitt, 2013; McEwen and McEwen, 2015)
Analysis of dam behavior during the 4-h recording sessions confirmed previous reports (Rice et al, 2008) that the ELS environment results in an increase in the number of nest entries by the dam, while the total duration of on-nest time is similar between the control and ELS groups (Figure 1, Table 1 for statistical test details of maternal behavior measurements in the ‘‘Results’’ Section)
At the end of the ELS period on P9, pups in the ELS environment had an increased morning baseline plasma corticosterone concentration compared to control pups. These results show that the ELS environment transiently alters dam nest entry behavior and nest quality, and, as has been reported previously (Rice et al, 2008), the altered environment physiologically affects pups by inducing a stress hormone response
Summary
Accumulating evidence from both prospective and retrospective clinical studies has demonstrated a significant relation between early adverse experiences, noted as early-life stress (ELS) or toxic stress, and later risk for cognitive, emotional and physical health problems (Shonkoff and Levitt, 2010; Shonkoff, 2012; Moffitt, 2013; McEwen and McEwen, 2015). Methods include separating pups from their dam for various periods of time during postnatal periods (maternal separation; Levine, 2005; de Kloet et al, 2005), and the introduction of limited nesting materials and bedding during early postnatal periods (Gilles et al, 1996; Ivy et al, 2008; Rice et al, 2008; Schmidt et al, 2011; Molet et al, 2014) Reports document that both maternal separation and limited bedding generate long-term changes in stress response circuitry and downstream biological and behavioral outcomes (Sanchez et al, 2001; Plotsky et al, 2005; Lippmann et al, 2007; Rice et al, 2008; Wang et al, 2011; Loi et al, 2014; Kohl et al, 2015; van der Kooij et al, 2015). Because the reproducibility of obtained rodent behavior can be impacted significantly by human factors (Sorge et al, 2014), models that reduce contact during periods of ELS may have technical, as well as practical advantages
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