Early Life Stress Delays Sexual Maturation in Female Mice

Abstract

In humans, some forms of early life stress (ELS) have been linked with precocious puberty, altered brain maturation, and increased risk for a variety of forms of pathology. Interestingly, not all forms of ELS have been found to equally impact these metrics of maturation. In recent work, we have found that ELS in the form of limited bedding (LB) from P4 to P11, was associated with precocious hippocampus maturation in males and increased risk for depressive-like pathology and attentional disturbance in female mice. Here, we sought to test whether ELS in the form of LB also impacted the timing of sexual maturation in female mice. To establish rate of somatic and sexual development, distinct cohorts of mice were tested for weight gain, timing of vaginal opening, and development of estrous cycling. ELS animals weighed significantly less than controls at every timepoint measured. Onset of vaginal opening was tracked from P21 to 40, and ELS was found to significantly delay the onset of vaginal opening. To test the impact of ELS on estrous cycle duration and regularity, vaginal cytology was assessed in independent groups of animals using either a continuous sampling (daily from P40 to P57) or random sampling approach (single swab at P35, P50, or P75). ELS did impact measures of estrous cycling, but these effects were dependent upon the sampling method used. We also tested the impact of ELS on anxiety-like behaviors over development and across the estrous cycle. We observed a developmental increase in anxiety-like behavior in control but not ELS mice. No effect of estrous cycle stage was found on anxiety-like behavior for either group of mice. Together these results provide evidence that ELS in the form of LB delays somatic and sexual development. Additional work will be required to determine the mechanism by which ELS impacts these measures, and if these effects are common to other models of ELS in rodents.

Early life adversity decreases pre-adolescent fear expression by accelerating amygdala PV cell development

“…Previous research from our group and others have found effects of LB on depressive-like behavior in females ( Goodwill et al, 2019 ), but failed to find significant differences in anxiety-like behavior in adult mice ( Goodwill et al, 2019 ; Manzano Nieves et al, 2019 ; Manzano-Nieves et al, 2018 ; Naninck et al, 2015 ). Consistent with previous work, we did not find an effect of LB on general measures of anxiety.…”

“…To assess anxiety-like behavior at PND 21 mice were placed in an elevated plus maze as previously described ( Manzano Nieves et al, 2019 ; Manzano-Nieves et al, 2018 ). The EPM consisted of two open (unprotected) and two closed (protected) arms.…”

“…Recently, a rodent model of resource insecurity, limited bedding and nesting (LB), was developed to simulate aspects of resource insecurity and altered parental care in human populations ( Bolton et al, 2019 ; Rice et al, 2008 ). LB has been shown to induce significant distress in the dam, alter patterns of maternal behavior ( Bolton et al, 2019 ; Gallo et al, 2019 ; McLoyd, 1998 ; Rice et al, 2008 ), and delay developmental processes such as sexual maturation and physical growth ( Manzano Nieves et al, 2019 ; Yam et al, 2017 ). In addition, LB impacts behavioral outcomes with effects that persist into adulthood, increasing depressive-like behaviors ( Goodwill et al, 2019 ), altering behavioral response to stress ( Cohen et al, 2013 ; Manzano-Nieves et al, 2018 ), and affecting hippocampal-dependent learning ( Bath et al, 2016 ; Bath et al, 2017 ; Manzano-Nieves et al, 2018 ; Wang et al, 2011 ).…”

Maternal care of heterozygous dopamine receptor D4 knockout mice: Differential susceptibility to early‐life rearing conditions

“…The minimal differences in body weight at puberty onset suggest that, irrespective of early life background and subsequent body weight at weaning, the majority of mice postpone the onset of puberty until a certain body weight is reached. This is in contrast to a recent study where body weight at vaginal opening was increased in female mice that were reared in a LN condition from P2‐9 28 . However, because body weight at weaning of control groups is similar in both studies, this is unlikely to be a result of measurement differences.…”

“…In line with a previous study, 18 we focused on timing of puberty onset, a key moment in development that is malleable by environmental influences as part of an adaptive reproductive strategy 25 . Although adverse rearing conditions in females are linked to accelerated pubertal onset in humans 26 and rats, 27 such effects have not yet been observed in mice 18,28 . In human males, adverse rearing conditions had no effect on puberty onset, 29 while puberty onset in male rodents was either unaffected or delayed 18,27,30 .…”