Early Life Stress Delays Sexual Maturation in Female Mice

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

Fragile X mental retardation protein regulates olfactory sensitivity but not odorant discrimination

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and is characterized by cognitive impairments and altered sensory function. It is caused by absence of fragile X mental retardation protein (FMRP), an RNA-binding protein essential for normal synaptic plasticity and function. Animal models have provided important insights into mechanisms through which loss of FMRP impacts cognitive and sensory development and function. While FMRP is highly enriched in the developing and adult olfactory bulb (OB), its role in olfactory sensory function remains poorly understood. Here, we used a mouse model of FXS, the fmr1 (-/y) mouse, to test whether loss of FMRP impacts olfactory discrimination, habituation, or sensitivity using a spontaneous olfactory cross-habituation task at a range of odorant concentrations. We demonstrated that fmr1 (-/y) mice have a significant decrease in olfactory sensitivity compared with wild type controls. When we controlled for differences in sensitivity, we found no effect of loss of FMRP on the ability to habituate to or spontaneously discriminate between odorants. These data indicate that loss of FMRP significantly alters olfactory sensitivity, but not other facets of basal olfactory function. These findings have important implications for future studies aimed at understanding the role of FMRP on sensory functioning

Early life stress leads to developmental and sex selective effects on performance in a novel object placement task

Disruptions in early life care, including neglect, extreme poverty, and trauma, influence neural development and increase the risk for and severity of pathology. Significant sex disparities have been identified for affective pathology, with females having an increased risk of developing anxiety and depressive disorder. However, the effects of early life stress (ELS) on cognitive development have not been as well characterized, especially in reference to sex specific impacts of ELS on cognitive abilities over development. In mice, fragmented maternal care resulting from maternal bedding restriction, was used to induce ELS. The development of spatial abilities were tracked using a novel object placement (NOP) task at several different ages across early development (P21, P28, P38, P50, and P75). Male mice exposed to ELS showed significant impairments in the NOP task compared with control reared mice at all ages tested. In female mice, ELS led to impaired NOP performance immediately following weaning (P21) and during peri-adolescence (P38), but these effects did not persist into early adulthood. Prior work has implicated impaired hippocampus neurogenesis as a possible mediator of negative outcomes in ELS males. In the hippocampus of behaviorally naïve animals there was a significant decrease in expression of Ki-67 (proliferative marker) and doublecortin (DCX-immature cell marker) as mice aged, and a more rapid developmental decline in these markers in ELS reared mice. However, the effect of ELS dissipated by P28 and no main effect of sex were observed. Together these results indicate that ELS impacts the development of spatial abilities in both male and female mice and that these effects are more profound and lasting in males