Childhood trauma and neglect influence emotional development and increase the risk for and severity of mental illness. Women have a heightened susceptibility to the effects of early life stress (ELS) and are twice as likely as men to develop debilitating, stress-associated disorders later in life, such as major depressive disorder (MDD). Until now, mouse models of depression have been largely unsuccessful at replicating the diverse symptomatology of this disease and the sex bias in vulnerability. From P4 to P11, a limited bedding model that leads to fragmented maternal care, was used to induce ELS. Early adolescent and young adult mice were tested on an array of assays to test for depressive-like behavior. This included our newly developed automated home cage behavioral recognition system, where the home cage behavior of ELS and control mice could be monitored over a continuous 5-10 day span. ELS females, but not males, exhibited depressive-like behaviors on traditional assays. These effects emerged during adolescence and became more severe in adulthood. Using the novel home cage video monitoring method, we identified robust and continuous markers of depressive-like pathology in ELS females that phenocopy many of the behavioral characteristics of depression in humans. ELS effects on home cage behavior were rapidly rescued by ketamine, a fast-acting antidepressant. Together, these findings highlight that limited bedding ELS (1) produces an early emerging, female-specific depressive phenotype that responds to a fast-acting antidepressant and (2) this model has the potential to inform sex-selective risk for the development of stress-induced mental illness.

Early life adversity (ELA) is associated with altered neural development and increased risk for the development of psychopathology across the lifespan. Rodent models of ELA are an important tool for investigating the possible mechanistic underpinnings of pathology development. We used a limited bedding and nesting model (LBN) to induce stress in the dam and alter dam-pup interactions during a sensitive period in early postnatal development. The primary characteristics previously identified in this model include fragmented and unpredictable maternal care and possibly neglect. However, previous studies have not considered the effects of this manipulation over the full circadian cycle and the evolution of changes of maternal behavior throughout the duration of the manipulation. In the current study, we leverage a novel continuous video monitoring setup to unobtrusively observe and subsequently analyze maternal behaviors. Through this more in-depth analysis, we discovered that LBN dams spent more time than control dams on their nest, returned to their nest more frequently than control dams, and showed intact maternal care. Importantly, a subset of LBN dams (~40%) engaged in abusive-like kicking, a behavioral pattern not previously identified in this paradigm. Exposure to ELA and abusive-like kicking were associated with differences in risk-taking behavior in adulthood. The LBN model of ELA may drive a more complex constellation of effects on maternal behavior driving a pattern of increased dam-pup interactions and increased abuse-like kicking behavior, with unique consequences for pup outcomes.

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.