Differential susceptibility to rearing conditions in mice

Abstract

The research presented in this thesis is the result of our efforts to study differential susceptibility in an animal model. By exposing heterozygous MR or Drd4 knock-out mice and control litter mates to negative, neutral or positive rearing conditions, we aimed to create a study design for detecting for better and for worse gene-by-environment interactions while controlling for non-specific environmental and genetic variation. While the effects of the early-life manipulations were mild, they were consistently observed in the expected directions when significant. I therefore conclude that the models are suited for this type of work, although they could be further fine-tuned in terms of duration, timing and severity of early life interventions. In addition, future studies should broaden the scope of genetic manipulations, studying multiple genes and genetic models that optimally mimic the human situation. If successful, researchers can start to utilize other advantages animal models offer that we have not exploited to their full potential; 1) studying the underlying neurobiology of differential susceptibility in greater spatiotemporal detail, 2) studying within-litter variation in the early-life environment and its role in differential susceptibility. The aim of this work was to study the differential susceptibility theory in a controlled setting using a mouse model. Based on the evidence provided in this thesis I conclude that: 1. Manipulations of the early-life rearing environment of mouse pups requires careful alignment of the timing and duration of exposure and the behavioral domain of interest in order to elicit robust effects. 2. In contrast to the acceleration hypothesis, puberty onset in mice is delayed following early-life adversity through a reduction in body weight (chapter 3 and 4) and potentially by increased unpredictability (chapter 3). The latter finding would be interesting to validate in humans, where the effects of early-life adversity on sexual maturation are opposite. 3. Both genetic and early-life environmental factors independently or interactively have the potential to shape offspring development and adult behavior, including maternal behavior of female offspring towards the next generation. 4. Differential susceptibility can be studied using mouse models, but requires further fine-tuning of rearing conditions and genetic tools in order to achieve more robust effects and optimally utilize the added value of rodent models. 5. The newly described maternal retrieval behavior during communal nesting is an intriguing and as of yet unresolved social behavior that deserves further investigation.