Animal Models

Gene x environment interactions determine individual resilience and vulnerability to disease. For example, we showed in collaboration with the University of Amsterdam, that the extent of maternal care received by rat pups during infancy may prepare them for their future living environment. Using morphometric analysis, electrophysiology and behavioral testing, we found that adult rats, exposed as pups to high levels of maternal care, display attenuated stress responsiveness and features of enhanced synaptic plasticity underlying learning compared to their less groomed littermates. Remarkably, offspring of the other less intensely grooming mothers faired well under stressful conditions and outperformed their ‘wellgroomed’ peers. Nature Neuroscience Reviews: ‘moderate levels of deprivation and stress during development might prepare individuals for a tough life’. The article received Faculty of 1000 rating: ‘This work is important... It will be of interest, and potentially not too difficult, to examine whether retrospective studies in humans support these findings.’
However, the consequences of these interactions are very poorly understood. We are gaining novel insights by the use of automated tracking and analysis of animal movement and activity allows a much more comprehensive analysis of the behavior of the animals from our models. In addition, we are imaging brain activity in small rodents, closing the gap between human brain imaging and post-mortem mapping of brain activity in rodents by evaluating the expression of immediate early genes (collaboration Radiology, LUMC).
In one ongoing project it was found that the degree of adversity during an early life experience aggravated an enhanced startle reaction and an impaired pre-pulse inhibition, two responses that can be linked to activation of fear-related pathways. These studies are now performed in animals that have been selectively bred for high and low susceptibility to psychostimulants, in order to specify the role of gene X environment interaction underlying susceptibility to features of schizophrenia (TI Pharma). Another ongoing project (EU lifespan (lifespannetwork.nl) is aimed to understand the underlying mechanism of the action of early postnatal dexamethasone administration. This treatment saves the life of prematurely born children, but the downside is that the child suffers from impaired psychomotor development. In an animal model, postnatal dexamethasone administration leads to a 25% reduction in lifespan. In this project we found protective effects of a central administration of a GR antagonist.

Our models now include the zebrafish stress system, which in some aspects is more similar to the human than that of rodents (Schaaf et al, Endocrinology, 2008).

30/07/2009