Effects of early life stress: Opportunities for pharmacological intervention

Abstract

Moderate acute activation of the body’s stress response system is considered an adaptive mechanism that increases the chance of survival, but severe stressors early in life may disturb brain development. In agreement, epidemiological data suggest that adverse experiences early in life, such as parental neglect, abuse, or maternal depression, are associated with vulnerability to develop cognitive and emotional disorders later in life. Numerous studies have shown that early life adverse experiences have a life-long impact on mental health. Due to the importance of adversities to the developing brain, several lines of studies have focused on this and examined the underlying mechanism. A better understanding of the neurobiological mechanisms that result from early life adversities may eventually provide a target for preventing the development of pathologies later in life. The first objective of the studies presented in this thesis was to examine (in rats) the immediate and long lasting effects of early life stress on the neuroendocrine responses and behavior. For this purpose early life adversity was defined as stress that results from manipulation of the mother-pup relationship. We applied a paradigm based on a single episode of 24 hours of maternal deprivation in rat pups on postnatal day (PND) 3. The second objective was to study the differences between males and females. The third objective was to explore opportunities for pharmacological intervention, targeting the glucocorticoid receptor (GR), after the severe experience of maternal deprivation; on this purpose we used the glucocorticoid receptor antagonist Mifepristone. In the experiments reported in this thesis we found that: I) Stress early in life affects neurogenesis in an age and sex-dependent manner; II) Maternal deprivation impairs adult decision making performance in males and alters dorsomedial striatum’s glutamatergic transmission; III) Long term effects of early life stress on hippocampus dependent memory were found in male rats, together with alterations in the glutamatergic transmission; IV)Exposure to stress early in life impairs neuroendocrine processes but has less clear or no effects on adult memory and decision making performance in female rats. Dentate gyrus structure, cell proliferation and neurogenesis were also not affected in females. This finding fits with the existing literature; V) Treatment with mifepristone administered during early adolescence was able to rescue the negative effects of maternal deprivation in male rats; VII) Maternal deprivation has very modest effects on white and grey matter structural properties of the entire adult rat brain. The few changes that we observed were not normalized by mifepristone treatment during adolescence. Although the mechanism underlying the activity of mifepristone still needs further study, with the experiments presented in this thesis we can definitely present this approach as a potential candidate for the treatment of (early life) stress induced disorders. Furthermore the fact that mifepristone treatment administered later in life (and not during the stressful event) was sufficient to ameliorate the behavioral effects of stress in adulthood is another significant finding. The experiments reported in this thesis can therefore be seen as a first step in a new direction and future studies should be directed towards investigating the mechanistic basis underlying the beneficial effects of mifepristone.