Mechanisms of effects of prenatal stress
There is no precise understanding of how prenatal stress induces cognitive disturbances in later life. Both a changed activity of the stress system and a different trajectory of brain development are likely.
Programming of stress sensitivity
Stress sensitivity depends on the activity of the stress axis with the two limbs, the autonomous nervous system and the hypothalamo-pituitary adrenal axis. The current (somewhat simplified) concept is that stress sensitivity is programmed prenatally in the last third of gestation when the hypothalamo pituitary adrenal axis matures. If, at this time fetal glucocorticoid concentrations are higher than appropriate for the current stage of maturation, glucocorticoid receptor expression and sensitivity in the hippocampus and hypothalamus, both critical for normal negative feedback to "turn off" the stress response, are permanently reduced by epigenetic modification of the glucocorticoid receptor genes. These mechanistic changes result in hypothalamo pituitary adrenal axis hyperdrive in the presence of glucocorticoid receptor resistance in many animal studies. Importantly, prenatal stress does not only alter activity of the hypothalamo-pituitary adrenal axis permanently, but also changes activity of the second limb of the stress axis, the autonomic nervous system.
Apart from this general mechanism, we do not have a detailed understanding of how the stress axis in later life is altered after prenatal stress. For example, following prenatal stress exposure, human and animal studies show that the HPA axis and the ANS are even less active during certain stages of life. Generally, effects of prenatal stress on stress sensitivity during later life seem to depend on poorly determined conditions such as stress sensitive periods during early life, the amount of stress, and the adversity of the stressor.
Effects of increased stress sensitivity
Hypothalamo-pituitary adrenal axis hyperactivity leads to increased stress sensitivity. Increased stress sensitivity contributes to biological ageing through both excessive catecholamine and glucocorticoid secretion and through glucocorticoid receptor resistance. The latter increases the production of pro-inflammatory cytokines, accentuating potential neuronal damage. There are hints that prenatal stress may not only affect brain ageing but also predispose to brain-related diseases. Data from Roseboom's group from the Dutch famine cohort suggest that the cognitive function may deteriorate faster in those subjects who were prenatally exposed to the famine.
Van den Bergh's group is the only group who has tested whether the hypothalamo-pituitary adrenal axis mediates the link between prenatal maternal stress and offspring behavioral problems in humans. It was shown in the 15-year-old offspring that maternal anxiety during weeks 12 to 22 of pregnancy is associated with a high flattened diurnal cortisol profile that shows elevated cortisol secretion in the evening.
Moreover, the interaction of increased stress sensitivity and the serotonergic system may explain the occurrence of depressive disorders since cortisol inhibits this amine system. Indeed, van den Bergh's group has shown an effect of prenatal anxiety on depressed mood that, in part, can be due to a flattened cortisol profile. Depression can impact on the objective age-related cognitive impairment.
Changes in the trajectory of brain development
Maternal stress, glucocorticoid treatment and nutrient restriction during pregnancy may also change the trajectory of fetal brain development. Nathanielsz's and Schwab's groups have shown that prenatal glucocorticoid treatment at the clinical dose used to enhance fetal lung maturation affects neurogenesis and myelination in fetal sheep. Studies in rodents clearly show that nutrient restriction alters brain development and cognitive function in later life. Nathanielsz's and Schwab's groups have shown that even moderate maternal undernutrition affects neurogenesis and development of neuronal network formation in the fetal non-human primate. Similarly, abnormalities in brain structure were found in schizophrenic patients exposed to the Dutch famine winter.