Impact of Prenatal Stress on BRAIN AGEing

Healthy brain ageing is a major determinant of quality life-long health, allowing integration into society at all ages. Human epidemiological and animal studies indicate that in addition to life style and genetic factors, environmental influences in prenatal life have a major impact on brain ageing and age-associated brain disorders. We hypothesize that:
(1) Prenatal stress programs early brain ageing;
(2) This predisposes to age-associated brain diseases including cognitive decline and stroke;
(3) epigenetic changes affecting glucocorticoid receptor (GR) sensitivity, altered autonomic nervous system (ANS) reactivity and cerebrovascular tone are important mediators of these processes;
(4) these changes represent targets for diagnosis and therapeutic interventions.
Our consortium has unique access to well-defined human and non-human primate cohorts (age range 25-115 y equivalents) that have been exposed to different types of prenatal stress. For experimental analysis of mechanisms of prenatal programming, we apply innovative techniques to characterize brain ageing, namely MRI based volumetry, non-linear analysis of EEG and ANS, advanced molecular techniques including epigenetics and metabolomics and neuropsychological and behavioural tests.
Human subjects, non-human primates and rodents (including transgenic models) exposed to maternal stress, glucocorticoids or undernutrition are examined in order to:
(1) Determine structural (MRI based volumetry) and functional (metabolomics, brain function, cerebrovascular tone) indicators of brain age;
(2) Relate them to susceptibility to stroke and cognitive decline;
(3) Determine to what extent GR resistance, stress sensitivity, and cerebrovascular contractility mediate premature brain ageing and disease susceptibility;
(4) Dissect mechanisms and pharmacological interventions relevant for aged subjects. Data from the study allow to identify subjects at risk for premature brain ageing and to initiate interventional therapy.