Professor Astrid C E Linthorst

My research group investigates neurochemical and neuroendocrine mechanisms in the brain that support coping with stress. We have a particular interest in the role of GABA and serotonin in the regulation of the neuroendocrine and behavioural responses to stress. We recently characterised the role of synaptic and extrasynaptic GABA transporters in the regulation of extracellular GABA which is of importance for improved understanding of tonic inhibition by GABA in the brain. We also found that stress changes GABAergic neurotransmission in a stressor-dependent manner in the hippocampus, a brain region of critical importance in the stress response.

In another line of research we are studying the distinct regulation of free glucocorticoid hormone levels under baseline and stress conditions. In the blood, glucocorticoids are largely bound to plasma proteins and the concentration of free hormone is very low. However, given that only the free fraction of glucocorticoid hormone is biologically active, it is crucial to study its regulation. We recently discovered that free glucocorticoid hormone responses to stress are 20-30 min delayed compared to the responses of total hormone. The cause of this phenomenon is a rapid, within 5 minutes, release of corticosteroid-binding globulin (CBG) from the liver. This delay will have an important impact on glucocorticoid hormone-mediated responses to stress both in peripheral tissues and in the brain. We are therefore currently investigating the mechanisms underlying the rapid stress-induced release of CBG.

Exercise has been found to improve coping with stress and is regularly used in the treatment of stress-related psychiatric disorders such as depression and anxiety. We are currently investigating the effects of exercise on GABAergic neurotransmission and on the regulation of free glucocorticoid hormone. This research includes studies on extracellular GABA, GABA transporters and synthesising enzymes, and epigenetic changes in promoter regions of selected genes.

Finally, we have recently established a method to measure free cortisol levels in human volunteers by in vivo microdialysis. Our method allows continuous collection of dialysate samples over several days while the volunteer is ambulant. This new approach will allow us to study the levels, circadian rhythms and stress responses of free glucocorticoid hormone in human volunteers and in patient populations.

Our research is currently funded by the Wellcome Trust and the European Union.