Neuroendocrine and (epi)genetic impact on HPA function
E. de Kloet
The HPA axis facilitates adaptation to stress and is essential for metabolism and health, but dysregulation of the HPA axis compromises resilience and promotes vulnerability to stress-related diseases. This includes diseases of the brain where an aberrant stress hormone action targeting susceptibility pathways causes emotional and cognitive disturbances, and affects the onset and progression of neurodegenerative processes, while impairing recovery and neurogenesis. This action exerted by the hormone involves genes, but also epigenetic modulations triggered by early life experience may permanently alter behaviour and HPA axis activity. The focus is on the action of the HPA axis endproduct cortisol and its dual high- and low affinity receptor systems: mineralocorticoid (MR) and glucocorticoid receptors (GR). Both receptor types are co-expressed in abundance in limbic brain regions and serve together as a master switch in the control of neural network responses that underly activation and suppression of HPA axis activity. Imbalance in MR:GR driven pathways caused either by genetic receptor variants or by experience-related factors compromises processing of stressful information and dysregulates the HPA axis. Therapies are therefore envisioned to rebalance the HPA axis for protection or repair from damaging signaling pathways. Here I will discuss indepth our recent data on i) functional implications of genetic receptor variants as presented recently by MD Klok and RH de Rijk (Translational Psychiatry (2011) 1, e62), and ii) the work of NP Daskalakis (Thesis Leiden University, 2011) regarding the role of genetic predisposition in the programming effects of adverse early life/adolescent experiences on the HPA axis.
Declaration of interest: The author declares that there is a conflict of interest.
Funding: This work was supported, however funding details are unavailable.