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    Stress, Resilience and the Brain

    During a stressful encounter, cortisol activates the mineralocorticoid receptor (MR) in limbic brain circuits that governs response selection based on retrieval of previous experiences. In a healthy organism, the situation is correctly appraised and the most appropriate response is selected based on previous experiences. Meanwhile, stress-induced cortisol levels increase and activate the second cortisol receptor type, the glucocorticoid receptor (GR), which promotes memory storage of the stressful experience and the selected coping style in preparation of future encounters. The MR and GR work in complementary fashion to enable the appropriate  response to a stressful environment, to promote adaptation and to facilitate recovery. Both receptors need to operate in the right balance to maintain healthy and for optimal resilience.

     

    Supporting the importance of the MR in health and disease, MR expression in limbic brain structures is decreased during chronic stress and depression, whereas MR activity is increased by antidepressant treatment. Such increased MR expression is associated with suppression of cortisol secretion, promotion of slow wave sleep, together with increased cognitive performance and reduced anxiety.

     

    We discovered three common and functional sets of single-nucleotide polymorphisms (haplotypes) in the human MR gene based on rs5522 and rs2070951. Testing in a laboratory setting in vitro disclosed differences in activity of the three MR-haplotypes. Haplotype 2 was (frequency 35%) found most active, followed by haplotype 1(frequency 50%) , while haplotype 3 (frequency 12 %). was least active. Using these human MR-gene variants we tested several human cohorts and found haplotype 2 to be associated with a more dynamic cortisol response, increased optimism, less rumination, less burn-out and less risk for depression. Importantly, the effect of the haplotype is most prominent in an interaction with early life adversity (trauma), while gender effect were often observed.

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