Hormones & Brain Function (overview)

Research question
A fundamental question in our work is why some individuals suffer from stress-related brain disorders, while others are protected and maintain excellent mental health under similar (adverse) conditions. It is generally thought that psychosocial stressors in individuals predisposed by genetic background, experience-related factors and cognitive inputs precipitate these brain disorders. However, the genes predisposing for these disorders are not known. We test the hypothesis that genes responsive to stress hormones are the key to resolve the question as to how the action of these hormones can change from beneficial to harmful.


The stress system is organized in two complementary, anti-parallel modes of operation. One mode dealing with an immediate response to stressors driven by corticotropin-releasing hormone (CRH), a neuropeptide that organizes via CRH-1 receptors the sympathetic and hypothalamic pituitary adrenal (HPA) axis responses to stressors. The other - slower - mode facilitates coping with stress and behavioural adaptation and depends on the stresscopin (related peptide) acting through CRH-2 receptors. The two modes of operation also control the secretion of hourly steroid pulses secreted from the adrenals. This ultradian rhythm synchronizes and coordinates daily- and sleep related events.  Homeostasis and health depend on the balance of these two opposing modes of operation regulating basal pulsatility and stress responses, a process also indicated as allostasis.

The HPA axis drives the secretion of glucocorticoid hormones (corticosterone and cortisol) from the adrenals. We have discovered that the glucocorticoids readily enter the brain and bind with high and low affinity to nuclear corticosteroid receptors, which regulate as transcription factors the expression of highly specific patterns of genes. The high affinity or mineralocorticoid receptors (MR) initially control the threshold or sensitivity of the stress response system by facilitating information processing underlying the selection of the most appropriate behavioural coping response. The MR already respond to minute amounts of steroid and are localised in abundance in hippocampus, amygdala and frontal cortex, which are limbic brain structures involved in emotion, cognition, motivation and goal-directed behavior.
The low affinity glucocorticoid receptors (GR) are widely expressed and occupied only by high levels of cortisol attained during stress and the circadian peak. GR facilitate termination of stress-induced responses and help to provide energy resources required for recovery from stress. In the limbic brain GR promote the storage of information for the next encounter and eliminate behaviour that is no longer relevant.
Recently, it was discovered that the nuclear steroid receptors have their membrane-associated counterparts that mediate rapid steroid responses. This discovery made by our Amsterdam colleagues explained our behavioural and neuroendocrine data. Hence it is now understood that besides the maintenance of neural integrity under control of the high affinity MR, a lower affinity variant in the membrane can respond to increasing levels of the hormone in boosting the release of excitatory transmitters and excitability, thus the onset of the stress response.

We postulate that the balance of neuronal systems controlled by activating and suppressive modes of stress system operation – as represented by the MR:GR balance- is essential for cell homeostasis, mental performance and health (de Kloet et al, 2005).

Major results 2002-2008
The past period was marked by innovative gene technology, such as lentiviral gene transfer. Novel animal models for depression and psychosis were developed with the goal to link gene networks with emotional and cognitive processesGene networks were identified that point to novel stress responsive signaling pathways involved in (re)modellingand plasticity of neuronal circuits.Fundamental for this new knowledge is the glucocorticoid stress hormone and its two receptor types: MR and GR. Factors modulating glucocorticoid action and receptors in the brain were identified that potentially can boost resilience in the diseased brain.These findings ledto a better understanding how anti-glucocorticoids can ameliorate therapy-resistant psychotic depression within a few days.
We found that experiences early in life have the potential to shape brain and behavior of the adult and aging organism along the so-called theory of the three-hits: unfavorable genetic load, early adversity and later life experiences. To explain this, the glucocorticoids were found to modulate gene X environment interaction underlying developmental programming with profound consequences for phenotypic plasticity and disease vulnerability in later life.