Rapid corticosteriod actions in the hippocampus and amygdala. The relevance of timing

Following stress exposure, the rodent brain is exposed to a cocktail of hormones, such as the adrenal hormone corticosterone, catecholamines like noradrenaline and neuropeptides. In concert these hormones enable the animal to face the challenge, adapt its behavior and remember the information about the stressful event for future use. Up till now it was generally thought that noradrenaline and peptides are the main actors in the initial phase of the stress response, enhancing alertness, vigilance and attention. Corticosteroids were thought to be important later on, for normalization of brain activity and consolidation of the event, via a genomic pathway. This project shows that corticosteroids can also exert rapid effects that do not involve gene transcription, in various parts of the brain. We demonstrated these rapid effects (among other areas) in the hippocampus, an area important for memory formation. The effects take place via mineralocorticoid receptors that are positioned in or close to the plasma membrane, which is unexpected, because so far these receptors were only observed within the cell, i.e. in the cytoplasm or nucleus. We showed that rapid corticosteroid actions increase the chance that glutamate –the main excitatory transmitter in the brain- is released. At the same time, the receptors that mediate effects of glutamate move to a site where they are more active. What is the relevance of these rapid corticosteroid actions? Our hypothesis was that through these rapid effects, the brain can quickly adapt its function to fluctuations in hormone levels. Such fluctuations happen after stress, but also during the active period of the day, when corticosterone is (spontaneously) released in hourly pulses. We indeed demonstrated that the membrane mineralocorticoid receptors are the means for hippocampal cells to quickly and accurately translate the hourly fluctuations of corticosterone into changes in glutamate transmission. A second hypothesis was that –because corticosterone acts in the same rapid time-domain as noradrenaline- stress hormones affect each other’s function. This is indeed the case, at least in the amygdala, an area important for emotion. Noradrenaline quickly increases the activity of amygdala cells. This is very much amplified when corticosterone is present at the same time. However, surprisingly, if corticosterone reaches amygdala cells some time after noradrenaline, it is no longer able to affect amygdala cell activity. Finally, we examined if chronic stress and adrenalectomy (removal of adrenals/corticosterone from the system) limits the potential of hippocampal cells to respond to corticosterone with rapid non-genomic effects. We observed that in both of these rather extreme conditions, responses to a high dose of corticosterone are largely suppressed. These studies greatly advance our current understanding of how stress affects the brain especially hippocampus and amygdala.