Ending stress: switching off cortisol

Ending stress reactions is needed after a stressful event has been dealt with successfully. Cortisol levels in the blood will come down to the same low levels before the stress had started. Chronic, bad stress and illness will thus be avoided. You can even help to bring cortisol levels down again!

As we have written in earlier articles, the hormone cortisol is the end product of the hypothalamus-pituitary-adrenal axis. It is released into the blood and plays a major role in the generation and redistribution of energy to those organs that become active to combat the stressor (the problem that causes stress). When cortisol levels are too high for a long period of time, cortisol can cause a variety of health problems. In this case, the stress reactions have not been shut off properly. Perhaps because the stress reactions were not effective in dealing with the stressor. Or perhaps the stressors follow each other in quick succession. Normally, however, stress responses are terminated in due time, and this is done by cortisol itself. It acts by a process of negative feedback, signaling back to the hypothalamus and other parts of the brain that the stress reactions should stop.

Fast direct negative feedback by cortisol

Negative feedback by cortisol is fast, and starts already a couple of minutes after the stress has started. This may seem a bit early, as cortisol levels normally peak after 60 minutes following stress onset, and as cortisol levels can remain elevated for a few hours. However, the inhibition of cortisol on its own production serves to prevent an overshoot of cortisol in the blood. Cortisol levels will thus rise, but within reasonable limits. After an hour or so, the negative feedback will overpower the stimulation of new cortisol synthesis, so that cortisol levels drop.

Cortisol binds to its receptor, a sort of antenna that detects cortisol that is present on cells in the hypothalamus where the HPA-axis begins. These cells produce a small protein called CRF, which activates the pituitary gland, the second station of the HPA-axis.

When cortisol binds to its receptor on the CRF cells, something really interesting happens. The CRF cells start to secrete so-called endocannabinoids. These molecules look a lot like psychotropic substances from Cannabis plants (hence the names of molecule and plant). The endocannabinoids signal to the brain that it is time to stop activating the CRF cells. Thus the CRF cells stop their activity. And when CRF cells stop their activity, the pituitary and later also the adrenal glands will also stop, and cortisol will no longer be produced and released into the bloodstream.

The fast feedback mediated by cortisol. A) CRF cells (green) are directly activated by brain cells (brown) that convey stress-related signals. As a result, the CRF cells will release CRF in the pituitary gland, which will in turn stimulate the release of cortisol into the blood by adrenal gland cells. B) Cortisol signals back to the CRF cells by binding to its receptor. This makes the CRF cells secrete endocannabinoids to the cells that convey stress-related signals. The endocannabinoids will inactivate these cells, so that the CRF cells are no longer activated and cortisol is no longer secreted into the blood. The HPA-axis will be turned off.

Slow indirect negative feedback by cortisol

Whereas cortisol and the endocannabinoids signal fast within the hypothalamus to inhibit stress signals to CRF cells, cortisol also inhibits HPA-axis activity in an indirect manner. In this case, cortisol acts in the prefrontal cortex and the hippocampus.

The prefrontal cortex is part of the executive brain, where decisions are being made about what to do. It is also part of the emotional brain, lining up executive functions with emotions. It is involved in the body's stress reactions as it has control over the HPA-axis. The hippocampus is an important site in the brain where memory is stored and is also involved in emotional reactions to threats and stressors (things that cause stress).

Cortisol signals to both the prefrontal cortex and the hippocampus. Both brain regions will then activate an inhibitory system in the brain that stops the activity of the HPA-axis. In the case of the prefrontal cortex, cortisol inhibits HPA-axis activity when the stress is psychogenic (mental), but not when it is physiological (like breathing stress at high altitude for example). For the hippocampus, researchers have not yet made such a distinction between different types of stressors. Nevertheless, it seems that they work in parallel, so that the inhibitory effect of the prefrontal cortex can be summed with that of the hippocampus.

Cortisol inhibits its own production through activation of the prefrontal cortex (green) and the hippocampus (brown). The prefrontal cortex and the hippocampus inhibit the hypothalamus (blue), which is the first station of the HPA-axis. The hypothalamus will no longer be instructed to activate the pituitary gland (orange), so that ACTH and cortisol levels in the blood drop and stress stops. This process is part of the negative feedback system that keeps the brakes on stress responses.

The slow and fast negative feedback by cortisol together are quite effective in putting HPA-axis activity to a halt. So effective that the HPA-axis cannot be activated anymore for several hours. The body will therefore not be able to launch a full-fledged stress response when a new stressor would appear within this time window.

Feedback in chronic stress

When stress becomes chronic, negative feedback by cortisol does not work as efficiently as during acute, short-lasting stress. This is because the receptor for cortisol in the hippocampus and prefrontal cortex is present in lower quantities. Cortisol can therefore no longer transmit the message that its own production should stop. This leads to hyperactivity of the HPA-axis, with resulting high cortisol levels that can damage health.

Feedback following stressful childhood

Animal studies in laboratoria have shown that stress during early life permanently lowers the presence of cortisol receptors in the hippocampus and prefrontal cortex. This prolongs the activity of the HPA-axis, also during adulthood. This likely also applies to humans.

The opposite is true for young animals, and likely children, who grow up in a caring environment. The presence of the cortisol receptor is higher, the negative feedback is stronger, and the activity of the HPA-axis is shortened.

Negative feedback and pathology

There are diseases in which cortisol is either too high or too low, and this is caused by abnormal negative feedback of the HPA-axis. Many patients with depression, for example, have high cortisol levels as a consequence of impaired negative feedback. Patients suffering from posttraumatic stress disorder (PTSD), on the other hand, have strong negative feedback and consequently low cortisol levels. PTSD patients have difficulties in launching an adequate stress response when a stressful event presents itself, and can therefore not always cope with stress in a proper manner.

Understanding cortisol in stress responses

Cortisol has important functions during stress. It redistributes energy to organs that need extra energy so that you can deal with a stressor. This goes at the expense of organs that perform other functions that may be very important in the longer term. To spare these organs, cortisol makes sure that stress responses do not last too long and that cortisol levels go down quickly. Negative feedback is thus important to protect health.

Unfortunately, this wonderful system of negative feedback does not always work. This is the case when you are not able to deal with a stressor successfully. The hippocampus and prefrontal cortex keep pushing the HPA-axis to produce cortisol, overriding the negative feedback signal. Inefficient negative feedback leads to deleterious effects on mood and cognition.

What you can do to make negative feedback more efficient and end stress

To inhibit the activity of the HPA-axis and to reduce stress, it seems necessary to find ways to increase the amount of cortisol receptors in the prefrontal cortex and the hippocampus. Are there things you can do to achieve this yourself?

Fortunately, the answer is yes! A functional magnetic resonance imaging study where scientists can follow brain activity in real time has shown that physical exercise changes the activity of the prefrontal cortex and the hippocampus. As both are important for negative feedback, the researchers proposed that negative feedback is important for the stress-reducing effects of physical exercise.

Subsequent studies in rodents have shown that physical exercise does indeed increase the amount of cortisol receptors in the hippocampus. For the prefrontal cortex, this is not precisely known. However, it should be said that exercise not only changes the amount of cortisol receptors in the brain. Exercise also changes the pituitary gland and the adrenal glands, so that the adrenals become more sensitive to ACTH (the stress hormone from the pituitary) and produce cortisol faster but during a shorter period of time. There are still many other beneficial effects of physical exercise that help to reduce stress. We have written a separate article on the beneficial effects of exercise to highlight this further.

We hope you agree with us that understanding stress, including negative feedback, helps to motivate you to exercise. Now that you know that you can shorten the periods of stress by exercise, it may have become easier for you to reduce your sedentary habits and be physically more active.

References

Hare et al., Exercise-Associated Changes in the Corticosterone Response to Acute Restraint Stress: Evidence for Increased Adrenal Sensitivity and Reduced Corticosterone Response Duration. Neuropsychopharmacology 39, 1262-1269 (2014).

Pan-Vazquez et al., Impact of voluntary exercise and housing conditions on hippocampal glucocorticoid receptor, miR-124 and anxiety. Molecular Brain 8, 40 (2015).

Rostami et al., The downstream effects of forced exercise training and voluntary physical activity in an enriched environment on hippocampal plasticity in preadolescent rats. Brain Research 1759, 147373 (2021)

Zschucke et al., The stress-buffering effect of acute exercise: Evidence for HPA axis negative feedback. Psychoneuroendocrinology 51, 414-425 (2015).