2.1 The operation and control of the HPA axis
The following activity includes an interactive animation that will help you to appreciate the nature of stress and the role played by stress and the hypothalamic–pituitary–adrenal (HPA) axis when we come to consider the aetiology of emotional disorders such as depression and anxiety.
The animation is designed to help you understand the operation of the HPA axis – how it is controlled under normal conditions and how the controls are disrupted under conditions of chronic stress.
Activity 6 The operation and control of the hypothalamic–pituitary–adrenal (HPA) axis
The stress response has evolved to mobilise the body and mind for action when a threat is perceived. The response has two main strands which act in parallel. The first is the sympathetic response, which triggers the release of adrenalin from the medulla of the adrenal gland. The second strand involves the hypothalamic–pituitary–adrenal, or HPA, axis, and triggers the release of cortisol from the cortex of the adrenal gland.
In this activity you will look at the operation and control of the HPA axis in three different conditions – first, under normal relaxed or baseline conditions; second, under normal conditions when there is an episode of stress which is resolved; and third, under conditions of continual or chronic stress when regulation of the HPA axis breaks down.
Overview of the HPA axis flow diagram
The HPA axis consists of two brain structures, the hypothalamus and the pituitary, and an area outside the brain, the adrenal cortex, which is part of the adrenal gland that sits atop each of our kidneys. The HPA axis has important links to other parts of the brain, such as the amygdala, the hippocampus and the prefrontal cortex.
Communication between the different structures is shown by connecting arrows or lines, and by the direction of travel of chemical messengers such as CRF from the amygdala and hypothalamus, ACTH from the pituitary, and cortisol from the adrenal cortex. Cortisol is released into the bloodstream, and its breakdown by enzymes in the blood is shown as a fading-out of the cortisol molecules. Action potentials travel from the hippocampus and prefrontal cortex to the hypothalamus.
Signals are received by receptors, shown as solid semicircles, on the different brain structures. Signals to some receptors are stimulatory, as shown by radiating red lines. The more red lines generated, the stronger the stimulation. Signals to other receptors are inhibitory, as shown by the blue lines. The more blue lines generated, the greater the inhibition. Of particular interest in this animation are the black receptors, which are glucocorticoid receptors. These are the receptors to which cortisol attaches. The grey semicircles represent non-glucocorticoid receptors.
Baseline, acute and chronic stages
This shows the HPA axis in a ‘resting’ or ‘baseline’ state. A small amount of the hormone cortisol, a glucocorticoid, is secreted continually from the adrenal cortex into the bloodstream. Cortisol is broken down by enzymes in the blood, so levels in the blood remain low.
When a stressor is perceived the brain triggers a cascade of events that leads to a surge in the level of cortisol secreted by the adrenal cortex. In this next sequence you will see the events involved in this cascade, and how feedback loops operate to return the activity of the HPA axis and levels of cortisol back to baseline.
When we see, hear or think of something that is frightening, the sensory and higher reasoning centres in the cortex are activated. The cortex then sends a message to the amygdala.
The amygdala releases corticotropin releasing factor, or CRF, which activates the hypothalamus. As a result the hypothalamus also releases CRF which activates the pituitary gland, eliciting release of adrenocorticotropic hormone, or ACTH, into the blood.
ACTH stimulates the adrenal cortex to release cortisol into the bloodstream.
Cortisol travels to the prefrontal cortex, the hippocampus, the hypothalamus, and the pituitary which all carry glucocorticoid receptors.
Cortisol stimulates the prefrontal cortex and hippocampus to send signals to inhibit the activity of the hypothalamus. Cortisol also has a direct inhibitory effect on the activity of the hypothalamus and pituitary.
So indirectly or directly, cortisol inhibits the hypothalamus and the pituitary causing secretion of CRF and ACTH to decline.
As stimulation by ACTH of the adrenal cortex declines, the amount of cortisol secreted also falls. So cortisol levels normally have a lowering, or negative, effect on their own levels – this is a negative feedback system. Cortisol is also broken down in the blood. So after a stressor has disappeared cortisol levels return fairly quickly to baseline levels.
If an external stressor remains, or if an individual continues to feel threatened, the stress response is prolonged. What happens if the HPA axis is stimulated chronically?
If stress is chronic the HPA axis is being constantly triggered to secrete cortisol. Levels of cortisol in the blood climb as the breakdown of cortisol by enzymes in the blood cannot keep pace with the amount released. So if stress becomes chronic, the blood levels of cortisol are elevated.
The constant barrage of cortisol has a toxic effect on glucocorticoid receptors, which decline in number and influence.
This results in reduction of inhibition on the hypothalamus and pituitary, so CRF and ACTH continue to be released, and the adrenal cortex continues to be stimulated to release cortisol.
So when the HPA axis is over-stimulated, high levels of cortisol in the blood drive the levels of cortisol in the blood even higher – this ‘runaway’ effect is called positive feedback.
Re-run of HPA animation stages
HPA axis components: more information
Identify two factors from the list below that would help to bring cortisol levels back to baseline levels after experiencing a stressful event.
(a) The positive feedback loop.
(b) Stimulation by the amygdala.
(c) Enzymes in the blood that break down cortisol.
(d) The negative feedback loop.
(e) The secretion of ACTH.
The correct answers are c and d.
Identify the correct statements about cortisol from the following:
(a) Cortisol is released upon stimulation of the adrenal cortex by ACTH.
(b) Cortisol is released upon stimulation of the adrenal cortex by CRF.
(c) Cortisol attaches to glucocorticoid receptors on the adrenal cortex.
(d) Cortisol has an inhibitory effect on secretion of ACTH by the pituitary.
(e) Cortisol attaches to glucocorticoid receptors.
The correct answers are a, d and e.
Cortisol acts via glucocorticoid receptors to inhibit the activity of the HPA axis, so less cortisol is secreted. Why does cortisol become less effective in inhibiting the HPA axis during chronic stress? Select the best explanation from the list below.
(a) Because the high levels of cortisol present during chronic stress damage the glucocorticoid receptors via which cortisol exerts an inhibitory effect on the HPA axis.
(b) Because there is less cortisol present during chronic stress to exert an inhibitory effect on the HPA axis, including on the hypothalamus and the pituitary.
(c) Because there is more activity in the HPA axis during chronic stress, as the axis is constantly being stimulated by stressors to release CRF, ACTH and cortisol.
The correct answer is a.
Statement (a) provides the best explanation for why cortisol becomes less effective in inhibiting the HPA axis during chronic stress. Statement (b) is incorrect because there is more, not less, cortisol present during chronic stress. Statement (c) is correct in that there is more activity in the HPA axis during chronic stress, but it does not explain why cortisol fails to control the activity of the HPA axis.
Select, from the following, the statement(s) that explain why the high activity of the HPA axis during chronic stress can affect how we feel and act.
(a) The adrenalin secreted makes us more alert and makes our hearts beat faster.
(b) High levels of cortisol secreted during chronic stress can damage neurons in the hippocampus, which can affect conscious memories, including recall of events and facts.
(c) High levels of cortisol secreted during chronic stress can damage neurons in the prefrontal cortex, which can affect our ability to evaluate and plan, and to make judgements.
(d) The amygdala is less active when the HPA axis is more active, so we are less likely to react to stressors.
The correct answers are b and c.