Cerebral Hemispheres 2


Know your brain: HPA axis

Where is the HPA axis?

HPA axis activation, proceeding from the hypothalamus to the pituitary gland to the adrenal glands. Image courtesy of Brian M Sweis.

The hypothalamic-pituitary-adrenal axis, or HPA axis as it is commonly called, describes the interaction between the hypothalamus, pituitary gland, and adrenal glands. The hypothalamus and pituitary gland are located just above the brainstem, while the adrenal glands are found on top of the kidneys.

What is the HPA axis and what does it do?

The main function generally attributed to the HPA axis involves the body's reaction to stress. When something stressful happens to us, our initial response is mediated by the sympathetic nervous system. This response occurs almost immediately, and results in the secretion of epinephrine and norepinephrine, both of which work to enact changes that you would generally expect if you felt stressed and/or frightened, like increased heart rate and perspiration.

About 10 seconds later, the HPA axis is stimulated. The hypothalamus responds to signals like elevated norepinephrine levels by secreting corticotropin-releasing hormone into the bloodstream. Corticotropin-releasing hormone (also known as corticotropin releasing factor or CRH or CRF for short) itself increases the activity of the sympathetic nervous system, perpetuating effects like elevated heart rate. CRH, however, also tells the pituitary gland to secrete a substance called adrenocorticotropic hormone (ACTH) (for more on how the hypothalamus and pituitary gland communicate, see this article). The pituitary gland releases ACTH into the bloodstream, and the hormone travels down to the adrenal cortex, which is a term for the outer layer of the adrenal glands. ACTH binds to receptors on the surface of the adrenal cortices, leading to a series of intracellular events that result in the adrenal glands secreting glucocorticoids like the hormone cortisol.

Watch this 2-Minute Neuroscience video to learn more about the HPA axis.

Cortisol has a number of effects on the body that are thought to be carried out in order to help the body deal with a stressor that lasts longer than a few minutes. For example, it increases blood pressure and cardiac output, providing more blood to your skeletal muscles in case the stressor you're dealing with involves some sort of physical exertion (like running for your life). It acts to increase circulating levels of glucose in your blood as well. As glucose is a crucial energy source for your cells, this also provides your body with extra energy to deal with the stressor.

Additionally, cortisol acts during the experience of a serious stressor to inhibit processes that are deemed to be of lesser importance at the time. For example, reproductive activity is decreased. From the body's perspective, activities that don't allow you to deal with the stressor at hand should be ignored until the acute stress has ended. Thus, sex should be considered more of a leisure activity and not something you become preoccupied with when, for example, you are running from an axe-wielding murderer.

While proper functioning of the HPA axis is essential for dealing with stress, when the HPA axis is stimulated too much (for example in someone who faces extreme stress on a daily basis), it can lead to physical and psychiatric problems. Individuals with elevated cortisol levels may experience a suppressed immune system response, making them more susceptible to infection. Repeated HPA axis activation has been linked to type 2 diabetes, obesity, and cardiovascular disease. Cortisol has also been demonstrated to have detrimental effects on memory and cognition, and high cortisol levels are implicated in mood disorders like depression. Additionally, baseline activity of the HPA axis can be affected by early life experiences, and some studies suggest that early-life trauma may lead to an over-reactive HPA axis later in life. This may contribute to increased anxiety and potential metabolic effects, including excess fat deposition and insulin resistance.

Thus, proper functioning of the HPA axis is crucial in helping us to deal with stressors, but repeated stress has the potential to disrupt the beneficial physiological role of the HPA axis. Because of its integral role in a healthy response to stress, and the disease that can result when that response is disrupted, the HPA axis is an important area to understand and represents a potential target for therapeutic drugs.

Reference (in addition to linked text above):

Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009 Jul;5(7):374-81. doi: 10.1038/nrendo.2009.106. Epub 2009 Jun 2. PMID: 19488073.


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