The Biology of Stress

What is stress?

Stress is our body’s response to a threatening stimulus. The stimulus is usually termed the “stressor.”

Why is it important to understand the biology of stress?

Stress is implicated in many health problems such as depression, anxiety, heart disease, obesity, high blood pressure, and chronic pain to name a few.

A small amount of stress in the right situation can be lifesaving. Our body’s ability to respond appropriately to a stressful situation, or stressor, is adaptive and essential to survival.

Stress becomes a problem when our bodies respond inappropriately in the wrong setting.

During our lives we are constantly exposed to different stressors that perturb the balance (i.e., homeostasis) that our bodies work hard to maintain.

Stress can be acute (quick, short-lived) or chronic (long-lasting, recurrent). Our bodies respond to stressors through physiological changes with the goal of restoring balance.

Before we illustrate how our bodies respond to stress, it is important to address a dilemma that accompanies studying the human body.

The tradition has been to separate the body into different systems. This helps simplify things and makes it easier to learn how the body works.

But the human body is not really divided into separate systems. The body is one integrated system, like a “well-oiled” machine. Therefore, it should come as no surprise that human behavior is most likely the result of all of these “systems” working together simultaneously in real time. This concept is important to remember as we study the human body.

The Major Systems of the Human Body

THE CARDIOVASCULAR SYSTEM represents the plumbing system that circulates nutrient-rich blood throughout our bodies to keep our 30 trillion (30,000,000,000,000) cells alive.

THE NERVOUS SYSTEM represents the bodily components that allow us to sense, integrate, and plan the most appropriate response to stimuli in our external and internal environment.

THE IMMUNE SYSTEM represents the army of cells and proteins that protect us from foreign invaders like bacteria, viruses, and parasites. The immune system also provides the necessary components for healing our wounds.

THE GASTROINTESTINAL (“GUT”) SYSTEM represents the hollow tube running from our mouth to our anus. Our guts are full of enzymes and acids that break down food and absorb necessary nutrients with the help of various types of bacteria. Immune cells survey the foreign material from the outside world and protect us from dangerous bacteria, viruses, and parasites.

THE MUSCULOSKELETAL SYSTEM represents the mechanical components essential for the complex movements that are coordinated by our nervous system so we may appropriately respond to, and manipulate, our environment.

THE ENDOCRINE SYSTEM (HORMONE SYSTEM) represents the components that work to regulate our energy needs, our core body temperature, our sexual functioning, our circadian rhythms (sleep cycles), and much more. Let’s take a closer look at a specific component of the Endocrine system, the hypothalamus-pituitary-adrenal (HPA) axis, which is an important component of our stress response.

Hypothalamic-Pituitary-Adrenal (HPA) Axis

The hypothalamic-pituitary-adrenal (HPA) axis is a complex neuroendocrine system responsible for regulating the body’s response to stress and maintaining overall homeostasis. It involves a series of interactions between the hypothalamus, pituitary gland, and adrenal glands.


The HPA axis begins with the hypothalamus, a region in the brain that detects stressors and triggers a response. In response to stress, the hypothalamus releases corticotropin-releasing hormone (CRH) which travels to the anterior part of the pituitary gland, a small gland located at the base of the brain.

Pituitary Gland

As previously mentioned, the CRH released by the hypothalamus travels to the anterior part of the pituitary gland. In turn, CRH stimulates the anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH then travels to the adrenal glands, which are located directly above the kidneys. 

Adrenal Glands

The adrenal glands consist of two parts: the outer adrenal cortex and the inner adrenal medulla.

Adrenal Cortex: ACTH stimulates the adrenal cortex to release glucocorticoids, primarily cortisol. Cortisol is a stress hormone that plays a crucial role in regulating metabolism, immune response, and inflammation. It helps the body respond to stress by increasing blood sugar levels, suppressing the immune system, and promoting energy production.

Adrenal Medulla: While the hypothalamus-pituitary pathway primarily regulates long-term stress responses, the adrenal medulla is involved in short-term stress responses. It releases adrenaline (epinephrine) and noradrenaline (norepinephrine), which prepare the body for a “fight-or-flight” response by increasing heart rate, blood pressure, and alertness.

Negative Feedback

Once cortisol is released into the bloodstream, it acts as a negative feedback signal to the hypothalamus and pituitary gland. Elevated cortisol levels inhibit the release of CRH and ACTH, thereby reducing the stimulation of the adrenal glands. This feedback loop helps maintain cortisol levels within a normal range.

In general, hormones that are secreted by the hypothalamus, pituitary gland, and target organs inhibit their own release. For example, ACTH released by the pituitary gland inhibits the hypothalamus and pituitary gland from releasing more CRH and ACTH, respectively. This prevents unregulated release of hormones. See the figure below for the various hormones and their actions. While all of these hormones are important, we will be primarily focusing on the hypothalamic-pituitary-Adrenal (HPA) axis as it relates to the stress response in humans.

FIGURE: CRH (Corticotropic Releasing Hormone), GnRH (Gonadotropic Releasing Hormone), GHRH (Growth Hormone Releasing Hormone), ACTH (Adrenocorticotropic hormone), TSH (Thyroid Stimulating Hormone), FSH (Follicle Stimulating Hormone), LH (Luteinizing Hormone), ADH (Antidiuretic Hormone/Vasopressin)
In summary, the HPA axis is very important in the stress response. The end result of HPA Axis stimulation is increased cortisol release. Cortisol is considered a corticosteroid and has many important functions in the acute stress response. The most important functions of cortisol are to quickly prepare us to fight, flight, or freeze when threatened. See the figure below with the most common functions of cortisol.
Overall, the HPA axis is crucial for the body’s stress response and maintaining physiological balance. Dysregulation of the HPA axis can lead to various health issues, including chronic stress, anxiety disorders, depression, and adrenal insufficiency.


As you will learn in the scenario below, cortisol helps us in the short term, but it actually hurts us in the long term. As they say, too much of a good thing isn’t always a good thing.

When stress is prolonged or repeated, cortisol levels remain elevated and the mechanism for inhibiting further cortisol release goes awry. In fact, the receptors for cortisol become desensitized to the persistently elevated cortisol levels which then leads to a dysregulated cycle and continuous cortisol secretion.

Persistently elevated cortisol levels have been implicated in the pathophysiology of many neuropsychiatric disorders such as depression and post-traumatic stress disorder (PTSD). In addition, elevated cortisol impairs our ability to heal wounds, suppresses our immune system, elevates our blood pressure, causes peptic ulcers, and erodes our bones (e.g., osteoporosis).

The Clown Scenario

Imagine you grew up in the woods somewhere remote and isolated. At some point during your childhood a family friend of yours played a prank by dressing up as a killer clown. While you were playing and enjoying your toys in the yard, the scary clown (your family friend) jumped out at you.

Immediately, your body responds (in milliseconds). In fact, before you even know what’s going on, your body has already started to respond. Your sympathetic nervous system becomes activated thanks to direct connections between the brain’s sensory areas and the central nucleus of your amygdala, a structure located deep in the brain that is responsible for processing fear-based stimuli.

The amygdala has connections to nearly all areas of the brain (which makes sense since the amygdala is involved in adding fear-based emotions to our experiences). The reasoning centers of the brain, such as parts of the frontal lobe, are bypassed because they aren’t a priority at the moment–there is no time for pondering the meaning of a killer clown charging at you. Evolutionarily this is important because it allows the senses to bypass your reasoning centers so you can act without knowing what you are doing.

When your amygdala fires, it immediately sends signals to the adrenal glands to secrete Epinephrine (also called adrenaline) and simultaneously activates the sympathetic division of the autonomic nervous system. This causes increased respiration, cardiac output, arousal, and mobilization of energy stores from the liver and fat cells. As the heart pumps faster, your blood pressure rises.

Blood flow is diverted away from the skin and gut and begins flooding your skeletal muscles so you can run away fast. A few minutes later, your Hypothalamus Pituitary Adrenal axis kicks in. CRH, a hormone, from the hypothalamus acts on the pituitary gland to release a protein called ACTH which acts on the adrenal cortex to release cortisol. Cortisol works in tandem with epinephrine and norepinephrine to improve your chances of survival. Cortisol sensitizes our body’s response to epinephrine and norepinephrine.

Cortisol also works at the genomic level to regulate the body’s response to the stressor over a longer period of time. The outcome of the situation will determine how cortisol changes the genetic expression of various proteins. So, at this point you’ve been running as fast as you can. Eventually you get away and find shelter. Your cortisol and adrenaline levels decline and your heart rate and breathing slow down. Blood flow returns to your guts and skin and color returns to your face. You are back to baseline and now you start ruminating and reasoning through what happened.

When this happens to us, those connections between our sensory areas and the amygdala strengthen and become very efficient–so efficient that the next time you even see something that resembles a clown you begin to experience a fear response.

If these types of scenarios happen often or one scenario is severe enough, the whole system can become dysregulated, and may remain in a persistently hypervigilant state. 

Studies in both man and animals have shown that chronic stress is associated with enlarged pituitary and adrenal glands, sustained increases in levels of cortisol in the body, increased levels of CRH in both the cerebrospinal fluid and limbic regions of the brain. Lastly, and most importantly, the sustained elevated cortisol levels in the brain have been shown to cause atrophy of neurons, decreased dendritic density, atrophy of glial cells, and decreases in hippocampal, amygdala and prefrontal cortical volumes. Atrophy in the prefrontal cortex means our impairment in our ability to reason, problem-solve, plan, concentrate, and control our emotions. Atrophy in the hippocampus means we forget things or remember events in a distorted way.


  1. Benjamin J. Sadock, Virginia A. Sadock. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. Philadelphia :Lippincott Williams & Wilkins, 2000.
  2. Ebenezer, Ivor. Neuropsychopharmacology and Therapeutics. John Wiley & Sons, Ltd. 2015.
  3. Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
  4. Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
  5. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  6. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
  7. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.
  8. Levenson, J. L. (2019). The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. Washington, D.C.: American Psychiatric Association Publishing.
  9. Blumenfeld, Hal. Neuroanatomy Through Clinical Cases. 2nd ed. Sunderland, Mass.: Sinauer Associates, 2010.
  10. Bear, Mark F.,, Barry W. Connors, and Michael A. Paradiso. Neuroscience: Exploring the Brain. Fourth edition. Philadelphia: Wolters Kluwer, 2016.
  11. Higgins, E. S., & George, M. S. (2019). The neuroscience of clinical psychiatry: the pathophysiology of behavior and mental illness. Philadelphia: Wolters Kluwer.
  12. Mendez, M. F., Clark, D. L., Boutros, N. N. (2018). The Brain and Behavior: An Introduction to Behavioral Neuroanatomy. United States: Cambridge University Press.
  13. Sixth Edition. Edited by Dale Purves, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, Richard D. Mooney, Michael L. Platt, and Leonard E. White.

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Thanks for visiting!

Enter your email to continue.

%d bloggers like this: