The Biology of Stress
What is stress?
Why is it important to understand the biology of stress?
Stress has been implicated in many conditions including depression, anxiety, posttraumatic stress disorder, heart disease, high blood pressure, chronic pain, and psychosis to name a few.
During our lives we are constantly exposed to different stressors that perturb the balance (homeostasis) that our bodies try to maintain. Humans have an incredible capacity to reestablish balance when disturbed. 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.
Here is a brief overview of the different systems:
- The cardiovascular system represents the plumbing system that circulates nutrient rich blood throughout our bodies to keep our nearly 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 and also provides the necessary components for healing our wounds.
- The Gastrointestinal (“gut”) system represents the hollow tube running from our mouth to our anus that is in direct contact with the outside world. Our guts are full of enzymes and acids that break down food and absorb necessary nutrients with the help of various types of bacteria living in harmony with us at all times. 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. We could go on and on.
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.
Now that we’ve addressed the dilemma, lets take a look at one of the primary systems involved in the stress response. That is, the endocrine system. More specifically, the hypothalamus-pituitary-axis.
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)
The Hypothalamic-Pituitary-Adrenal (HPA) Axis
While cortisol helps us in the short term, 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. While cortisol helps us in the short term, it actually hurts us in the long term. As they say, too much of a good thing isn’t always a good thing. 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 (via increased gastric acid secretion) and bone deterioration (e.g., osteoporosis).
The Clown Scenario
Imagine you are hiking in the woods but find yourself lost. Night falls and you are alone in the dark forest.
Epinephrine (also called adrenaline) is released from the chromaffin cells of the adrenal medulla and norepinephrine is released by sympathetic nerve terminals. This causes increased respiration, cardiac output, arousal, and mobilization of energy stores from the liver and fat cells. 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 HPA axis kicks in. CRH from the hypothalamus acts on the pituitary to release 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).
Here is a list of cortisol’s functions:
- Breakdown of proteins
- Stimulates Urea cycle
- Inhibits the immune system
- Promotes epinephrine synthesis from norepinephrine (the enzyme required to convert norepinephrine to epinephrine is regulated by cortisol)
- Promote Gluconeogenesis and Glycogenolysis (via epinephrine)
- Increases blood glucose levels
- Breaks down subcutaneous fat and relocates it
- Decreases synthesis of bone collagen
- Decreases blood calcium
- Stimulates Parathyroid Hormone (PTH) secretion and promotes bone resorption
- Increases diuresis (via decrease in ADH release)
- Increases Cardiac Output
- Increases muscle strength and vigor
- Increases gastric pepsin and gastric acid (HCl) secretion
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.
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.
- Benjamin J. Sadock, Virginia A. Sadock. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. Philadelphia :Lippincott Williams & Wilkins, 2000.
- Ebenezer, Ivor. Neuropsychopharmacology and Therapeutics. John Wiley & Sons, Ltd. 2015.
- Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
- Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
- Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
- Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
- Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.
- Levenson, J. L. (2019). The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. Washington, D.C.: American Psychiatric Association Publishing.
- Blumenfeld, Hal. Neuroanatomy Through Clinical Cases. 2nd ed. Sunderland, Mass.: Sinauer Associates, 2010.
- Bear, Mark F.,, Barry W. Connors, and Michael A. Paradiso. Neuroscience: Exploring the Brain. Fourth edition. Philadelphia: Wolters Kluwer, 2016.
- Higgins, E. S., & George, M. S. (2019). The neuroscience of clinical psychiatry: the pathophysiology of behavior and mental illness. Philadelphia: Wolters Kluwer.
- Mendez, M. F., Clark, D. L., Boutros, N. N. (2018). The Brain and Behavior: An Introduction to Behavioral Neuroanatomy. United States: Cambridge University Press.
- 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.