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 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.

Our body’s ability to respond appropriately to a stressful situation, or stressor, is adaptive and essential to survival. A small amount of stress in the right situation can be lifesaving. However, when our bodies respond inappropriately in the wrong setting, what was supposed to be an evolutionarily adaptive response becomes problematic.

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 Dilemma

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.

Hypothalamic-Pituitary Axis

Now that we’ve addressed the dilemma, let’s 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.

 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 Hypothalamus

The hypothalamus is a group of neuronal cell bodies, also called nuclei, that sit just below the thalamus (hence, “hypo”-thalamus). The hypothalamic neurons are unique because they release hormones directly into the blood stream. Then these hormones travel to the pituitary gland. The hormones released from the hypothalamic neurons are called “releasing hormones” because they stimulate the release of more hormones in the pituitary gland. Recall that the pituitary gland is located just inferior (underneath) and slightly anterior to (in front of) the hypothalamus. The hypothalamic nuclei have different functions which are outlined in the table below.

The Pituitary Gland

The pituitary gland is separated into the anterior pituitary and posterior pituitary. As previously mentioned, the anterior pituitary receives signals from the hypothalamus via the releasing hormones secreted directly into the circulation. The posterior pituitary, however, receives signals in a slightly different way. The neuronal cell bodies located in the hypothalamus extend their axons all the way down to the posterior pituitary where they release hormones that then travel to target organs.

Negative Feedback

Hormones that are secreted by the pituitary gland and their target organs inhibit their own release. For example, ACTH released by the pituitary and Cortisol released by the adrenal glands both inhibit the hypothalamus and pituitary gland from releasing more CRH and ACTH, respectively. In other words, hormones regulate themselves by a negative feedback mechanism so that the response will eventually shut down. 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.

The Hypothalamic-Pituitary-Adrenal (HPA) Axis

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 either fight or run away from a threat. See the figure below with the most common functions of cortisol.
As you will learn in the scenario below, the hypothalamus secretes Corticotropin Releasing Hormone (CRH) in response to stress. CRH then stimulates the release of ACTH from the anterior pituitary. ACTH then acts on the cortex of the adrenal gland and promotes the release of corticosteroids (i.e. cortisol). Cortisol then acts on a number of different tissues and organs in the body to prepare us to fight the imminent threat or run away from it. Once the threat is removed, cortisol levels drop because cortisol inhibits the anterior pituitary, hypothalamus, and other brain regions from producing more hormones. In other words, cortisol regulates itself.

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.

All of a sudden, you look behind you and see a scary clown charging at you with a balloon and a knife.

Your body’s response begins within seconds of seeing the clown. 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 the central nucleus of your amygdala. The reasoning centers (prefrontal cortex) aren’t a priority at the moment as your amygdala and other subcortical structures light up like fireworks on the fourth of July. There is no time for pondering the meaning of life as a clown is charging at you.

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).

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.
As stated previously, cortisol levels fall after acute stress. Recall that cortisol released from the adrenal glands acts in a negative feedback manner on cortisol receptors in the hypothalamus and pituitary to decrease the secretion of CRH and ACTH respectively. However, high levels of chronic stress disrupt this feedback system. The elevated levels of circulating cortisol render the cortisol receptors less sensitive to cortisol in the hypothalamus, pituitary and other brain regions. This desensitization results in failure of the feedback inhibition system to operate normally. This means an even greater release of cortisol from the adrenal glands.

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.


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