The Science of Stress: Evolution, Hormones, and Epigenetics

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Between 1967 and 1989, the country of Romania had a communist dictator under the name of Nicolae Ceausescu.

Romania was neither wealthy nor stable during this time. As Ceausescu realized that the strength of his country was dependent on human capital, based on Stalinist dogmas from the 1930s, he had one main goal for the country: to boost its population.

To do so, Ceausescu decided to increase the population by completely banning contraception and abortion. Fertility became a matter of government control. This system was ruthlessly enforced by the secrete police, called the securitate.

As a result of these bans, there was an immense surplus of children being born. However, many families could not afford to raise the many children they were birthing. The country was unstable, food supplies were not abundant, and families could not feed their children. Therefore, the government had to take in over a hundred thousand orphans, with the overall population reaching a record of over 23 million individuals by the end of Ceausescu’s regime.

Yet, the orphanages lacked adequate resources to care for the huge numbers of children that were left under the hands of the government. Therefore, many of these orphans were widely neglected and abused both by caretakers and by other children.

Scientists who later studied these subjects realized that they had been raised in extremely stressful environments from the beginning of their lives. Since this was happening on a massive scale for a well-defined period of time, scientists were able to stud these orphans as a model of chronic stress. They found patterns of delayed motor development, impaired cognitive function, and abnormal emotional regulation, with children lashing out and exhibiting extremely aggressive behaviors, and psychosocial dwarfism, where elevated cortisol and low levels of growth hormone stunt growth due to constant stress and emotional deprivation.

In order to understand stress, and what differentiates chronic stress from it’s temporary counterpart, we have to go back to evolutionary development and our hormonal regulation.

Whether it the fear of failing your Calculus exam or trying to find your next meal, all of humanity is stressed in some form.

We always think of stress as being a very negative experience. And it is. Stress alters so many of our biological capabilities, resulting in a plethora of mental and physical health problems; from diabetes and high blood pressure, to anxiety and depression.

However, our ability to percieve stress and exert a biological response to it is critical to our survival.

The lack of an active stress system, with the respective hormones involved, can be extremely detrimental to our bodies.

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We can think of stress as having an Inverted-U Effect. We can observe the amount of stress, or pressure, an individual faces on the x-axis and the performance on the y-axis.

The Inverted-U Effects shows us that our optimum pressure level for our peak performance, including optimal learning and memory, focus, and cognition, is neither too high nor too low.

On average, we find that most individuals perform the best within this happy medium of pressure. A high amount of stress can cause performance anxiety, test anxiety, forgetfulness, emotional turmoil, unhappiness, and a plethora of other physical and mental conditions that can manifest in more serious forms.

On the opposite extreme, individuals who cannot mount a stress response at all also have impaired performance. This does not apply to just humans, but to species across the animal kingdom.

From a biological perspective, this means that your body is unable to release the appropriate stress hormones, resulting in the individuals facing a lack of motivation, and can even lead to apathy and depression.

The hormones we secrete are extremely important in our stress regulation.

Evolution has allowed us to secrete these hormones in order to keep ourselves alive.

The stressors within our environment depend on the context in which we are in. A college student is likely worried about their academic prospects, financial costs, and other social stressors, while another individual struggling to survive is likely much more worried about their next meal, finding a place to sleep, and staying warm.

Anything that stimulates our body to mount a stress response can be considered a stressor. Stressors induce the release of certain hormones through a stress response. In general, we have 3 main types of stressors in our environment; environmental, physiological, and psychosocial.

In the past several decades, we have been exposed to environmental stressors with a much greater frequency. These include things like record-breaking temperatures, fires, rain, hurricanes, floods, and other natural disasters.

The stressors in our environment are not directly in our control. Due to the technological advancement of society, we have the ability to prepare, evacuate from, and avoid these stressors. However, the stressor is not necessarily the extremity with which these conditions occue, but rather, the uncertainty of when certain extreme conditions will come again.

Physiological stressors are ones that disturb our internal biological balance, necessitating some form of regulatory mechanism afterward in order for the body to restore homeostasis. These might include hunger, thirst, fatigue, and pain.

On the other hand, psychosocial stressors are “lifestyle” stressors, consisting of various aspects of our lives, from academics to sports to time constraints. These stressors are what contribute to the feeling of being “out of control” and as if your life is not in your hands.

The whole point of hormones in our stress regulatory response is to provide us with energy.

We can think about this in terms of our fight or flight response. If we are on a hike and encounter a mountain lion, the only goal we have in that one moment is to stay alive. While it may seem like our only option at that moment is to escape, in reality, we have two options that evolution has set course for us:

  1. Run as fast as you can to flee from this terrifying creature
  2. Look at the mountain lion and decide that it could be your next dinner

Regardless of if we decide to engage in battle and come out with a reward in the form of our next meal, or decide that it is not worth it and run for our lives, both options require a surge of physical energy.

In order for our body to survive, we have two different stress responses; a fast response and a slow response.

Both of these stress responses are critical to our survival; they determine if we are going to survive or if we are going to die.

The fast response is initiated right away. As soon as we see or come in contact with this stressor, in this case, the mountain lion, a burst of hormones are released in less than a second. These are the hormones that power us to decide if we are going to fight or flee, prepare for that decision, and execute.

If a mountain lion jumps in front of you, you won’t have time to weigh the pros and cons of that decision. Therefore, an immediate burst of hormones gives us the energy to decide and prepare.

The fast stress response comes from our sympathetic nervous system, which is a part of our autonomic nervous system. Our autonomic nervous system controls the basic physiological functions we don’t even need to think about, such as the digestion of food, maintaining a basal body temperature, and our pulse.

In less than a second after we encounter the mountain lion, our autonomic nervous system floods our bodies with norepinephrine, a hormone, and neurotransmitter, which increases our heart rate, blood pressure, and initiates the breakdown of fat and excess glucose to increase blood sugar levels in an attempt to supply the body with more energy.

The norepinephrine is released from the neurons extending out of the spinal cord, and therefore, floods the entire circulatory system immediately. When the adrenal glands are stimulated with norepinephrine, the adrenal medulla, the inner section of the adrenal gland, produces even more norepinephrine, along with the hormone epinephrine which we know as adrenaline, allowing the increase of blood circulation, strength, and physical performance, heart rate, etc.

Both norepinephrine and epinephrine are catecholamines, neurotransmitters released into the blood in response to physical or emotional stress. Although both compounds are similar, epinephrine is much more potent and stronger.

The slow response is delayed and comes 15 to 30 minutes after the fast response. This response is responsible for repairing your body from the physical demands of your initial response.

The slow stress response comes from the production of glucocorticoids, essential steroid hormones secreted from the adrenal gland in response to stress, by our HPA axis (hypothalamic-pituitary-adrenal axis).

The glucocorticoids that initiate the slow stress response are released by the adrenal cortex. However, multiple endocrine glands are involved within the process, The hypothalamus must first release CRH, corticotrophin-releasing hormone, which stimulates the pituitary gland to release many hormones, including ACTH, adrenocorticotropic hormone. In turn, ACTH stimulates the adrenal cortex, or the outer shell of the adrenals, to secrete glucocorticoids.

Glucocorticoids elevate the blood sugar within the body, causing energy levels to peak approximately 15 to 30 minutes after the immediate stressor, as it takes time for the glucose to break down and the energy to be utilized and activated by the body.

If we follow the blue line, we can see what we expect to be a normal stress response, peaking about 15 to 30 minutes after the stressor which has hopefully disappeared by this point, and the glucocorticoid levels go back down as normal. 1.5–2 hours after experiencing the stressor, the glucocorticoid concentrations should be back at their baseline due to negative regulation.

However, some individuals might have disrupted negative feedback, in which case their glucocorticoid concentrations never peak as high as they should, and/or their stress response level takes longer to come back to a baseline. While it is important to have an adequate stress response, it is equally as important for that response to come back to a baseline.

When your body is in fight or flight mode, it doesn’t really care about certain biological processes, such as your immune system, ovulation, or digestion. A lot of these processes are placed on hold in order to focus on your survival which is at stake.

The other hormones produced by the pituitary gland in the HPA axis as part of the slow response include prolactin, disrupting the release of GnRH (gonadotropin-releasing hormone) which is responsible for stimulating the secretion of LSH (luteinizing hormone) and FSH (follicle-stimulating hormone) and stopping the function of the ovaries and testes. If a mountain lion is about to kill you, your body literally places reproductive function on hold.

Glucocorticoids also suppress immune function. For example, if you have hives or rashes from poison ivy on your body, you will often be prescribed ra hydrocortisone treatment, which is a glucocorticoid in order to suppress your immune system from working overtime.

The negative regulation aspect of our stress response is crucial. Since stress essentially shifts our bodies from a state of storing energy to a state of using energy, it puts a huge amount of pressure on our bodies. Therefore, while acute stressors allow us to survive, chronic stress is immensely detrimental to our health because we are experiencing stress on a constant daily basis rather than in a one-time situation.

The overload of these hormones during acute stress is immensely beneficial for your body, but if these hormone levels remain elevated for long periods of time, they become pathological. Our bodies are not designed to be exposed to long bouts of increased epinephrine or glucocorticoid steroid hormones.

In the long term, elevated levels of these hormones can lead to fatigue, myopathy (degeneration of muscles), or steroid diabetes, which occurs when excess glucose is being released due to the overload of epinephrine and glucocorticoids working to release glucose.

In addition, the constriction of blood vessels can lead to hypertension and chronic high blood pressure, with the potential for cardiac fatigue and cardiac arrest, because the heart is not designed to be overworked for extended periods of time. The inhibition of digestion can lead to ulcers and perforations within the weakened gut lining; the inhibition of growth often results in individuals not reaching their full height potential; and the inhibition of reproductive function can lead to impotence or anovulation. In addition, altered immune function and inflammatory response can lead to higher chances of cancer, as the body cannot constantly conduct immune surveillance to destroy cancerous cells, and impaired disease resistance, making individuals more susceptible to disease and illness.

The brain suffers greatly under chronic stress as well. Although individuals have enhanced cognition under acute stress, in order to increase their chances of escaping the stressor and making certain decision in order to reach a stable condition, leading to enhanced cognition, this leads to accelerated neural degeneration during aging. Since your body is not operating in its most optimal way and is constantly over the edge when epinephrine and glucocorticoid levels are high, your brain is consistently encoding details of its surroundings with the inability to let go and fully experience things. Chronic stress also suppresses neurogenesis, the generation of new nerve cells, so nerve cells are generated at a much slower rate. Furthermore, it affects the brain’s synaptic plasticity — the effectiveness with which neurons communicate, and the strength of the communication pathways between them.

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Psychological Factors in Controlling Chronic Stress

There are certain behaviors we can engage in, in order to cope with chronic stress.

Many individuals feel as though their stress manifests when they are not in control of situations in their lives. The feeling of being out of control is something many of us inherently fear. Therefore, having some element of perceived control, whether that be artificial, allows us to feel as though we have regained some essence of our individual power over any situation.

Predictability also ensures some level of control. Establishing routines within our lives adds an aspect of balance, and keeps us centered.

Having outlets for frustration is one of the most beneficial things we can do to prevent and fight chronic stress. By allowing ourselves time to step away from the constrictions of reality, and engage in some activity that relieves us, we can step away from the hyperactivity within our biological and neurological systems.

In the late 1980s scientists conducted a study on rodents looking at the effects of chronic stress on lesions in the gut. The rodents were placed in a chamber with a metal grid floor, and an electrical gradient was applied across the metal grid floor, implementing a foot shock. Although it was a very mild current, it still shocked the animals.

There was one control group and two experimental groups in this study; a group that received a signaled shock, meaning that the rodents were trained to associate some signal or cue right before the shock was delivered, and an unsignaled shock, in which the shocks were delivered in a completely unpredictable manner. However, the electrical current applied on both experimental groups was the exact same.

The scientists found that the animals who could predict the shock were very similar to the control group. The lesions in their gut were not significantly larger by any means. However, the group receiving an unsignaled shock had drastically larger lesions in their gut.

The graph on the right measured the hydrocorticosteroids in the rodents across a full hour. The solid black line shows the levels of the control group, who was not stressed at all. The middle group (Novelty 1) experienced chronic predictable stress, and the Novelty 2 group experienced chronic unpredictable stress, causing their HPA axis to be constantly stressed.

Epigenetic Influences on Stress Response

In 2005, researchers looked at how the licking and grooming behaviors of female rats towards their children affected the stress response of their own children. In essence, they were looking at the experience of how the rodents were raised, rather than their biological DNA, to determine their stress responsivity. Instead of genetic changes, they looked at epigenetic influences.

When a rodent pup receives a lot of licking and grooming from its mother, its genes don’t change. However, many chemical modifications occur on top of the genes, such as changes in electrical and chemical charges of proteins in regions surrounding the DNA.

We can think of DNA as a book, consisting of the words, letters, and paragraphs. However, epigenetic changes occur if you use a black marker and crossed out content in the book so that no one can read it, and highlighted certain sections you enjoyed. While you aren’t changing the underlying code of the book, the epigenetic changes change the way in which the content is interpreted.

Just the same, the maternal behaviors and tactile stimulation of the rats change the way that the DNA is marked.

When a mother engages in a high rate of licking and grooming, she gives her pups a high rate of physical contact, increasing the production of seretonin.

The increase in seretonin increases the expression of a transcription factor, which interacts with certain regions of DNA, called NGFL-A in the hippocampus. The transcription factor results in various epigenetic changes, including chemical modifications, demethylation, and acetylation around the gene that codes for the glucocorticoid receptor.

Higher levels of certain hormones, such as glucocorticoids, allow for better negative regulation of the HPA axis. Therefore, low levels of glucocorticoids can shut down the stress response quickly.

Epigenetics shows us that the outcome of our lives is a perfect blend of nature versus nurture. While the specific genes and DNA must be there, the experiences we have can interact with our biology.

Genes are a part of our destiny; not our whole destiny.

The hippocampus itself is crucial for both learning and memory, especially short-term memory. Damage to the hippocampus prevents you from being able to form new memories. The hippocampus also has a very high density of glucocorticoid receptors.

While the adrenal glands are the only endocrine organs that can secrete glucocorticoids, the hippocampus contains such a high density of glucocorticoid receptors for two reasons:

  1. Cortisol awakening response
  2. Activation of the HPA axis

Hormones always need to bind to receptors. Without receptors, hormones serve no function. Therefore, the hippocampus is highly receptive to stress. The glucocorticoids help to negatively regulate the stress response, and shut off the HPA axis.

The way in which our bodies respond to stressors in an ever-changing environment is dependent on how evolution has shaped the primitive instincts of our species, the regulation of our hormones, and the environments which have influenced our epigenetic makeup. By understanding the ways in which our bodies process stress, we can optimize our environments for our benefit.

While there are more complex and detailed biological processes that take place, as well as the influence of other brain structures such as the amygdala, our evolution, epigenetics, and biochemistry shape the basis for how our bodies interact with our internal and external environment.

When looking at all the ways in which chronic stress impacts our bodies, it’s amazing to think about the resilience in our biological makeup that allows us to walk, talk, and be alive. As Robert Sapolsky, known for his work in stress and neuroendocrinology, says, “it’s amazing to you that anybody is still alive, that we haven’t just collapsed into puddles of stress-related disease.”

If you are interested in exploring the subject further, here is some content I enjoyed!

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