"The Physiology of Stress" by Sarah Watanaskul
Though stress is encountered in everyday life, the body has mechanisms that assist in confronting stress and then returning itself to a normal homeostatic state. Although the body can adapt well to short-term stress—which, in small amounts, may offer temporary benefits—long-term stress can be detrimental to several physiological systems in maintaining homeostasis.
Imagine that you walk into a final exam. As you open your exam booklet, you feel your heart thumping against your chest, you begin breathing faster, and you can barely contain all your energy. What’s causing all of these symptoms? When a stressful situation or stimuli is first encountered, the elicited response begins in the brain, which leads to subsequent effects on different areas of the body via the transmission of hormones through the blood to their target organs. The brain’s response to stress can activate different axes (biochemical pathways), culminating in symptoms we commonly associate with stress.
The autonomic nervous system (ANS), a component of the peripheral nervous system, consists of two antagonistic systems called the sympathetic (SNS) and parasympathetic nervous systems (PNS) . The SNS prepares the body for increased energy expenditure through increased catabolic activity, which breaks down metabolites to generate energy that can be used for movement. The PNS is involved in controlling energy conservation and relaxation, or the body’s anabolic functions.
Let us examine in detail how the brain elicits the “fight or flight” response with the help of hormones and the SNS. There are two parts to activating this response. The first part consists of the hypothalamus directly activating the adrenal medulla (the inner part of the adrenal glands) via a direct neural pathway connection[3,4]. The main function of the adrenal medulla is to release the catecholamines [5,6] epinephrine and norepinephrine (also known as adrenaline and noradrenaline). These hormones have a variety of effects on the body, including increased heart rate and force of contraction, vasodilation of arteries in areas used in responding to the stress, dilation of the pupils and bronchi, increased breathing rate, decreased digestive activity, and the release of glucose from the liver, among others. Thus, some of your immediate responses to taking the final exam are caused by adrenaline and noradrenaline.
The second part of the “fight or flight” response involves the hypothalamus in the hypothalamic-pituitary-adrenal axis (HPA). The HPA is initiated by the release of corticotropin-releasing hormone from the hypothalamus, which causes the pituitary to release adrenocorticotropic hormone (ACTH) . ACTH travels through the blood stream to activate the adrenal cortex of the adrenal glands that sit atop the kidney. The main function of the adrenal cortex (the outer layer of the adrenal gland) is to release steroid hormones like glucocorticoids and mineralocorticoids, which have roles in increasing metabolism and maintaining a salt-and-water balance respectively. Cortisol, a glucocorticoid , affects metabolism by generating glucose via the degradation of liver proteins (gluconeogenesis) or the breakdown of fats (lipolysis). Aldosterone, a mineralocorticoid, helps to maintain plasma volume and electrolyte concentration by increasing reabsorption of water and salts in the kidney, thereby reducing urine production ; this mirrors the effect of anti-diuretic hormone (ADH), which is secreted as part of the hypothalamus’ response to stress and serves to increase blood volume (and blood pressure) through water reabsorption.
Overall, the HPA axis ensures an adequate supply of glucose in the blood as well as increased blood circulation. This provides an immediate source of energy for any muscles, organs, etc. that are needed to respond to the stressful stimuli [1,2], and the increased blood volume, heart rate, and force of heart contractions ensures that glucose and oxygen get to where they are needed. The increase in blood glucose levels accounts for the burst of test-taking energy in our hypothetical scenario, and the elevated blood pressure and heart rate may explain why some people hear their “hearts pounding in their ears” when they are stressed.
So what happens after the final exam? Since the exam is a stimulus of short-term stress, the body will return to homeostasis once the ordeal is over. This is accomplished by the PNS, which stimulates the release of acetylcholine in order to decrease metabolic rate, heart rate, breathing rate, and muscle tension, among other things . The PNS serves to reverse the effects of the SNS.
Short-term stress may offer benefits like alertness, a burst of energy, and improved memory and cognitive functioning , but chronic stress can interfere with the body’s ability to return to homeostasis and may contribute to other health complications. Consider the weeks before the final exam. As a busy college student you probably have many obligations outside of class, and the challenge of balancing extracurriculars with homework and study time can quickly turn into a source of long-term stress. It’s likely you’ve heard people blame stress for hypertension, weight gain, or sickness, but why do they say that, and is it true?
Under conditions of long-term stress, regulatory mechanisms can begin to lose their effectiveness, and the secretion of ADH from the hypothalamus will still increase blood pressure even if a person already has a high resting blood pressure . This augmentation of an already-elevated blood pressure leads to hypertension.
Another example of detrimental long-term stress involves cortisol. Cortisol is normally released in a diurnal rhythm (high levels after awakening and then lower levels throughout the day)  and is involved in several processes including energy regulation, the control of salt and water balance, and immune system function [9, 11]. Though having sufficient cortisol levels is essential for health, elevated cortisol levels from chronic stress can lead to symptoms like weight gain and impaired immune function . On a basic level, higher cortisol levels are correlated with an increase in appetite and cravings for foods high in sugar and fat , a result of the body’s need to replenish energy stores . One potential consequence of this effect on appetite involves the release of neuropeptide Y (NPY). Neuropeptides can act as chemical signals in the endocrine system  and NPY is a sympathetic neurotransmitter, one of whose functions is to stimulate adipocyte differentiation. If the receptors for NPY are significantly expressed in visceral fat, it can result in the rapid growth of the type of fat linked to an increased risk for diabetes, obesity, heart disease, and/or stroke [14,15]. Cortisol also promotes fat cell maturation and fat storage, so elevated amounts of cortisol in visceral fat (surrounding the stomach and intestines) compared with those in subcutaneous fat (underneath the skin)  can contribute to obesity . Furthermore, since one of cortisol’s responsibilities is to increase the availability of energy sources like glucose in the blood, it is necessary to temporarily stop the storage of glucose. To do so, cells decrease their responsiveness to insulin, a hormone that stimulates glucose uptake from the blood. Prolonged unresponsiveness to insulin because of long-term stress can lead to insulin resistance, thereby increasing risk for diabetes.
Short-term stress temporarily boosts and enhances immune function, but chronic stress and prolonged, high levels of cortisol can lead to the suppression or impaired function of the immune system. This is caused by several factors, including the shrinkage of the thymus gland (an important part of the immune system) , the decrease in white blood cell production, and the inhibition of white blood cell secretion of proteins that regulate immune response and inhibit virus replication . Thus, if you see fellow students coughing and sniffling when finals week rolls around, it may be due to the cumulative effects of long-term stress rather than “another bug going around.” This may seem a bit counterintuitive. If cortisol can enhance immune function in situations of short-term stress, wouldn’t more cortisol result in a better immune system? As it turns out, the anti-inflammatory and immunosuppressive effects of elevated levels of cortisol are a defense mechanism against autoimmune disease. Because short-term stress enhances immune function, repeated enhancements due to a continued stream of stressful encounters will generate an overactive immune system, which can lead to autoimmune diseases. As a measure of prevention, chronic exposure to cortisol impairs the components of the immune system, thereby “protecting” us from autoimmune diseases, though ironically making us more susceptible to pathogenic disease .
All in all, stressful stimuli can initiate many physiological and biochemical pathways in the body that prime the body and give it the resources necessary to respond to the stressful encounter. The interaction between the nervous and endocrine systems produces the classic symptoms that we associate with stress, and the long-term consequences of these symptoms and their underlying mechanisms help to explain the conditions potentially affected by stress.
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