Introduction

Picture the following scenario. Two students are jogging at dusk along a fire trail in the Berkeley, California hills. As they approach a small grove of trees, they spot a mountain lion lurking in the shadows. The students freeze. They can feel their hearts pounding, their breath quickening, their muscles are tense, their palms sweaty. All they can see is the mountain lion as it crouches and prepares to attack. The students turn towards the mountain lion, waving their arms and creating noise in an attempt to ward it off. They hurl strewn rocks until the mountain lion finally retreats.

Weeks later, one of the students keeps remembering the encounter and experiencing distress, is having trouble sleeping and no longer wants to jog in the hills. The other does not show signs of distress after the initial shock.

Encountering a mountain lion ready to attack would be a very stressful event for most people. A pounding heart, shallow breathing and sweaty palms are all part of the body’s response to stress—an adaptive response which ensures our survival by preparing us to fight, flee or freeze in the face of threat. In the aftermath of this stressful encounter, why does one student experience lasting effects while the other has none?

In this chapter you will learn about stress and the stress response, the mechanisms regulating it, how stress affects brain circuits and behavior, and what sets up the variability between people in how they respond to stress.

What is stress?

Most of us will never encounter a mountain lion, but we have all experienced stressful situations or the feeling of being ‘stressed out’. Take a moment to think about a stressful situation you have experienced. How did it make you feel (physically, emotionally, cognitively)? Because stress is ‘personal’ (i.e., a subjective experience), it can mean different things to different people. In order to study it from a biological perspective, however, we need a scientifically tractable definition to start from. It can be helpful to distinguish between stress as a feeling, a stressor as a cause of stress, and the stress response in the body.

Hans Selye—the founder of the field of stress research—defined stress from a physiological viewpoint as “the nonspecific response of the body to any demand made upon it.” According to Selye, “anything that speeds up the intensity of life, causes a temporary increase in stress” (Selye, 1974). To fully understand this definition, we need to first define the concept of allostasis. Allostasis means “achieving stability through change.” It includes the mechanisms that maintain life-sustaining functions (for example, body temperature, blood sugar levels, fluid balance, etc.) which must be kept within a pre-set range (i.e., homeostasis). In addition, allostasis also includes processes that promote adaptation to challenge and expand our survival or coping capabilities. A classic example is fat accumulation in a bear preparing for hibernation. Fat accumulation is an anticipatory change that prepares the bear for survival during winter. Here, allostatic mechanisms accommodate this change, i.e., an expanded physiological state to promote survival.

Based on Selye´s definition, any stimulus that speeds up the intensity of life (be it good or bad, pleasurable or painful, real or implied), and perturbs the physiological and psychological integrity of an organism is defined as a stressor. Interestingly, these can be deviations in variable, and even opposite directions: exposure to extreme heat or cold, starvation or obesity, injury, or threat to one’s well-being, like when encountering a predator. The stress response is the body’s stereotyped physiological response to that stimulus. It is an evolutionarily conserved response and essential for survival. The stress response is orchestrated across all cells and tissues of the body to mobilize energy to support vital functions which are necessary to survive the immediate threat. For example, pumping glucose and oxygen to the heart, skeletal muscles and brain, and away from functions that are not pertinent to the immediate survival (e.g., digestion and reproduction). Regardless of the specific stressor that initiated it, the broad physiological response will largely be the same. For example in our mountain lion scenario, both the students (i.e., potential prey), as well as the mountain lion itself, experience a stress reaction during the encounter. It is important to note that a similar physiological cascade of events can be initiated by an internal cue, in the absence of a physical threat. One can be sitting in a room, thinking about a fearful situation, and this may be sufficient to mount a full physiological response.

Most of us have probably experienced the feeling of being ‘stressed out’, the point at which a stressor becomes too much (i.e., it lasts too long, is too intense, or too much for a certain person to deal with) and leads to detrimental effects on the body. The term ‘stressed out’ was coined by another of the founders of the field of stress research, Bruce McEwen, to mean only the negative aspects of the response. Scientifically this concept is referred to as allostatic (over)load or toxic stress.

The stress response

The stress response is a physiological reaction that occurs in response to an actual or perceived harmful event, attack or threat to survival, which results from the coordinated action of the central and peripheral autonomic nervous systems and endocrine (hormonal) system; to generate physiological, cognitive, cardiovascular and metabolic changes that allow an organism to respond to a perturbance, promoting survival and fitness.

Generally, an event (a stressor) occurs, like a mountain lion appearing on our morning run. Or there is the perception that a threatening event might happen. This can be hearing a roar, or the thought that a mountain lion was spotted here last week. This is briefly followed by an appraisal of the threat. This appraisal relies on neural activation in the amygdala (the brain’s alarm center), the prefrontal cortex (which regulates decision-making) and other circuits. And finally, there is a response to the threat (fighting, running away or freezing). The appraisal of the threat, the predictability of the stressor (whether you expected it or not) and sense of control over the situation (controllability) are three critical factors in mounting the stress response and in regulating its termination.

While the ‘fight-or-flight’ response is commonly referenced, there is also a freezing response. Freezing is a form of behavioral inhibition and functions to decrease the likelihood of detection since the visual cortex of many predators is programmed to detect moving objects. Freezing also reduces the chance that we make inadvertent sounds that other animals might detect. Freezing is not a passive state (i.e., the brain has not ‘stopped working’). Rather it allows for perception and preparation of further defensive responses.

Stress response over time

The body responds in different ways to short-term stress and long-term stress following a pattern known as the general adaptation syndrome (GAS). Stage one of GAS is called the alarm reaction. This is short-term stress, the fight-or-flight (or freeze) response, mediated by the sympathetic nervous system causing the adrenal gland to release the hormones epinephrine and norepinephrine. Their function is to prepare the body for extreme physical exertion. Once this stress is relieved, the body quickly returns to normal. If the stress is not soon relieved, the body adapts to the stress in the second stage called the stage of resistance. If a person is starving for example, the body may send signals to the gastrointestinal tract to maximize the absorption of nutrients from food. If the stress continues for a longer term however, the body responds with symptoms quite different than the fight-or-flight response. During the stage of exhaustion, individuals may begin to suffer depression, the suppression of their immune response, severe fatigue, or even a fatal heart attack. These symptoms are mediated by the hormones of the adrenal cortex, especially cortisol, released as a result of signals from the HPA axis.

Stress response functions

The stress response orchestrates all body systems so that they are primed and optimized to deal with the emergency situation at hand (Figure 33.1).

If an individual needs to quickly run away from something, what functions would support this? Attention needs to be focused on the situation right now, so there are brain connectivity changes that occur to promote vigilance and sharpen attention. Pupils dilate to better detect even faint stimuli. Quick and deep breathing occurs to increase oxygen supply to the heart, skeletal muscles, and brain. Similarly, there are metabolic changes that increase the energy supply (increased blood sugar and fat concentrations) in the blood. Blood pressure and heart rate increase and blood flow is diverted away from other parts of the body and redirected to the muscles. As muscles become more tense, trembling can occur. Blood vessels in the skin constrict since blood flow is being diverted to muscles, resulting in chills or sweating. Everything else, that is, all non-vital functions like digestion, kidney filtration, and reproduction are slowed down. Thus, there is a decrease in saliva production (a person’s mouth getting dry when they’re nervous or anxious) and the output of digestive enzymes decreases. A slowdown of food movement through the bowels also occurs.

Sympathetic versus parasympathetic nervous system

The autonomic nervous system (also known as the involuntary nervous system) regulates housekeeping bodily functions. The autonomic nervous system has two ‘branches’: the parasympathetic nervous system and the sympathetic nervous system. Both systems innervate the same organs, but in an opposing manner. The sympathetic nervous system is involved in the ‘fight-or-flight’ response whereas the parasympathetic nervous system mediates the ‘rest-and-digest’ functions (Figure 33.2).

The sympathetic nervous system mediates a rapid neural response to stress in two ways:

1. Direct innervation of organs/tissues to effect changes through neural signaling. This pathway originates in the hypothalamus and releases norepinephrine (noradrenaline) onto visceral effectors in target organs, e.g. the heart, lungs, stomach, liver, etc.
2. Through innervation of the adrenal gland, triggering the release of epinephrine (adrenaline) into circulation.

Epinephrine and norepinephrine are very similar in structure and function. Their downstream effects are broadly to increase heartbeat resulting in increased blood pressure, shunt blood away from the skin and viscera to the skeletal muscles, create a rise in blood sugar, and increase metabolic rate, bronchodilation, and pupillary dilation.

After a stressful event has passed, balance must be restored to the organism through deactivating the sympathetic nervous system and activating the parasympathetic nervous system. One of the ways to engage parasympathetic nervous system function is through deep breathing. This expands the diaphragm which stimulates the vagus nerve. The vagus nerve supplies parasympathetic information to visceral organs of the cardiovascular, respiratory, digestive and urinary systems and vagal stimulation activates the parasympathetic nervous system.

HPA axis stress response

Coincident with the sympathetic nervous system activation upon perceiving a stressor, the hypothalamic-pituitary-adrenal axis (HPA axis) is also activated, leading to a chain of events involving multiple glands in order to produce powerful and sometimes long-lasting effects. While the sympathetic nervous system activation takes milliseconds, the sequence of steps in HPA activation take several minutes to be triggered one after the other. Like the sympathetic nervous system, though, the HPA axis is typically tightly regulated by multiple excitatory and inhibitory signaling inputs, ensuring a rapid response to stressful events, and a timely shut down of the response and return to equilibrium.

The HPA axis consists of the tiered release of three hormones from the three structures/glands that comprise it (the hypothalamus, the pituitary and the adrenal glands). The sequence of steps is diagrammed in Figure 33.3.

The hypothalamus, which sits below the thalamus, integrates information from many regions of the central nervous system and plays a critical role in maintaining homeostasis in the body. When a stressor is perceived, the hypothalamus releases corticotropin releasing hormone (CRH) into the hypophyseal portal system, a small blood network that connects the hypothalamus to the anterior pituitary (step 2 in Figure 33.3). The pituitary gland is comprised of two distinct anatomical parts: the anterior pituitary and posterior pituitary. The anterior pituitary produces and secretes various hormones in response to signals from the hypothalamus. Most relevant to the stress response, CRH from hypothalamic neurons stimulates the anterior pituitary gland to produce and secrete adrenocorticotropic hormone (ACTH) into the systemic bloodstream (step 3 in Figure 33.3).

ACTH circulates throughout the body, eventually reaching the adrenal glands, which sit on top of the kidneys. ACTH induces the adrenal glands to synthesize release cortisol, a glucocorticoid hormone (step 4 in Figure 33.3). Glucocorticoids have massive and far-reaching effects on the body and brain, including increases in blood pressure, increased glucose circulation, decreased reproductive axis output, complex effects on immune functions and various other effects (step 5 in Figure 33.3).

In addition to glucocorticoids, the adrenal gland also produces epinephrine and various other hormones in response to the fast sympathetic nervous system  stress response described above. The adrenals are therefore a convergence location for HPA and neural components of the stress response, albeit via separate parts of the gland. Epinephrine/norepinephrine and cortisol result in mostly the same physiological effects. This is because the rapid neural response and slower HPA endocrine response converge on the same organ systems. At first glance, this seems redundant. This convergence, however, means that there are numerous spots for regulation such that if a particular mechanism fails, there is a backup mechanism that can orchestrate the same alarm response.

Effects of Stress: The Yerkes-Dodson Law

We now know that the stress response is critical to survival but it has also garnered the reputation of being detrimental to health and wellbeing. This brings up the question of valence: is stress always a bad thing?

It turns out that some amount of stress is actually good and can enhance performance in the same domains where too much stress is detrimental. This type of relationship where increasing amounts of some factor (stress in our case) results first in an increase and then a decrease of a second factor (performance for example) is referred to as an inverted-U relationship. This inverted-U relationship between stress and performance is referred to as the Yerkes-Dodson law (Fig 33.4).

Beneficial effects of stress

Notice that there is a point on the curve where performance reaches a peak, where attention gets very focused, rational thinking sharpens and emotional regulation is at its best: an optimal level of stress. This region of positive stress or eustress is defined as stress that is perceived as within an individual’s coping abilities, motivates and focuses energy, may feel exciting, improves performance, and can protect against future stressors.

The functions that support the stress response (e.g., sharpening of attention and focus, the increased energy supply in the bloodstream) create a physiological state which means that you are prepared and ready to tackle a challenge. For example, an upcoming final exam. You need to be focused and energized. Interestingly, viewing a challenge, for example, a slew of final exams or a tough new project at school or work as a positive thing can result in eustress. The key is not the stressor itself but how we perceive it. If we see it as an opportunity to learn new skills and showcase our abilities, we will feel energized and motivated to tackle it. On the other hand, if we perceive this as an obstacle or something beyond our coping capacity, we will not feel these positive effects of eustress and instead will likely feel signs of distress. Thus, the mindset with which we approach stress can have a significant impact on the outcome. Reframing stress-induced physiological reactions like a ‘racing’ heart as helpful and adaptive versus harmful has been shown to result in improved cognitive and physiological outcomes during/after a stressor (Jamieson et al., 2012).

Detrimental effects of stress

When there is too little or too much stress (negative stress or distress), performance is decreased. With too little stress or stimulation, there might be impaired attention, boredom or even apathy. With too much stress (chronic or traumatic stress exposure), performance declines even further, resulting in impaired memory and executive functions or even burnout. Eventually, this could lead to the development of psychiatric disorders, for example, anxiety, depression, posttraumatic stress disorder (PTSD) or other stress-related pathologies.

An important question, then, is when exactly does stress become detrimental? There is no exact answer because it differs from person to person based on an individual’s genetics, epigenetics, life history, capabilities/resources at the moment the stressor occurs, appraisal of the situation and other factors. All of these vary amongst individuals and some factors will vary even for the same person at different times.

Allostasis vs. allostatic (over)load

The stress response is a necessary, survival-promoting response that allows us to adapt to challenges. What happens, however, if this response is activated for too long or too often, as a result of repeated exposure to stressors, or lack of proper shut down?

The continuation of the beneficial, life-saving aspects of stress that become detrimental when they are prolonged or chronic. Think about the acute effects of stress. For example, you are confronted with a stressor and your blood pressure increases because that is what is needed in order to run away from the threat. But, if your blood pressure is increased constantly, that becomes your new set point and now you have hypertension. Hypertension is a disease that affects most organ systems in the body. In the long-term, it increases wear and tear on many systems and accelerates the aging process. Other bodily systems are similarly affected. The immune and reproductive systems are turned down leading to immune suppression and reproductive distress/dysfunction. In the digestive tract, you can develop ulcers and decreased nutrient absorption. If the excessive stress exposure came early on in life, it can result in stunted growth. In terms of metabolism, glucose thrown into the bloodstream helps the muscles in the short run (escaping the threat) but can lead to diabetes if chronic. Similarly, in the brain, prolonged or severe stress exposure can lead to regional changes in brain structure (dendritic hypo/hypertrophy, remodeling, circuit plasticity) that can alter brain function and lead to pathologies such as anxiety, depression, and PTSD.

Allostasis refers to the processes that restore homeostasis and also allow us to adapt through change. Our body’s activation of the nervous, endocrine (and immune) systems during a stress response, for example, are allostatic mechanisms that allow us to adjust and increase our resilience in the face of stress. Allostatic (over)load, on the other hand, is the physiological cost of that adaptation to our body, i.e., the ‘wear and tear’ that accumulates after repeated or chronic stress exposure (Figure 33.5).

Types of allostatic (over)load include:

1. Frequent activation of allostatic systems: e.g., repeated hits from multiple stressors resulting in overexposure to stress hormones.
2. Lack of adaptation to a repeated stressor: e.g., not getting used to public speaking.
3. Failure to shut off stress response activation after the stressor has passed: i.e., the inability to efficiently shutoff the stress response resulting in overexposure to stress hormones.
4. Failure to adequately activate the stress response: e.g., an inability to mount the proper HPA activation.

These are not mutually exclusive. There can be combinations of these occurring at the same time. Ultimately, continual or chronic stress exposure results in allostatic (over)load. Allostatic (over)load serves no useful function and can predispose individuals to stress-related disorders and pathology.

References

Adapted from

Kirby, E. D., Glenn, M. J., Sandstrom, N. J., & Williams., C. L. (2024). Introduction to Behavioral Neuroscience. Open Stax. Retrieved from https://openstax.org/books/introduction-behavioral-neuroscience/pages/12-1-what-is-stress

Betts, J. G., et al., (2022). Anatomy and Physiology 2e. Open Stax. Retrieved from https://openstax.org/books/anatomy-and-physiology-2e/pages/17-6-the-adrenal-glands

Jamieson, J. P., Nock, M. K., & Mendes, W. B. (2012). Mind over matter: Reappraising arousal improves cardiovascular and cognitive responses to stress. Journal of Experimental Psychology: General, 141(3), 417–422. https://doi.org/10.1037/a0025719