Great Ideas from the Brain Sciences: the Stress Response
By: Mirela C. C. Ramacciotti
In this issue dedicated to Rest, there might be some of you wondering why I’m writing about stress. The reason is simple enough. Rest is the natural, biological stress antidote. If you do not give rest serious consideration, chronic stress might set in. That is something our bodies are not meant to deal with, especially during the school term.
As usual, in this article I’ll guide you through main discoveries made in the brain sciences that led to our current knowledge about stress. Meanwhile, I’ll also explain in more neurobiological terms what a stress response is and why it is not something our bodies should endure without a heavy cost. That, by the way, was the underlying topic of one of my doctoral dissertations and what follows is heavily based on that work (Ramacciotti, 2022).
Let’s start with a working definition of stress. Stress here refers to a set of reactions to adverse or threatening situations. These situations can be physical or psychological – that means that what might seem neutral for one person, might be perceived as threatening by another. Once the person perceives a stimulus as threatening, at an unconscious (most often) or conscious level, the result is a physiological and behavioral response.
Thus, the factors that lead to a stress response vary for each individual. That is the first lesson we need to understand. The second lesson is easier because it involves all of us, that is, what our stress response looks like once it is triggered. In this article, we will take a tour spanning over two centuries of important discoveries.
Claude Bernard coined the term internal milieu in 1879. What he meant by that is that the body’s internal environment is in constant change. That was an important stepping stone for Walter Cannon’s work in 1929, when he defined homeostasis as the balance of bodily functions and feelings for optimal wellbeing. In the following decade, in 1936 more precisely, Hans Selye set in motion a more systematized understanding of what the body was doing when presented with an adverse stimulus. He laid out the three phases—alarm, resistance, and exhaustion—that together compose the physiological defensive reaction processing of any adverse stimulus. This became known as the general adaptation syndrome. Some decades after that, in the year of 1988, Peter Sterling and Joseph Eyer coined the term allostasis, meaning the dynamic process of seeking homeostasis (via mediators like cortisol). This transient process promoted adaptation when dealing with environmental changes. A decade later, Bruce McEwen developed the field in great leaps and bounds by bringing to the fore the concepts of allostatic load, the bodily wear and tear incurred in adapting to adverse psychosocial or physical conditions, and adaptive stress, a positive set of mechanisms that enhance survival chances. At the turn of the century, Antonio Damasio developed the concept of homeostatic feelings. The driving force for this concept lies in its interactional dimension. In other words, Damasio proposed that our bodily functions operate in sync with our emotions. But such operation does not happen at fixed set points; rather, he proposed that it fluctuates within ranges, at an individual level, according to cultural and temporal constraints (Damasio & Damasio, 2016).
Readers of the Great Ideas in Brain Sciences series must have noticed how I love an analogy. This time round, I’ll aim high to connect the historical aspects of our understanding of the stress response to how the brain processes stress. This was also part of my doctoral dissertation and I’ll paraphrase here. Not to mince words, I’ll invoke Tolstoy’s much-loved novel Anna Karenina. In its opening, he states: “Happy families are all alike; every unhappy family is unhappy in its own way” (1875-1877/2001, p. 1). These lines have since served to illustrate how different aspects, or variables, co-occur in an (unsuccessful) trajectory. The same can be said of learning.
For a complex behavior such as learning, many factors come into play. These factors can be internal, like motivation and memory, or external, like getting a good grade. Further, such factors may occur in isolation, for instance, in the case of students who show greater or lesser degrees of motivation to learn something. The same factors may occur together for optimal learning, as when attention and memory are recruited because students feel motivated to learn about something.
However, a failure in any single factor may jeopardize the whole enterprise that learning entails. That is how the Anna Karenina Principle (AKP) works. This principle appeared first in a geographical context (Diamond, 1994; 1997) and later in other sciences (Bornmann & Marx, 2012). The AKP is simple yet profound: components of any complex construct have to behave within a certain range to allow for the desired success. In other words, the absence or less-than-good performance of any variable can account for overall failure (Bornmann & Marx, 2012). It is all or nothing—much like the potentiation in our synapses (if you want to learn more about this, check https://www.youtube.com/watch?v=mYq1mi8fLaQ ). AKP is applied to learning, all factors matter: cognitive factors, such as attention and memory, are intertwined with emotional states, such as motivation and anxiety, and have biological underpinnings, like different stress response profiles, affected by contextual modulators, like a threatening stimulus, to combine into a general behavior. This behavior is adaptable to contextual factors, such as stressors, within a range. Let me illustrate this.
Imagine a student who is under chronic stress, such as violence at home. In class, that student does not pay attention to the task at hand and could not care less about getting a good grade. Thus, attention, memory, and motivation are out of the equation when stress is in. As a result, learning is doomed. Therefore, how nature responds to nurture in learning should be considered. And this starts with the brain.
As you might have noticed, the stress response starts in the brain. There are two mechanisms, or axes, responsible for this processing. One is fast and the other is slow, but both are activated when stress sets in.
When a stimulus is perceived as threatening, our brain detonates a stress response that mobilizes the autonomic Sympathetic nervous system and the Adrenal Medulla, that is, the SAM axis. It is characterized by the fight-flight mechanism with regard to the perceived threat. It is mediated by catecholamines, that is, epinephrine and norepinephrine. In this axis, they act as stress hormones enabling the fast reaction to a threat in a situation of acute stress response. Let’s break that down.
Deep in the brain, our gateway for emotional processing, the amygdala, signals an affective or aversive valence of a stimulus. If the stimulus is considered aversive and threatening, the signal is sent to a very close structure, central to our control system, the hypothalamus. I say central because it controls our heart rate, blood pressure, sleep cycles, and body temperature. It also detonates the fight-flight response involving the SMA axis. This triggers the release of stress hormones (epinephrine and norepinephrine) to enable the musculoskeletal, respiratory, and cardiovascular changes needed to fight or to flee. That is a neurobiological first response craftily engineered by nature to serve a higher purpose: survival.
Simultaneously, but at a slower processing rate, a second mechanism gets activated involving the Hypothalamus, the Pituitary gland, and the Adrenal cortex, the HPA axis. This axis acts as a feedback system, signaling adaptation or maladaptation to environmental conditions. In tandem, both axes constitute the ability of each organism to respond to contextual stressors.
If the stressor goes away, bodily functions revert to ordinary operating conditions—the homeostatic balance—and life proceeds. However, if after the acute stress response, there is the lingering sensation that the body is still threatened (the stressor remains), chronic stress sets in. That can cause physical and psychological harm (Ramacciotti, 2022). Let’s break that response down by examining the slower axis this time.
As before, it all starts in the amygdala. When processing the valence (positive or negative) of a stimulus, the amygdala works like a “switch-on button” for the HPA axis, alerting the brain to a stimulus that is perceived as threatening. This signal is passed onto the hypothalamus, where a lot is happening. It is there that a hormone is released and cascades into a stress response. The hormone has a name: the corticotropin-releasing hormone (CRH) produced at the center of the hypothalamus, in its paraventricular nucleus (PVN). That is why the PVN is regarded as the “core” of the HPA axis.
The cascade travels downstream and is joined by a peptide hormone called arginine vasopressin (AVP). This hormone regulates water consumption and blood pressure. Once we realize that under stress we forget about going to the toilet and feel our heart in our mouths, we quickly understand why this hormone is part of the process.
So, CRH and AVP flow into the pituitary gland, this time to stimulate the production of another hormone, the adrenocorticotropic hormone (ACTH). That hormone is an important messenger as it delivers the molecules necessary for the adrenal glands to release glucocorticoids, that is, cortisol being the main hormone in that class which is widely connected to stress (Ramacciotti, 2022).
Now, there is a very interesting characteristic of glucocorticoids: they are liposoluble. In other words, they dissolve in fat. Let’s take a breather here and tackle this fact from another angle.
Your attentive mind might remember that our brain is heavily protected. Nature and evolution have carefully designed an organ that is covered by bone, the skull, different layers, the meninges, and also a barrier that prevents most substances from finding their way into the brain. This is the blood-brain barrier and it repels water molecules, that is, it prevents most of what circulates in our body from getting into the brain. However, it has a layer that is made of fat. That means that fat molecules can get into the brain. Now comes the time to connect the dots.
As we have seen, cortisol is a glucocorticoid and hormones in that class are steroids. That means they control enzymes that break down fat. In sum, they regulate energy homeostasis by controlling our lipid (or fat) metabolism. By breaking down fat, cortisol crosses the blood-brain barrier. In short, cortisol flows from the adrenal glands to the brain to signal whether adaptation has happened or not.
According to the levels of cortisol, the brain decodes the signal, that is, it processes the message to keep active or shut off the stress response. If the stressor is no longer present, the mechanism gives negative feedback and the HPA axis ceases excessive activation. Such feedback is essential for our homeostasis.
Now comes the time to connect all this to learning. The HPA axis activity is involved in learning processes because its regulation involves the hippocampus. As it is a target for glucocorticoids and a hub for memory formation, the hippocampus has the task of switching off the stress response. In this process, it also enables the creation of memories regarding the valence of the stimulus so that, the next time round, we may learn not to activate the stress response for something that is not threatening.
However, if the stressor remains and the hippocampus does not switch off the stress response, we may end up with problems of a physiological nature, as in reduced capacity to form memories, and others of a behavioral nature, as in a forgetfulness fits, plus harm to our neural plasticity (Ramacciotti, 2022).
Neuroplasticity, as we all know, is the brain property that allows us to change and adapt successfully to contextual demands. Brain regions that have a greater number of glucocorticoid receptors — such as our watchtower of brain functions, the prefrontal cortex or PFC, and the hippocampus — become a larger target for stress-related effects. That is how our learning capacity is affected by a chronic stress response.
So now we come to our takeaways: 1. Rest is an antidote to stress; 2. What detonates a stress response is different from person to person; 3. Stress activates two different axes and both contribute to a fast response (flight-fight) and to a more delayed, crucial response that contributes to our survival in the long term by encoding information about what to regard as threatening; 4. Chronic or negative stress impacts learning processes at a very deep, molecular level; and 5. We should all learn that having a stress response may protect us from immediate harm but should never remain active for prolonged periods.
References
Bornmann, L., & Marx, W. (2012). The Anna Karenina principle: A way of thinking about success in science. Journal of the American Society for Information Science and Technology, 63(10), 2037-2051.
Damasio, A., & Damasio, H. (2016). Exploring the concept of homeostasis and considering its implications for economics. Journal of Economic Behavior & Organization, 126, 125-129.
Diamond, J. (1994). Zebras and the Anna Karenina principle. Natural History, 103(9), 4-10. 36.
Diamond, J. M. (1997). Guns, germs, and steel: The fates of human societies. W. W. Norton.
Ramacciotti, M. C. C. (2022). Neurobiological aspects of individual differences in early childhood education: an investigation of executive functions and stress response. PhD Thesis, Institute of Psychology, Neuroscience and Behavior Program, Universidade de São Paulo, São Paulo. https://teses.usp.br/teses/disponiveis/47/47135/tde-03102022-152249/publico/Ramacciotti_corrigida.pdf
Tolstoy, L. (1875-1877/2001). Anna Karenina (Original work published 1875-1877). Viking Penguin.
Mirela C. C. Ramacciotti is presently engaged as an external lecturer on the topics of Mind, Brain, and Education and the Bayesian Brain at the Graduate Level Course with the Psychology Department at the University of São Paulo. She holds a PhD in Neuroscience and Behavior and another in Human Communication Disorders.