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The Anatomy of Stress

illustration stress 01

© Rocco pour le Journal du CNRS


All it takes is a small upset, a new situation to deal with, or a tough task at hand, and suddenly your stomach tightens, your heart beats faster, and you find it hard to sleep. But behind this anxiety lies a biological mechanism that is not only quite normal, but actually beneficial. Any disturbance to the environment, whether it’s physical (cold, hunger, infection, etc.) or emotional (fear, mourning, deadlines, etc.), triggers a response from the body aimed at guaranteeing its survival by maintaining its internal balance. For instance, it’s stress that makes us react instantly when faced with danger. It’s nothing more than a means of defense that is both physiological and cognitive, based on complex interactions between the nervous and immune systems, hormones and even the mind. In fact, it’s only when the disturbances are too intense or too repetitive that detrimental effects make their appearance. Stress can then become pathological and lead to cardiac, digestive, immune, or mental disorders. “Stress is perhaps the phenomenon which most closely brings together the body and the mind,” points out Jean-Michel Thurin, a psychiatrist and psychoanalyst at the Pitié-Salpêtrière hospital in Paris. “The physiological and psychological reactions both use the same pathways which can reinforce each other.” This is what causes the direct link between emotional stress and its physical expression and, in some extreme cases, ailments such as ulcers, high blood pressure, or eczema. It might be hard to see it as a beneficial mechanism, when no matter your age, stress seems to be increasingly weighing down on you in your everyday life, at home and at work. In our society, where we are constantly pushed to achieve more, stress is fast becoming an ailment that can no longer be ignored.

A BRIEF HISTORY OF STRESS
The first studies relating to stress–called something else at the time–date back to the end of the 19th century. In 1878, the French physiologist Claude Bernard introduced a concept still relevant today: the constancy of the internal environment. It is based on the principle that, faced with a continuously changing external environment, all living beings need to preserve a certain internal stability. It was in 1932, about 50 years later that this idea was revived and further developed by American physiologist Walter B. Cannon in his work entitled “The Wisdom of the Body.”
Cannon described the mechanisms that governed such constancy of the organism, which he dubbed homeostasis (from the Greek homeo, “similar” and stasis, “condition”). He was the first to use the word “stress”–which he borrowed from the vocabulary of mechanics–to refer to the aggressions that were likely to upset homeostasis.
But the real turning point came in the
1940-1950s, with the work of the Canadian endocrinologist Hans Selye, who was then director of the Institute of experimental medicine and surgery at the University of Montréal. On the basis of numerous experiments on rats, he drew up the first complete theory of “medical” stress. For Selye, stress was indeed “a non-specific response of the body to any demand that was made on it.”1 He named this response the “general adaptation syndrome,” and identified three stages: alarm, resistance, and exhaustion (see diagram below). The first stage corresponds to the full set of responses by the organism to a sudden disturbance, and the second to the responses set up in the event of a lasting disturbance. As for the exhaustion stage, this occurs when the body is no longer able to adapt. This is followed by the numerous complications caused by stress, frequently characterized by inflammatory diseases.
This description, which is still valid today, was accompanied by a rough outline of its physiology: Selye revealed the importance of the hypothalamic-pituitary-adrenal axis–or HPA axis–which is made up of an area of the brain, the hypothalamus, an endocrine gland attached to the hypothalamus, the pituitary gland, and two other endocrine glands, the adrenal glands, located above the kidneys. The importance of the HPA axis has never been challenged, though we now know that this “axis of stress” is not the only one in cause. “Stress involves four major systems which constantly interact: the HPA axis, of course, but also the sympathetic and parasympathetic nervous systems,2 the immune system, and finally the brain–especially the areas involved in emotions, memory, and mood regulation,” Thurin explains.

THE BIOLOGICAL FACTOR

What does happen when we are subjected to stress? The initial stage in the chain of events that triggers the general adaptation syndrome lies in the interpretation of the stress-inducing factor. It is the most primitive areas of the brain that trigger the alarm, the so-called limbic system,3 which counts the amygdala and the hippocampus–the two brain structures most involved in the formation of memory and emotions. As soon as the alarm is given, the sympathetic nervous system springs into action. It releases noradrenaline and stimulates the production of adrenaline by the adrenal glands. These two hormones have an effect on a number of organs: on the heart to increase cardiac output, on the blood vessels to increase arterial pressure and massively irrigate the muscles, brain, and heart to the detriment of the skin and viscera, on the lungs to dilate the bronchial tubes and increase breathing rhythm, on the liver to trigger the release of glucose from the energetic resources, and so on. They also put the brain in an increased state of alertness. All these rapid reactions have one single objective: to prepare the body against a sudden, stressful event lasting anything from several minutes to an hour–a conversation, a math exam, or a parachute jump.

souris

© A. Chézière/CNRS phototèque

Mice raised in a stress free environment choose to spend less time in a compartiment associated with the administration of drugs.




If the stress-inducing factor continues, the body then moves into a stage of resistance (called allostasis) in which the brain’s limbic structures activate the HPA axis. The hypothalamus then produces corticotropin-releasing factor (CRF), which acts on the pituitary gland, causing it to produce several hormones including the adrenocorticotropic hormone (ACTH). The latter then causes the release of glucocorticoids, especially cortisol, by the adrenal glands. These hormones, like adrenaline and noradrenaline, have the ability to stimulate both the release of glucose–our body’s fuel–and its absorption by cells. At the same time, together with CRF and ACTH, they inhibit certain energy-consuming functions such as growth and reproduction. Lastly, they play a very important role in the self-regulation of stress: By blocking the synthesis of CRF and ACTH, cortisol and related hormones limit their own production. This is what is called a negative feedback loop, something that prevents the system from spiraling out of control. “The sympathetic and HPA systems work closely together,” Thurin explains. “It is generally thought that the autonomous nervous system is the emergency mechanism put in place not just for physical and mental activity, but also for the immune system, and that it is then regulated by the cortisol axis. The latter intervenes at a more regular pace, better suited to the longer term.”
If overused, however, these systems can malfunction. This heralds the appearance of the detrimental physical and mental symptoms of chronic stress. The body’s energy reserves run out, and fatigue sets in. And the longer the stress lasts, the less the body
is able to control it. “Confronted with the high levels of glucocorticoids caused by chronic stress, the cells that are sensitive to them react by reducing their number of hormone receptors, in order to avoid over-activation,” explains CNRS researcher Michèle Crumeyrolle-Arias.4 “This reduction means that glucocorticoids no longer play their role as a feedback control on stress. In fact, it’s interesting to note that such effects are comparable to those seen in old age, which also causes defective control of the glucocorticoids.”
Moreover, these hormones have the ability to inhibit immunity, which can eventually lead to many types of disease. So why is it that stress hormones undermine our defenses against invaders? Once again, it is undoubtedly to stop the system from spiraling out of control. In the event of physical stress–like an infection–the chemical messengers emitted by the immune system are able to activate the HPA axis and hence the general adaptation syndrome. By inhibiting immunity, the glucocorticoids exert a second feedback control, which this time is used to moderate the immune response. “It’s just as though the immune system was under the surveillance of the neuroendocrine system,” Crumeyrolle-Arias points out. But in the event of chronic stress, the glucocorticoids–the production of which is no longer under control–continue to undermine immunity. This explains why we are more vulnerable to disease when under stress.

OPENING THE BREACH
Albeit not the cause of diseases, stress is still an aggravating factor for many of them. It is now proven that stress increases the risk of cardiovascular diseases. An epidemiological study carried out in the late 1980s by Italian researchers5 showed that the effect of everyday stress was to gradually increase blood pressure. This result was obtained by monitoring two groups of women over a 20-year period. One group consisted of nuns living in a convent–in silence and meditation–while the other was made up of working women. Protected from the commotion of daily life, the nuns had kept their blood pressure unchanged over 20 years. And this is just one of the many studies clearly linking stress and high blood pressure. There exist a number of other studies that similarly link stress with digestive problems, skin diseases (such as atopic dermatitis, psoriasis, or alopecia areata), type 2 diabetes, or certain autoimmune diseases like lupus. Even our weight can be affected by our stress levels, since the activation of the HPA axis can lead to a stimulation of food intake and hence promote obesity.
And these aren’t the only detrimental effects of stress. In Poitiers, the team led by Mohamed Jaber,6 professor of neurosciences, is studying the connection between life events and drug dependence. “Our aim is to elucidate the relationships between genetic background, the environment, and vulnerability to drugs and toxins,” Jaber explains. Several experiments had already shown that stress hormones facilitated cocaine addiction.7 Working with two other teams–one in Bordeaux,8 led by Pier Vincenzo Piazza, the other in Paris, led by François Tronche9–the researchers in Poitiers studied the reaction to cocaine of transgenic mice lacking glucocorticoid receptors. The experiment showed that the mice, whose reactions to stress are of course altered, resist addiction considerably better than their normal peers. “The transgenic mice are far less inclined to self-administer cocaine and don’t develop any sensitization,” Jaber explains. So it really is via the glucocorticoid receptor that stress hormones increase the effects of cocaine.” But then, shouldn’t chronic stress, which leads to the loss of these receptors, also have beneficial effects with respect to drugs? For Jaber, the answer is no. “Even though chronic stress reduces the number of receptors, and therefore feedback, those that remain are nonetheless activated by the very high concentrations of glucocorticoids in circulation. So stress hormones can still have an influence on the brain’s affinity for drugs.”
On the other hand, a so-called enriched environment–i.e., one that is stimulating without being stressful–limits addictive behavior. Mice raised in larger than average cages equipped with a nest and toys that are regularly changed have greater resistance to the addictive effects of drugs. But is this transposable to humans? It’s hard to say from the purely neurobiological standpoint, but according to Jaber, “several epidemiological studies have already shown that people born in a deprived environment–which is therefore potentially stressful–are at greater risk of getting into drugs than those from a better-off background.’”
Between disease and addiction, chronic stress can really endanger our health. Amazingly enough, this is true right from the moment we’re conceived. It has now been proven that stress can have profound repercussions on babies–even on fetuses. Studies on animal models show that premature stress–such as prolonged separation from the mother–increases cortisol levels in infants, and causes them to reject the mother. Although studies like these are harder to carry out on humans for obvious ethical reasons, it has been shown that prolonged separation–though not significantly increasing cortisol levels–has a negative influence on the mother-child relationship.
At the prenatal stage, stress caused by a difficult pregnancy or one during which the mother suffers a traumatic event, increases the risk of premature birth and subsequent disorders, like gastroesophageal reflux. As for children, repeated stress can slow growth and lead to what specialists call “psychosocial dwarfism.”

souris 2

© A. Chézière/CNRS phototèque

The mice raised in an enriched environment, one which is spacious and pleasant, have greater resistance to the addictive effects of drugs.





FROM BODY TO MIND
Although stress is an adaptive response by the body, it doesn’t just come down to a straightforward biological response. “Stress is also cognitive,” points out Roland Jouvent,10 director of the Emotion Center in Paris.” It depends just as much on our personality and on our memory.” Not every disturbance in our environment necessarily sets off a severe state of stress. In fact, stress frequently only occurs when we don’t feel able to deal with the disturbance, a phenomenon known as “coping.” A situation we feel we can overcome, or one which we’ve already experienced, causes less stress. The connection between stress and memory is all the stronger since memory is partly controlled by the limbic structures–the areas of the brain that are also responsible for triggering the adaptation reaction. The intensity of the stress also depends on our state of mind (whether we’re depressed or not), our personality traits (sense of humor, pugnacity, pursuit of pleasure and self-fulfillment), and our beliefs. It can even depend on our social interactions. “A calm social environment strongly limits our states of stress,” Jouvent says. “Whereas some types of collective stress can cause group panic, by paralyzing the individual’s ability to reason.”

virtuel

© H. Raguet/CNRS phototèque

Virtual reality can be used to overcome distressing situations. The patient , immersed in a distressing virtual environment, gradually overcomes his fear.




While most of us more or less manage to control stress, some people are absolutely incapable of doing so. They may then suffer from what psychiatrists call anxiety disorders. Panic attacks, social phobia, obsessive-compulsive disorder (OCD), and post-traumatic stress are all anxiety disorders which are caused by excessive, poorly controlled states of stress. “Generalized anxiety disorder (GAD), for instance, associates several symptoms of long-lasting stress,” explains Antoine Pelissolo from the Emotion Center, also a psychiatrist at the Pitié-Salpêtrière hospital. “The patients are incapable of coping with the uncertainty of the future, or of controlling minor stress factors that occur in daily life. They show both generalized anxiety and an inability to relax their vigilance which is biologically associated with hyperactivity of the sympathetic system.” For people affected by anxiety disorder, there is a disturbance of the systems based on serotonin, which is a neurotransmitter involved in a host of functions like the sleep-wake cycle, pain, or motor control. As a result, they suffer genuine mental strain unlike those who suffer from straightforward “chronic stress,” for whom only the HPA axis is severely put to the test. But is it possible to treat this type of disorder? “Of course we have drugs for this. They are based on antidepressants that inhibit serotonin recapture–they should really be called emotional regulators– and are preferable to minor tranquilizers, which cause dependence,” Pelissolo explains.
“Some types of psychotherapy, like cognitive-behavioral therapy (CBT), are also very effective against anxiety disorders.” At the Emotion Center, researchers are even studying the possibility of treating anxiety disorders–and especially certain phobias–with new technologies. At the forefront of this is a virtual reality system used to immerse patients in an environment they find distressing (this could mean placing an agoraphobic in the middle of a city, for example) and gradually let them overcome their fear. “Although completely paralyzed at first, our patients eventually manage to move around the virtual environment,” says Jouvent. This type of therapy appears to let patients gradually regain confidence once they come back to reality.
As for the majority of people who don’t suffer from anxiety disorders but nevertheless have to deal with the stress of daily life, Pelissolo’s advice is simple: “Have a healthy lifestyle, give yourself a break from time to time, stand up for yourself and know when to say ‘no,’ cut down on–or even give up–anxiety-provoking substances like tobacco or alcohol. Start exercising, and above all, go out and meet people.”

Fabrice Demarthon

Stress under the microscope
oxygen or glucose, or infections, are all types of stress that threaten our cells’ survival. To protect themselves, they have a battery of proteins known as heat-shock proteins or chaperone proteins. “Chaperone proteins form a universal mechanism of response to toxic attack,” explains Michel Morange, senior researcher at ENS in Paris.1 “They are synthesized in large quantities during the initial stress and are used to improve resistance during subsequent stress.” For instance, some of these molecules–which are called chaperonins, and are cage-shaped–have the ability to isolate damaged cell proteins and thus facilitate their repair. But is there a connection between stress in organisms and stress at the cellular level? “We don’t really know,” Morange admits. “The data are contradictory depending on the tissue and the situations, and there doesn’t appear to be a general rule. Not everything that goes on in the body can necessarily be traced back to the level of the cell.”
F.D.
1. Régulation de l’expression génétique (CNRS / École normale supérieure Paris).
Contact : Michel Morange, morange@biologie.ens.fr
The positive side of stress
At first sight, stress, which is the body’s normal reaction to a disturbance in the environment, appears to be beneficial. With this observation in mind, Éric Le Bourg, at CRCA, in Toulouse,1 studies the effect of mild stress on fruit flies. “Mild stress at an early age, like a two-week exposure to hypergravity,2 or a brief exposure to a temperature of 0°C, slightly increases longevity and resistance to subsequent stress, and delays the behavioral signs of aging. Stress of this kind enables the flies to improve their resistance to very hot weather when they are old.” Does this mean that mild stress might be good for us? It all depends on the type of stress. Slight emotional stress, induced by job interviews or exams for example, clearly does appear to reinforce certain organism functions such as memorization or immunity (unlike chronic stress). For the other types of stress, the research has yet to be done.3 With respect to toxic substances, Éric Le Bourg has a word of warning: “This work in no way justifies what certain lobbies say when they fail to suppress toxic emissions in the environment, on the pretext that low doses are not harmful to humans, and could in fact even be good for them.”
1. Centre de recherches sur la cognition animale (CNRS / Université Toulouse-III).
2. Gravity higher than normal gravity.
3. See “Mild stress and healthy aging. Applying hormesis in aging research and interventions,” Le Bourg E. and Rattan S.I.S. (editors), Springer, 2008, ISBN 978-1-4020-6868-3.
Contact : Éric Le Bourg, lebourg@cict.fr

Notes :

1. From “Stress, pathologies et immunité,”
Jean-Michel Thurin and Nicole Baumann (eds), Editions Flammarion, 2003.
2. The sympathetic and parasympathetic nervous systems correspond more or less to a car's accelerator and brakes. The sympathetic system puts the body on alert and prepares it for physical activity. Its neurotransmitter is noradrenaline. The parasympathetic system does the opposite and is chiefly active during rest and recovery. Its neurotransmitter is acetylcholine.
3. The limbic system is made up of a number of areas of the brain involved in the sense of smell, emotions, learning, and memory. From an evolutionary point of view, these are some of the oldest structures, since they are found in many other species.
4. Neurobiology and psychiatry unit (Inserm / Université Paris-XII).
5. Timio et al., “Age and blood pressure changes: a 20-year follow-up study in nuns in a secluded order,” Hypertension. 12: 457-461. 1988.
6. Institute of physiology and cell biology (CNRS / Université de Poitiers).
7. Mainly carried out by Pier Vincenzo Piazza and Michel le Moal, at Inserm.
8. Unit for psychobiology of adaptive behavior (Inserm / Université Bordeaux-II).
9. Laboratory for Molecular genetics, neurophysiology, and behavior (CNRS / Collège de France).
10. Vulnerability, adaptation, and psychopathology unit (CNRS / Université Paris-VI).

Contacts :

Jean-Michel Thurin, jmthurin@internet-medical.com

Michèle Crumeyrolle-Arias, crumeyrolle@creteil.inserm.fr

Mohamed Jaber, mohamed.jaber@univ-poitiers.fr

Roland Jouvent, rjouvent@ext.jussieu.fr

Antoine Pelissolo, antoine.pelissolo@psl.aphp.fr


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