Neurobiology of Stress

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Basic Mechanisms of Stress

Although stress appears in a negative sense in daily life, it is divided into two as good and bad stress in the literature. While good stress is the stress we experience while acting towards achieving a short-term and challenging job; Bad stress is referred to as a type of stress that is long-lasting, emotionally exhausting, and over which the person has no control. The most important indicator of the stress response is the activation of the autonomic nervous system and the hypothalamus-pituitary-adrenal (HPA) axis (McEwen, 2007). These two systems are activated in nature in response to deadly threats such as predators and natural disasters. Even if modern humans do not face such deadly threats today, stress is a part of life, especially for urban people. This is because the aforementioned mechanisms still have central roles in the human brain; but the threats that cause the evolution of these mechanisms are not encountered in urban life. This change in the lives of modern people has caused the events that we encounter as a matter of life and death in the evolutionary process to be replaced by factors such as life-long exams, noise pollution, economic problems, social exclusion and interpersonal conflict (Sapolsky, 2017). Therefore, city life activates these mechanisms, which have evolved to process momentary mortal threats, more frequently than in nature.

Studies to understand the damaging and protective factors that cause stress have led to the emergence of the terms allostatic and allostatic load or overload. While allostasis defines the emergence of processes such as the secretion of stress hormone in order to maintain the self-balance (eng. homoestasis) in the face of a stressful situation; allostatic overload describes the damage caused by allostatic in the body (McEwen, 2007). These damages occur as a result of disturbances in allostatic processes, especially when stress hormone production is not stopped. However, the disorders caused by stress are not limited to the mentioned autonomic nervous system and HPA axis. Stressful events experienced by individuals have representations in the entire cortex through the hypothalamus; It can cause damage even in the frontal area, where high-level cognitive activities such as attention and decision making take place (McEwen, 2007). This situation causes people to struggle with stress disorder during early life experience stressful-traumatic events and also leads to deterioration of cognitive functions in people (Brunson et al., 2005).

Researchers examining the relationship between aging and stress weathering hypothesis’ i(tr. attrition hypothesis) has been put forward (McEwen, 2007; Sapolsky, 2017). With this hypothesis, researchers suggested that stressful events accelerated aging. For example, Gerlach and McEwen (1972) observed adrenal steroids in the hippocampal formation where memory, spatial and contextual memory is processed. This observation showed that the factors that emerge as a result of the stress response affect the brain area where memory is stored and processed. The hippocampus is involved in terminating the stress response of the HPA axis, and it is known that damage to the hippocampus causes longer HPA axis responses as well as impairments in this termination task (Herrman & Cullinan, 1997; cited from McEwen 2007). This is aging and stress. glutocorticoid cascade (tr. glutocorticoid cascade) hypothesis (Sapolsky, Krey & McEwen, 1986). This hypothesis suggests that the glutocorticoid hormone secreted in the adrenal cortex with aging causes damage that accumulates over time in the brain regions that stop this secretion process, and that this damage causes disturbances in the secretion arrest process with advanced age (Figure 1). While the researchers did not show the validity of the findings in primates and humans in 1986 rat studies, the hypothesis was shown to be valid in their subsequent studies (Sapolsky, Krey & McEwen, 1986; McEwen, 2007). Similarly, Lupien et al. (1998; quoted from McEwen (2007)) predicted decrease in hippocampus volume with saliva cortisol level and associated this with poor performance on hippocampus-related memory tasks. Of course, the brain is a complex system and there are many factors that affect the amount and release of glutocorticoids. One of these factors is the 11-Hydroxysteroid Dehydrogenase-1 (11-HSD1) enzyme. This enzyme reactivates deactivated 11-dehydrocorticosterone and converts it to corticosterone and cortisone to cortisol. In other words, the increase in the amount of 11-HSD1 in the brain reactivates the inactive substances that cause the stress response and causes the stress response (McEwen, 2007). Yau et al. (2001) showed that rats with genetically deleted 11-HSD1 have less age-related cognitive dysfunction than natural phenotype rats.

Childhood Negative Experiences and Stress

In addition to the factors whose neurobiological basis we have discussed so far, the experiences of the person or animal also contribute to aging caused by stress (McEwen, 2007). Positive and negative events experienced at work, school or in a romantic relationship can affect people’s reactions to events in a negative or positive way. For example, the behavior of people who have been betrayed in a romantic relationship in their next relationship will be shaped according to these experiences. Experiences at an early age affect this formation more seriously (McEwen, 2007). Felitti et al. (1998) childhood negative experiences (eng. adverse childhood experiences ) has been associated with risk factors such as premature death and hypertension. 52.1% of 9508 people who participated in this study conducted in the United States of America (USA) stated that they had experienced one of the negative experiences described in the study. It has been reported that individuals who experience 4 or more of the categories of negative childhood experiences (MPS) have a 4- to 12-fold increase in the probability of turning to one of the important risk factors such as drug use, suicide attempt and being diagnosed with depression. These studies show that the imbalance in the stress mechanism at an early age is associated with many lethal risk factors.

It is known that almost all patients receiving psychiatric treatment in the USA were abused as children (Kaufman, 1999). These children are at higher risk of having PTSD in adulthood than healthy children. Another finding related to neurobiological factors discussed in the previous section is also stated in this report by Kaufman (1999). According to De Bellis and Putnam (1994), higher levels of cortisol were found in the urine of abused children compared to non-abuse children. This shows that the previously mentioned HPA axis is more active in abused children and its function of inhibiting the stress response is impaired. These findings can also be explained by relating abused children’s perception of events that are perceived as normal by healthy people as threats. In parallel, studies in baby rats have shown that disruptions in the care of their mothers have serious psychological effects (McEwen, 2007). For example, it has been shown that pups who lack maternal care die earlier and experience cognitive decline earlier. In addition, it was observed that exploratory behavior decreased in rats with a lack of maternal care (McEwen, 2007). Puppies with good maternal care neophilic that is, it has been revealed to be prone to exploratory behavior (Cavigelli & McClintock, 2003). Conversely, offspring with a lack of maternal care neophobic that is, they have been shown to be rats afraid of innovation. It has been shown that the HPA axis of neophobic rats is more sensitive and their exploration behavior of new situations is reduced (McEwen, 2007). In one study, rats were taught the relationship between odor and electric shock using the fear conditioning method, and corticosterone levels of the rats were increased when the odor emerged (Sullivan et al., 2000). In the continuation of this study, the mothers of the baby rats were left with them and the odor stimulus was given again. It was observed that the HPA axis of the rats with their mothers was inhibited and stress response did not occur. This showed evidence that the presence of the mother reduces stress.

The stressors discussed so far have both short-term and chronic effects. For example, a cockroach seen in the kitchen immediately creates a stress response and raises the heart rate and blood pressure. This response adapts after a while and prevents these responses from remaining in the middle for a long time. However, the chronic emergence of the stress response continuously raises blood pressure and heart rate, and this causes pathophysiological consequences such as embolism over time (McEwen, 2007).

At this point, we return to the concepts of allostasis and self-balance mentioned at the beginning of this article. It is the defense mechanism of the organism that actually elicits the acute and chronic stress responses just mentioned. However, uncertainties in stressful events, especially in the complex social world of people, destabilize this protection mechanism. This disturbance of balance is also seen in the animal studies just mentioned. When laboratory animals are exposed to events that will cause intense stress response for a long time, it becomes difficult for the stress mechanism to return to self-balance. This experimental situation allowed the human-stress relationship to be studied in the laboratory. In all of the mentioned studies, it is seen that allostatis is higher than normal. It is seen that stressful events of much higher intensity than the person or animal can control or make sense of for the moment cause the mechanisms in the brain to perform the opposite actions required to restore the balance, higher than normal. These allostatic factors affecting the HPA axis, on the other hand, were seen to cause damage in areas such as the hippocampus and frontal cortex, where stress regulation takes place in long-term conditions.

Sleep and Stress

An example of this situation is insomnia caused by stress (McEwen, 2007). Allostatis leads to the production of proinflammatory cytokines to relieve poor sleep quality and the stress response caused by insomnia. But one of the most common causes of insomnia and poor quality sleep is stress itself. The allostatic load that arises as a result of this insomnia caused by stress also leads to harmful conditions in terms of health. Therefore, the response to inhibition of stress caused by insomnia causes an increase in stress. The reason for this is that the brain is both the mechanism that governs all these processes and is also an element that is affected by the situations produced by these mechanisms. As the neuroendocrine, immune and autonomic systems are regulated in the brain, stress-induced changes in the brain cause many different effects on health (McEwen, 2007). For example, reducing the sleep time to 4 hours causes an increase in blood pressure, an increase in cortisol and insulin levels in the evening, and an increase in appetite (Leproult et al., 1997). Similarly, in an experiment in which only 6-hour sleep restriction was applied per night, it was observed that the performance of the individuals in the psychomotor alertness task decreased. As mentioned before, it has been shown in animal studies that allostatic load causes damage to the hippocampus and frontal cortex, which play a role in memory, selective attention and executive control functions (McEwen & Chattarji, 2004). Similarly, it was stated in the study that allostatic load causes hypertrophy in the amygdala, which plays a role in anxiety and aggression.

It has been observed that insomnia inhibits the proliferation of hippocampal neurons in the rat brain (Hairston et al., 2005). It was also supported in later studies that the reason for this was the stress response caused by insomnia. For example, in one study, it was observed that the hippocampal neurons that normally occur as a result of spatial learning were not formed in rats that were left without sleep (Roman et al., 2005). Another effect of insomnia has been shown to decrease the amount of glycogen in the brain (Kong et al., 2002). In this study, it was shown that the amount of glycogen in the brain of rats deprived of sleep decreased by 40%. This is a very serious finding for the connectivity function in the brain. So much so that the function of axons that provide communication between neurons is replaced by glycogen in cases where glucose decreases. Therefore, the communication capacity of the brain will be seriously reduced in case of both insomnia and glucose deficiency. Such a deterioration will have many devastating cognitive, emotional and behavioral effects (Wender et al., 2004). These studies show how serious neurochemical brain responses related to stress can have in the structure of the brain. For example, it can be predicted with these findings obtained in the laboratory that people with a busy work schedule will have a decrease in their learning abilities if they are sleep deprived. So much so that researchers working on this specific issue supported these predictions with their findings. In a study, a negative relationship was shown between nurses’ sleep duration and psychomotor task performance (Arlene et al., 2010).

The studies mentioned above are about the short-term effects of insomnia in humans. But long-term insomnia has important health effects in humans as well as in animal experiments. Just as animal experiments have shown, people with unstable sleep patterns or who sleep fewer hours than normal have been shown to have lower life expectancy. In addition, there are studies in which a decrease in sleep quality or a lack of sleep hours is associated with high blood pressure, obesity and depression. It is also quite easy to relate the neurobiological basis of stress, which is the focus of this article, with these studies. As mentioned earlier, insomnia causes a stress response in the body by producing proinflammatory cytokines. If insomnia or sleep quality returns to normal in a short time, it can be predicted that this stress response will be balanced with the self-balance process. However, the dynamic feedback between insomnia and the stress response makes it difficult to return to this self-balance. When people are sleep deprived as a result of stress, the body responds even more to stress, reducing the possibility of quality and long sleep. This indicates an even higher allostatic load in the long run. Considering that the allostatic load continues continuously in this long-term scenario, it is expected that the blood pressure and heart rate of the people will be constantly high. In such a case, the risk of heart diseases such as hypertension will increase. In addition, proinflammatory cytokines also have appetite-enhancing functions. Increased proinflammatory cytokines as a result of insomnia will cause a continuous increase in appetite and increase the risk of obesity.

In addition, it is known that the stress response has an effect on growth hormones. This is because insulin-like growth factor-I (IBBF-I) has receptors in the hippocampus. Previous studies have shown that IBBF-I plays a role in cognitive functions and mood regulation (McEwen, 2007). It is known that IBBF-I expressed in the hippocampus is upregulated as a result of acute stress (Ahima & Harlan, 1990). . Therefore, it can be thought that acute stress, that is, a situation that does not create an allostatic load, will improve cognitive functions and emotional regulation through this mechanism. However, it is not known whether chronic stress that will create an allostatic load will cause any deterioration through this mechanism.

McEwen (2007) examined the effect of stress on human life under 3 main headings. The first of these is defined as the effects of stress and glutocorticoids on the structure of the human brain and mood disorders, food consumption regulation, chronic pain conditions and activity changes in the digestive system. Secondly, the effect of this relationship on positive health and low self-esteem; Third, the effects of socioeconomic status on the brain and health are discussed. In the next part of the article, considering this structure created by McEwen (2007), these three main headings will be emphasized and the measures that can be taken to prevent health problems related to these categories will be discussed.

Brain Structure and Function

In this review, the effects of cortisol on the brain and the autonomic system are discussed mainly through animal experiments. Although brain imaging studies with people diagnosed with anxiety and depression do not give as precise results as these experiments, similarities are striking. In these brain imaging studies, it was shown that the amygdala volume of people with the stated diagnosis increased (Drevets et al., 1997). In autopsy studies, it was observed that glial cell density of depressed patients decreased (Rajkowska, 2000). This indicates that there is a deterioration in the communication between neurons. The results of the effect of long-term allostatic load on the HPA axis, which is the main theme of this study, explain these findings.

Fatigue and Idiopathic Pain Disorders

Studies have associated an increase in factors related to allostatic load with chronic fatigue syndrome (CFS). Specifically, it has been found that urinary cortisol is low in people with CFS and this is associated with high proinflammatory cytokines (Fries et al., 2005). In addition, increased body pain and decreased physical performance, similar to anxiety disorders, were also reported in CFS. These findings show that diseases that indirectly affect the function of the HPA axis also cause the symptoms seen in stress disorders.

Stress Cognitive Control and Food Consumption

In previous chapters, the relationship between insomnia and stress with food consumption was mentioned. A dynamic directly related to this relationship was the role the hippocampus plays in appetite regulation. In parallel with this, it has been shown in a study that hippocampus lesion causes disturbances in the regulation of food consumption. As a finding on daily life, it was also shown in the study mentioned that this effect of the lesion causes an increase in body mass (Davidson et al., 2005).

Positive Health, Self-Esteem, and Brain-Body Interaction

There are studies showing the relationship between a positive approach to life and good self-esteem levels with low allostasis measures (Seeman et al., 2002). In addition, it was also reported that the variability in heart rate of the participants who had a generally positive mood during the day was low. The close association of heart rate variation with the stress response has been discussed previously, and it would be quite valid given the data to associate this reduced variability with a lower frequency of the stress response. Conversely, low self-esteem measures have been associated with repetitive stress responses in situations where habituation is expected to occur (Kirschbaum, 1995). Low self-esteem was also associated with 13% volume reduction in the hippocampus and high cortisol levels. However, the increase in cortisol and decrease in volume in this relationship can be both the cause and the result of low self-esteem (Pruessner et al., 2005).

Socioeconomic Level and Health

The concept that represents the education and income levels of people under one roof is called socioeconomic level. It has been shown that the life expectancy of people with low socioeconomic status in western industrial societies is lower than those of middle and high socioeconomic status (Adler et al., 1993). In the same study, people with low socioeconomic status were significantly more likely to develop many different diseases compared to the other two groups. It is thought that the reason for this is that low-level people have a lower sense of control in their lives than other categories (Signh-Manoux et al., 2005). In addition to this interpretation, the inevitably occurring differences in the use of nutrition and health services between socioeconomic levels should also be taken into account.

Managing Chronic Stress and Allostatic Burden

Brain-Centered Interventions

The brain is the most important center of the stress response. Therefore, interventions that will cause changes in brain structure and function are frequently used to cope with stress. These interventions included sleep duration and quality, dietary changes, and regular physical activity programs. Interventions such as speech therapy and cognitive behavioral therapy given by psychologists are also among brain-centered interventions.

Pharmacological Interventions

As mentioned earlier, there are many pharmacological agents that prevent and alleviate the destructive effects of the stress response. Some of these are antidepressants, sleeping pills and beta blockers. These substances act to reduce the symptoms of people by manipulating the functioning of stress mechanisms in the brain. However, because these substances have an effect on many different mechanisms, undesirable side effects may occur (McEwen, 2007). One of them is infection that occurs as a side effect of anti-inflammatory drugs. Anti-inflammatories reduce fever, but because the body raises the temperature to fight germs, lowering a fever can make it harder for the body to fight germs. Therefore, the risk of infection increases under the influence of these substances (McEwen, 2007). Therefore, the literature summarized here should be taken into account when prescribing for pharmacological agents.

Physical Activity

The positive effects of physical activity on health are a practical knowledge that is known in our society but not generally applied. Researchers in various fields have of course obtained this knowledge through experiments. For example, it has been shown that physical activity provides neurogenesis in the dentate gyrus in young and old rats (Van Praag et al., 2005). Previous studies have also shown that neurogenesis in the dentate gyrus has anti-depressant effects (Duman & Monteggia, 2006).

Social support

Social support can be briefly defined as the mutual exchange of information between people within the framework of trust. It has been shown that social support shown by family and friends is associated with a decrease in allostatic load measurements (Seeman et al., 2002). These findings show that social support is an important factor in the treatment of stress disorders.

Conclusion

In this study, which was largely based on McEwen’s (2007) review, the elements of the stress circuit in the brain were defined. In addition, the relationship between these circuits is discussed in the light of neurobiological factors. Rather than a linear cause-effect relationship, the dynamic relationship of the factors of the stress response has been explained through the concepts of homoestatis and allostatis. The most important point in this explanation is that the balance of the stress mechanism can be disrupted even with the responses to protect the body, and it has been shown in the light of important studies in the literature that such a disorder will increase in cases such as insomnia.

The body’s responses to self-balance cause structural and functional changes in the brain by causing allostatis. These changes have devastating effects on various cognitive functions such as memory and learning. In addition, the association of long-term allostatic status with obesity and hypertension reduces life expectancy in both animals and humans. In the studies, allostasis measurements are significantly higher in people with PTSD or borderline personality disorder compared to the healthy population. Similarly, there is a serious relationship between major depression and imbalance in stress responses. The majority of these relationships are due to the negative effects of childhood negative experiences on stress mechanisms in the brain.

The negative effects of allostasis on human health are quite high. However, in our age, there are many treatment methods that prevent these destructive effects. Pharmacological substances, physical activity, therapy and positive lifestyle changes prevent and significantly reduce the negative effects of stress.

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