The term stress is used in different disciplines with varying meanings. Here, the concept of stress is used as it is in biology, psychology, and medicine, describing an internal state of physiological imbalance, which is activating a typical set of responses with the aim to restore physiological balance. While the stress response is generally considered as unspecific and universal, it develops across the life span; furthermore, exposure to adverse experiences during early sensitive periods has long-lasting effects on the stress response in later life. This entry reviews the current knowledge on typical stressors, on stress response, and its regulation and describes the impact of early adverse experiences on the development of the stress response regulation across the life span.
Stress as a biological concept was first introduced by the pioneering work of Hans Selye. In a seminal letter to the journal Nature in 1936, he describes the stress response as a general unspecific syndrome in response to different types of nocuous factors (stressors). These stressors can be of physical or psychosocial nature. Examples for physical stressors are physical exercise, irregular or loud noise, injuries or disease states, intoxications, and change in climate. Common psychosocial stressors are critical life events such as changes in living conditions, occupational changes, or changes in personal life (marriage, divorce, loss of family members, loss of friends), experiences of abuse or neglect, social demands, and performance pressure. Minor annoyances, irritations, disappointments, and other daily hassles are regarded as microstressors, which have a different impact on the individual depending on their frequency and on the specific situation. Stressors can be perceived as negative or positive, which is expressed by the distinction between eustress (positive) and distress (negative). It is assumed that the stress response depends on the intensity and duration of the stressor but is independent from its type.
According to Selye, the stress response develops in as many as three stages. The first stage, the alarm reaction, is characterized by a rapid mobilization of one's own resources to immediately respond to the stressor. In case of persistent or severe stress, the stage of resistance follows, with the aim of activating additional resources to optimally cope with the stressor. If the stressor further continues, one's own resources might be increasingly depleted, leading to exhaustion, the third stage of the stress response. Selye defines the three stages as the general adaptation syndrome, which he regarded as a universal program observable across species.
There is common agreement that the stress response develops with a certain physiological response pattern. The alarm reaction is typically characterized by a rapid activation of the sympathetic nervous system, leading to the release of the catecholamines norepinephrine (from the postganglionic nervous fibers and partly from the medulla of the adrenal gland) and epinephrine (from the adrenal medulla). The surge of the catecholamines results in a physiological activation cascade including heart rate acceleration, increased blood pressure, improved muscular blood perfusion, dilation of the bronchial airways and increased respiration, and glucose synthesis and release from the liver, in combination with an inhibition of parasympathetic functions like salivation, digestion, and colon activity. In addition, the neuropeptides corticotropin-releasing hormone (CRH) and arginine vasopressin are released from secretory cells in the hypothalamus and transported in a system of vessels to the anterior pituitary to activate the release of adrenocorticotropic hormone (ACTH). ACTH is transported in the systemic circulation to the cortex of the adrenal gland to synthesize and release glucocorticoid (GR) hormones, in particular, cortisol (in humans). This endocrine component of the stress response system is known as the hypothalamic–pituitary–adrenocortical (HPA) axis (Figure 1).
GRs have a wide range of physiological functions; they stimulate the generation of glucose from muscle proteins and lipids, particularly in the liver, and restrict energy consumption by inhibiting glucose uptake in muscles and adipose tissue as well as by downregulating inflammation and immune function. These functions assure a fast and sustained energy supply for an optimal and enduring response to the stressor corresponding to the stage of resistance in Selye's concept of the general adaptation syndrome.
The stress response is a fundamental function allowing the individual to adapt to a challenging environment and thus is an important element of the behavioral arsenal ensuring survival and development for the individual. The primary aim of the stress response is the restoration of the physiological balance (homeostasis); the active process of restoring homeostasis on the expanse of energy is defined as allostasis. Prolonged or extremely intense activation of the stress response system can lead to an allostatic overload that triggers pathological processes, resulting in a dysregulation of the stress response system, which finally may translate into a stress-related disorder. Such a pathological development resulting from a prolonged stress response conforms to the stage of exhaustion as defined in Selye's model of the general adaptation syndrome. Typical stress-related disorders are psychophysiological disorders (e.g., cardiovascular, respiratory, or intestinal diseases), immunological disorders (e.g., chronic inflammation, persistent infections), and mental disorders (e.g., anxiety disorders, post-traumatic disorders, major depression). Although the etiology of these disorders is multifactorial, chronic or extreme stress combined with the inability of an adequate adaptation to the stressors is considered as a major factor triggering the onset of the disorder.
An effective regulation of the endocrine stress response, and thus, of the HPA axis, is essential to maintain the adaptive properties of the system. Specifically, the stress response needs to be quickly terminated after the stress challenge has been successfully managed to avoid the development of a pathological dysregulation. The primary regulatory elements of the HPA axis are the corticosteroid receptors, GR, and mineralocorticoid receptors. While the mineralocorticoid receptors are predominantly involved in the circadian regulation of the HPA axis, the GR primarily regulate the HPA axis activity in response to a stressor.
Stress-dependent activation of the HPA axis leads to a rise in the blood concentration of the GR hormone cortisol, which activates the GR at the level of the pituitary and, after passing the blood–brain barrier, also the GR at the level of the hypothalamus (see Figure 1). GR exhibit locally a negative feedback inhibition resulting in an attenuation of the CRH and arginine vasopressin release in the hypothalamus and of the ACTH secretion from the anterior pituitary. Thus, the negative feedback inhibition assures a rapid downregulation of the stress response once the stressor could be terminated or the individual has successfully adapted to the new situation.
Prolonged or extremely intense activation of the stress response system can contribute to a reduced GR sensitivity impairing the negative feedback inhibition, thereby, leading to chronically elevated ACTH and cortisol levels and to an increased and/or extended HPA axis activation in response to stress. An impaired negative feedback inhibition can be most sensitively diagnosed with the combined dexamethasone/CRH test, a neuroendocrine challenge test of the HPA axis. In this test, the stimulating effects of an exogenous CRH injection on ACTH and cortisol concentrations are evaluated under the suppressive effects of dexamethasone, which is a synthetic GR simulating the inhibitory effects of an increased cortisol concentration. A well-functioning HPA axis regulation is reflected by an attenuated ACTH and cortisol increase in response to the CRH stimulation, whereas a distinct ACTH and cortisol surge indicates an impaired negative feedback inhibition and thus a dysregulated HPA axis. Such a disinhibited endocrine response to the combined dexamethasone/CRH test can be observed in patients suffering from an acute stress-related disorder that usually normalizes after recovery.
Cortisol and other GRs bind to the GR as the major regulatory element of the HPA axis. GR belong to the group of nuclear receptors. As such, the activated GR travels from the cytosol, or cytoplasm, into the nucleus of the target cell to act as a regulator of the gene transcription. GR activation requires the presence of certain auxiliary proteins, whereas other proteins inhibit the binding of the ligands. These proteins are denoted as chaperones or co-chaperones and involved in regulating the sensitivity of the GR. Converging evidence points to a prominent role of the co-chaperone FK506-binding protein 5 (FKBP51 or FKBP5), which acts as a functional antagonist to the GR. An elevated activity of the FKBP5 protein leads to a desensitization of the GR, thereby impairing the negative feedback inhibition of the HPA axis, and increases the risk of the development of stress-related disorders.
Proper pre- and postnatal exposure to GRs is an important prerequisite for the regular growth and maturation of organ systems of the fetus and of the developing child. A maternal cortisol surge can be typically observed during the last few days of pregnancy prior to delivery, seemingly triggering the activation of the organ systems for the transition of the infant to postnatal life. After delivery, infant cortisol levels are high but decline during the first postnatal weeks and months until the circadian rhythm of the HPA axis develops. During the first years of development, the stress response system is highly plastic and can lead to development in different directions. For instance, human epidemiological data and findings from animal studies suggest that exposure to mild stressors during early life can enhance the proper development of the HPA axis, potentially contributing to an improved stress resilience during later life. However, it could also be shown that severe and/or prolonged stress during critical prenatal periods as well as postnatally until puberty can sustainably impair stress response regulation and brain development. Specifically, separation, neglect, and child abuse have been frequently reported as major risk factors for an impaired HPA axis regulation; for behavioral, emotional, and cognitive disturbances as well as for the development of stress-related (mental) disorders in adulthood.
Growing evidence suggests certain chemical alterations of the genome, summarized as epigenetic modification, as a possible mechanism for the long-term effects of prenatal and early life stress. Epigenetic mechanisms include the methylation of the genetic code (DNA); chemical modifications of histones, which assure proper winding and packing of the DNA in the cell nucleus; and small noncoding transcripts (RNA), so-called microRNAs. Epigenetic mechanisms are cell-specific and assure the individual differentiation of the cell; beyond this core function, they also influence the gene expression of the cell. Epigenetic changes usually survive cell division and thus can last over multiple generations of the cell. They can also be transgenerationally inherited from the parents to the offspring. Epigenetic modifications are potentially reversible, and certain enzymes specifically converting epigenetic modifications are discussed as putative candidates for future treatments in trauma-related disorders.
High GR exposure has been identified as a potential modifier of the epigenome. Research in animal models could show that neglecting maternal behavior leads to increased GR concentrations in the offspring, which affect the epigenetic programming of the GR in the brain. Also other core elements of the HPA axis including CRH and arginine vasopressin, the ACTH precursor protein proopiomelanocortin, and the GR-modulating factor FKBP5 can be directly or indirectly modified by epigenetic mechanisms in response to early life stress. It is assumed that such epigenetic modifications are responsible for the long-term effects of prenatal and early life stress on somatic and mental health.
Stress reactivity develops during the life span, which can in part be explained by the biological maturation of the HPA axis. Further important modulators of stress reactivity are personal experiences and attitudes leading to the development of individual coping skills during one's lifetime. The concept of coping summarizes all measures the individual is initiating to deal with a certain stressful situation. Generally, coping skills can be categorized as adaptive and potentially stress reducing or as maladaptive and potentially stress aggravating. The latter comprises, for instance, dissociations (e.g., feelings of being detached from oneself, avoidance of recalling prior events, and the development of apathy) that frequently occur following traumatic experiences, self-blame as a typical feature of depression, and avoidant behavior, which is a core symptom of anxiety disorders. Positive coping skills include anticipatory proactive measures, problem-focused strategies, as well as help- or support-seeking behavior. Certain maladaptive strategies like anxious-avoidant behavior seem particularly dependent on age and sex, with a higher prevalence in females and in younger individuals. Also the presence of mental disorders can affect the use of coping skills in response to stress. Major depression, for instance, is commonly accompanied by a profile of reduced adaptive and increased maladaptive coping skills, which is assumed to contribute to the perpetuation of the disorder.
The concept of stress initially introduced by Hans Selye inspired a large body of research in many disciplines. While the basic principles of the stress response are meanwhile well understood, the pathways from the stressor and the stress response to the development of stress-related disorders are not yet sufficiently elucidated. However, recent progress in the field of epigenetics, neuroscience, psychology, pharmacology, and medicine may open new avenues for improving the understanding of the effects of early trauma and adversity on the stress response regulation across the life span.
See also Allostatic Load; Autonomic Nervous System; Child Abuse and Neglect; Coping; Cortisol; Epigenetics; Hypothalamic–Pituitary–Adrenal (HPA) Axis; Traumatic Stress
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