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date: 20 January 2022

Stress-Modulated Pathwaysfree

Stress-Modulated Pathwaysfree

  • Nicolas RohlederNicolas RohlederFriedrich-Alexander-Universität Erlangen-Nürnberg

Summary

Stress is a condition or an experience that is pervasive throughout human life. While there are many definitions of stress, a common notion is that stress is processed in the central nervous system and has effects on health that are mediated by stress-modulated pathways. Several brain areas, such as the amygdala and the broader limbic system, are involved in interpreting situations as potentially stressful. The signals of these areas converge in the hypothalamus, which orchestrates peripheral stress-modulated pathways, mainly the hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS). Health effects of stress are mediated by long-term alterations of basic stress system activity, which has downstream effects on pathophysiological pathways such as the inflammatory system.

Subjects

  • Neuroendocrine and Autonomic Systems

Introduction

All human beings experience stress at least during some parts of their lives, but science has traditionally struggled with defining and describing stress. Accordingly, stress can and has been defined in many ways. While some define stress simply in terms of stimuli that activate biologically measurable stress responses, this view has been criticized for being for being circular (see, e.g., Slavich, 2018). Better definitions of stress focus on types or components of situations that are typically described as stressful (i.e., Mason, 1968), while others have focused on the psychological process of appraising a situation as threatening or challenging, and evaluating the available coping resources (transactional stress model; Lazarus & Folkman, 1984).

One of the most important distinctions that must be made when defining and investigating stress is between acute and chronic stressors. Acute stressors last from minutes to hours, and chronic stressors can be of several years of duration, up to an entire human life span. Elliot and Eisdorfer (Elliot & Eisdorfer, 1982) proposed a taxonomy that remains valuable for categorizing stressors. They differentiated stressors among the dimensions duration and course, that is, they described stressors that can be short and/or acute versus long-lived (dimension of duration), and they distinguished between continuous and discrete (dimension of course). Based on this taxonomy, five broader categories were proposed. Two categories described acute, short-term stressors, which are differentiated only by their degree of real-life meaning, acute time-limited stressors, and brief naturalistic stressors. The category stressful event sequences described repeated related stressors. Continuous stressors of longer duration were termed chronic stressors. Finally, the term distant stressors was used to describe stressors that have occurred in the past but remain a continuous burden, such as traumatic events. This taxonomy is well-suited to categorize and thereby differentiate between stressors and has therefore been used in reviews and meta-analyses (e.g., Miller et al., 2007; Segerstrom & Miller, 2004) describing, for example, consequences of different types of stressors.

Another distinction needs to be made between threats to the physical integrity of the organism, that is, physiological stressors, and threats to the organism, which result from the brain’s interpretation of environmental situations as, for example, in the Integrated Specificity Model of stress proposed by Margaret Kemeny (Kemeny, 2003). While threats to physical integrity are communicated to the hypothalamus from the brain stem, using rather direct neural signals, threats to the organism as a whole, also termed processive or anticipatory stressors, involve many higher level central nervous system (CNS) structures, such as the limbic system and the amygdala (Figueiredo et al., 2003; Herman & Cullinan, 1997).

A range of situations can be interpreted as threatening by these CNS structures, and these situations can vary significantly between individuals, based, for example, on experience and genetic makeup, which might shape stress appraisals described in the transactional stress model. Despite this variability, there are common characteristics of situations that are typically interpreted as threatening, as summarized, for example, by John Mason (1968). These include novelty, uncertainty, uncontrollability, unpredictability, and ego-involvement. Mason concluded that situations with these characteristics elicit the strongest biological stress responses. A further extension is the Social Self Preservation Theory (SSPT), which highlights the importance of an individual’s social standing, and proposes that threats to social position elicit the highest biological stress responses in order to modulate behavior aimed at preserving or restoring social standing (Dickerson et al., 2004; Gruenewald et al., 2004). The notion that social stressors are among the most potent was based on and supported by a meta-analysis of more than 200 acute stress studies in humans, in which laboratory stress paradigms with strong threats to the social self, together with perceptions of low control, were the strongest predictors of cortisol stress responses (Dickerson & Kemeny, 2004).

While these theories focus on experiencing and responding to acute stress situations, such as acute time-limited stressors or brief naturalistic stressors, long-term stressors have also been analyzed. When focusing on long-term stressors, it is important to consider experiences made over the entire life span of an individual. Stressors, if broadly defined as situational stimuli affecting stress systems and long-term health, can occur as early as during pregnancy (e.g., Barker, 2004; Entringer et al., 2012). Of particular importance seem to be experiences made in the early developmental period (Lupien et al., 2009), although the entire life span of a human being is subject to individual experiences, which, if processed as being a threat that cannot be adequately coped with, will leave a mark on stress-modulated pathways (see, e.g., Miller, Chen, & Cole, 2009; Slavich, 2016). An interesting gap in knowledge exists between conceptualization and understanding of acute, as well as chronic, stressors and the transitional period. In other words, at present it is unknown when, and under which conditions, repeated acute stressors alter stress systems in a way that leads to the well-described status quo of individuals suffering from chronic stress (Rohleder, 2019).

Stress can be acute or chronic and can be of a physical or psychological nature. Acute physical stress activates different pathways from acute psychological stress, which requires elaborate processing and therefore shows larger variations between individuals. Chronic stress leads to long-term alterations mainly of basal stress system activity.

Stress Systems in the Central Nervous System

A key hub of stress-modulated pathways in the CNS is the hypothalamus. The general principle here is that neurons located in different areas of the hypothalamus integrate signals from the periphery, from other areas of the hypothalamus, and from the remainder of the central nervous system, and based on this information regulate the activity of specific components of the neuroendocrine CNS-to-peripheral communication pathways. In simple terms, this is achieved by controlling the concentration of endocrine messenger molecules, or hormones, in the circulation, and/or activating or deactivating components of nerves projecting to the periphery. The main endocrine pathway communicating stress to the periphery is the hypothalamus-pituitary-adrenal (HPA) axis using cortisol as the main messenger molecule, and the main neural pathway is the autonomic nervous system (ANS) with the sympathetic (SNS) and parasympathetic (PNS) nervous systems, and their respective neurotransmitters norepinephrine and acetylcholine, as well as epinephrine and norepinephrine secreted as hormones from the adrenal medulla.

How and Where in the Brain Are These Interpretations Made and How Is This Signaled to the Hypothalamus?

Research on the brain areas involved in the processing of stress-related information is still evolving, in particular in humans. A comprehensive review of this research is out of the scope of this article. For a deeper reading, the excellent review by Herman et al. (2020) is recommended. In an earlier summary of animal literature investigating central stress circuitry, Herman and Cullinan (1997) reported that activation in the amygdala and the bed nucleus of the stria terminalis (BST) was necessary for mounting so-called processive stress responses. Both regions project directly to the paraventricular nucleus (PVN) of the hypothalamus, which coordinates activation of the HPA axis.

Other regions have been shown to inhibit HPA axis activation. The most important function of HPA axis inhibition is negative feedback, which allows the hypothalamus to control peripheral cortisol concentrations and keep them in a desirable range of concentrations. Negative feedback is mediated through glucocorticoid receptors (GR) in the PVN, but also through connected regions, most prominently the hippocampus, which is rich in GR, as well as mineralocorticoid receptors (MR). Lesion and stimulation studies in laboratory animals suggest a powerful role of the hippocampus in inhibiting HPA axis activation through the PVN of the hypothalamus (Herman & Cullinan, 1997). Further inhibition is exerted by the medial prefrontal cortex (mPFC) even though it signals indirectly, as it does not have direct connections to the PVN. Herman and Cullinan (1997) showed that interpretation of situations as threatening by the limbic system activates a stress response via signaling to the PVN of the hypothalamus, of which the amygdala and BST have stimulating effects, while the hippocampus and prefrontal cortex have suppressing effects.

Human studies using brain imaging during acute laboratory stress paradigms are largely in line with these data (Dedovic et al., 2009): cortisol responses to acute stress in humans are higher in individuals with lower brain activity in the orbitofrontal and medial prefrontal cortex. Dedovic et al. (2009) as well as Pruessner et al., (2008) suggest that these prefrontal structures, together with other limbic structures—such as the hippocampus—exert a tonic inhibitory influence on the PVN, which is removed when a situation is interpreted as a threat, thus permitting the HPA axis to respond.

While the HPA axis is the main neuroendocrine system responding to threatening situations, its activation is often accompanied by changes in the autonomic nervous system (ANS), mainly through activation of the sympathetic branch, but also through deactivation/suppression of the parasympathetic branch. SNS activation occurs frequently in concurrence with HPA axis activation, although it has a lower threshold, that is, it often responds to situations that are insufficient in duration or intensity to activate the HPA axis, for example, also physical threats. The locus coeruleus (LC) in the brain stem is important in activating the SNS, and its stimulation leads to activation of the brain noradrenergic system and the peripheral branches of the SNS. This allows widespread signaling to the periphery of the body using norepinephrine as a neurotransmitter and is enhanced by neuroendocrine function of the adrenal medulla, which releases epinephrine and norepinephrine into the circulation (Chrousos & Gold, 1992). Both systems, the HPA axis and the SNS, are connected through positive feedback loops, which allows activation of one system to typically activate the other as well.

In summary, this knowledge enables pinpointing of the psychological processes proposed by Mason, Lazarus, and Folkman, as well as the authors of the social self-preservation theory, to specific regions of the brain. These are the amygdala, certain regions of the prefrontal cortex, the hippocampus, and the remainder of the limbic system all connecting to the PVN of the hypothalamus, thereby affecting the HPA axis and the ANS.

Downstream Stress-Modulated Pathways From the CNS to the Periphery

Activation of stress systems serves the main purpose of allowing the organism to survive in the face of threats originating in the environment. Stress systems are the most immediate, direct stress-modulated pathways extending from the CNS, and they communicate threat to the periphery of the body. They affect a wide range of target tissues and organs through their messenger molecules cortisol (or corticosterone, in rodents), epinephrine, norepinephrine, and, to a certain extent, acetylcholine.

A key requirement for successful adaptation and survival of environmental threats is the balanced and concerted activation of both stress systems, the timely down-regulation of stress systems, as well as successful communication of their key messages to the different target organs. Healthy organisms are usually able to mount this adaptive response when experiencing acute, short-term stress situations, allowing them to not only survive the threat but also withstand their own physiological responses to the same threat.

However, stress systems and their affected downstream pathways can also do major damage to the body’s cells, tissues, and organs, leading to a host of diseases. To understand and—in the long-term—ameliorate such stress-related diseases, it is necessary to not only understand how stress systems are activated and shut down in healthy organisms, but instead or in addition, to understand the conditions under which such a concerted activation and de-activation does not function properly. Such dysregulations can take the form of altered responses to acute stress, but they can also result from chronic exposure to threatening life circumstances, which then leads to long-term alterations of basal activity of stress systems, as well as differences in reactivity to additional acute stressors. In particular, changes in basal activity of stress systems are related to many pathophysiological processes, ultimately leading to a host of stress-related diseases.

Concerted Activation of Pathways Modulated by Acute Stress

The importance of a concerted, well-balanced, and well-timed activation of stress-modulated pathways has been explained in a seminal article by Sapolsky et al. (2000). Their argument is that glucocorticoid effects on different target tissues have to be interpreted in relation to the effects of other stress-modulated pathways, such as the SNS, on these same target tissues. Assuming that, typically, SNS effects are fast and short-lived, and HPA effects are slower and more prolonged, they sorted glucocorticoid effects into four categories depending on whether they (a) need to be present before a stressor to allow a stress effect on target tissues (permissive effects), (b) down-regulate previously activated target tissue responses (suppressive effects), (c) enhance an existing stress response (stimulating effects), or (d) prepare target tissues for a subsequent response (preparative effects). Applying these categories allowed for the first time to make sense of seemingly contradictory effects of, for example, GC stimulation of energy release (stimulating effects) versus GC-induced down-regulation of immune functions (suppressive effects). Sapolsky et al.’s framework explained that both actions, in this example as contradictory as being stimulating on one system, and suppressive on another system, converge to promote adaptation to threat, by increasing energy available while at the same time protecting the body from damage by the immune system. The key conclusion here is that stress modulates different pathways in very different ways but needs to do so in a concerted and well-balanced fashion in order to promote survival, as opposed to harming the body.

While the central component of the theory described previously is timing and concerted activation to a singular, acute stress event, McEwen et al. (1993) expanded this view by formulating conditions that contribute to maladaptive, as opposed to adaptive, effects of stress responses. The key proposition made in the allostatic load model is that acute changes to the body’s set points brought about by the stress-modulated pathways are beneficial and adaptive when experienced once, or once in a while, but that they can also lead to accumulation of physiological damage (termed “allostatic load”) if experienced too often, or with maladaptive stress response patterns.

Maladaptive patterns were described as those in which, for example, one stress system would fail to respond despite experiencing a threatening situation. If this missing response would, for example, be that of the HPA axis, it would turn the adaptive, concerted, and well-balanced activation as described by Sapolsky et al. (2000) into an imbalanced one, because the lack of glucocorticoids would, for example, not stimulate energy release, and/or would not shut off potentially harmful immune responses.

Other maladaptive conditions proposed by McEwen are “failure to down-regulate” stress responses, in which a stress response, for example, glucocorticoid levels, would not return to its pre-stress baseline in time. This condition would disturb the ideally balanced and concerted activation and deactivation of stress responses in other ways, for example leading to long-term stimulation of immune activity, long-term blood sugar increases, or prolonged periods of increased blood pressure. Extending such acute stress scenarios into more long-term conditions are two further maladaptive response patterns, namely “repeated stimulation” and “lack of habituation” to repeated stressors. Both scenarios are classic examples of how allostatic responses can lead to allostatic load, leading to long-term accumulation of damage, for example through repeated activation of inflammatory immune activity, repeated blood sugar increases, or repeated blood pressure surges. If these responses occur too often, they can lead to long-term damage leading, for example, to hypertension, type 2 diabetes, or consequences of chronic inflammatory activation like cardiovascular disease.

Finally, a well-concerted stress response not only requires an adaptive and well-concerted activation and shutdown of stress responses, but also the ability of target tissues to respond to stress-system signals. In early studies investigating the ability of the immune system to respond to cortisol signaling, it has been found that glucocorticoid sensitivity of the inflammatory system is highly dynamic and characterized by sex-specific changes in the face of acute stress (Rohleder et al., 2001, 2002). It was further shown that in humans, exposure to acute stress leads to an increase in the ability of inflammatory immune cells to respond to glucocorticoid signals only in healthy young males (by showing a strong suppression of inflammation), while in women and older adults, a decrease in GC sensitivity occurred (those individuals did show a lesser suppression of inflammation after acute stress). This lesser ability of women and older adults to control inflammation in the face of acute stress is in line with their higher susceptibility to inflammatory diseases and highlights another important aspect of a well-balanced stress response, which is that target tissues need to have the ability to respond to stress signals (Rohleder et al., 2003).

Taken together, pathways modulated by stress systems in situations of singular or repeated acute stress typically show adaptive patterns in healthy individuals, but several conditions can lead these responses to become maladaptive and thereby damaging to the organism’s healthy function.

Pathways Modulated by Chronic Stress

Chronic or long-term stressors, as well as distant stressors such as traumata experienced in the past, affect the individual by leading to long-term alterations in the function of stress-modulated pathways. While acute stress experiences have well-defined and easy-to-describe effects on stress-modulated pathways, usually an upregulation during or shortly after stress, and a recovery minutes or a few hours later, chronic stress affects basal, unstimulated activity of stress-modulated pathways.

Stress-Modulated Pathway: Hypothalamus-Pituitary-Adrenal Axis

To understand the effects of chronic or distant stressors, it is important to first describe the function of stress-modulated pathways in the absence of acute or chronic stressors. The HPA axis in a healthy, non-stressed human is characterized by a pronounced circadian rhythm, regulated by internal zeitgebers, most prominently those located in the suprachiasmatic nucleus (SCN) of the hypothalamus (Koch et al., 2017; Mistlberger, 2005). HPA axis activity shows a pronounced increase within 30 to 45 minutes after waking up, in which cortisol concentrations typically double. This phenomenon is called the cortisol awakening response (CAR) (Clow et al., 2010; Pruessner et al., 1997), and represents one component of healthy, adaptive basal HPA axis function. Alterations of the CAR, in particular lower CAR, have been reported in patients with damage to the hippocampus (Buchanan et al., 2004), depression (Stetler & Miller, 2005), and hypertension (Wirtz et al., 2007). After the CAR, cortisol concentrations decline throughout the day and reach their lowest levels during the first half of the night (Van Cauter, 1995). In the absence of stress, diurnal cortisol increases are typically seen after meals (Follenius et al., 1982).

A myriad of studies has addressed basal HPA axis activity in relationship with stress, with a large heterogeneity of findings. The early view of the field was that chronic stress was expected to be associated with increased cortisol concentrations, due to the well-described fact that short-term, acute stress reliably activates the HPA axis and increases cortisol concentrations. Some studies appeared to confirm this expectation, and high cortisol concentrations were found in blood and urine of patients suffering from depression (e.g., Asnis et al., 1981), and individuals reporting increased experience of stress, or stressful life events (e.g., Jacobs et al., 1987; Schaeffer & Baum, 1984). However, the literature turned out to be very inconsistent, with some studies continuing to report higher cortisol in relation with stress or depression, and other studies reporting lower cortisol with chronic stress, and in particular in patients with posttraumatic stress disorder, that is, those with a distant stressor (e.g., Yehuda et al., 1995). This inconsistency was partially caused by a large variety of methods used to assess basal HPA axis activity, including 24 hr vs. 12 hr urinary cortisol excretion, single time-point plasma/serum measurements at different times of day, and assessment of cortisol in saliva. Healthy HPA axis function is characterized by a pronounced circadian variation, with the implication that 24 hr urinary cortisol levels will most likely reflect a different aspect of basal HPA axis function than plasma or salivary cortisol measured at a single time point at waking, 30 minutes post waking, or at some point during the day, maybe without controlling for wake-up time or recent meal intake. Miller et al. (2007) used the Elliot and Eisdorfer taxonomy to categorize stressors and conducted a meta-analysis of chronic stress studies, also taking into account the duration of stress exposure (for chronic stress), or time since stressor (for distant stressors).

Taken together, their results confirmed that chronic stress, as well as distant trauma, was related to decreased diurnal cortisol output, a flattening of the diurnal decline, and that this decline became more pronounced with longer exposure to chronic stressors, or longer time since distant stressors (Miller et al., 2007). This important study thereby provides the background for the understanding of long-term stress on stress-modulated pathways and, thereby, also paves the way for asking what consequences these alterations might have.

Stress-Modulated Pathway: Autonomic Nervous System

Zeitgebers in the SCN not only regulate basal HPA axis activity, but also lead to diurnal rhythms of autonomic function (Koch et al., 2017; Mistlberger, 2005). In general, although SNS and PNS are more responsive to acute stress, differences in basal activity have been frequently described. There are different ways to assess the activity of the ANS, which range from electrophysiological measurements such as heart rate (HR), heart rate variability (HRV; Thayer et al., 2010), and skin conductance, to saliva-based measures of proxies such as salivary alpha-amylase (sAA; Nater & Rohleder, 2009; Rohleder & Nater, 2009) to the measurement of epinephrine and norepinephrine in blood or urine. The latter have, for example, been shown to fluctuate throughout the day, with lower levels in the morning and higher levels in the evening (Dimitrov et al., 2009). Similar patterns have been reported also for sAA, a peripheral proxy for ANS activity (Nater et al., 2007). While these numerous methodological options to assess ANS regulation also carry the risk of obtaining heterogeneous study results, some common findings regarding the modulation by chronic stress have emerged.

Alterations in ANS activity are well-described in clinical depression, which is frequently reported to be associated with altered autonomic regulation of the heart, such as increased sympathetic and decreased parasympathetic stimulation of the heart, and reduced heart rate variability (Grippo & Johnson, 2009), and also higher plasma concentrations of norepinephrine (Carney et al., 2005). Similar ANS imbalance with sympathetic overactivity and altered daily rhythm are also found in posttraumatic stress disorder (e.g., Thoma et al., 2012; Yehuda et al., 1992), an exemplary case of distant stressor according to Elliot and Eisdorfer (1982). Does stress outside clinical/psychiatric disorders, that is, the Elliot and Eisdorfer category of chronic stress, modulate the ANS in the same way? Like the HPA axis, many individual studies have been conducted and published, and there is some heterogeneity as well, likely caused by two complicating issues. One is the fact that chronic stress has been operationalized in many ways, ranging from self-reports in daily lives using questionnaire tools, to assessment of work stress, to recruitment of specific, particularly stressed groups of individuals, such as caregivers to family members with chronic diseases. The second issue is that there are many ways to assess ANS activity, which do not necessarily reflect the same component of the system, and thus do not always correlate well with each other. With regard to caregiver stress, a review by Allen et al. (2017) found some evidence for higher plasma epinephrine and norepinephrine in caregivers, but also non-differences. Targeting work stress in a systematic review, Jarczok et al. (2013) found that occupational stressors are frequently (but not always) associated with decreased heart rate variability, indicating decreased parasympathetic control of the heart, and ANS imbalance. Not surprisingly, data about associations of self-reported chronic stress with indicators of ANS activity measured in healthy individuals from the community are mixed, and no systematic reviews or meta-analyses are available. Studies using larger, publicly available data sets such as the Midlife in the United States (MIDUS) study report associations of self-reported daily stress with lower measures of heart rate variability, indicating lesser parasympathetic control of the heart and, thus, ANS imbalance (Sin et al., 2016).

Taken together, ANS activity is clearly modulated by conditions such as distant and chronic stressors. Findings are more consistent for clinical psychiatric conditions such as depression and posttraumatic stress disorder, but data on other chronic stressors, while more heterogeneous, also point to dysregulations in ANS balance, typically with overactivity of sympathetic components.

Consequences of Alterations in Stress-Modulated Pathways

When evaluating the consequences of stress exposure on human beings, solely focusing on what could be described as immediate, or primary, stress stress-modulated pathways—HPA axis and ANS—might not be sufficient. While a more or less clear pattern emerges of how HPA axis and ANS respond, in an ideally concerted way, to acute stressors, and how they are altered in association with chronic or distant stressors, further dependent, downstream, or secondary stress-modulated systems need to be brought into focus.

It has convincingly been argued that such downstream, dependent pathways should be located closer to the actual damage, that is, that mechanisms need to be looked at that are involved in cellular function, or potentially confer tissue or organ damage. Several such targets have been identified, among others DNA damage and repair processes (Hara et al., 2011), mitochondrial function (Picard et al., 2014), and inflammatory mechanisms. While this list is certainly not exhaustive, inflammation is one of the processes that has received most attention, because inflammatory mechanisms are clearly involved in a host of diseases relevant for human health and longevity (Couzin-Frankel, 2010), and because it is equally undisputed that inflammation is regulated by stress (Rohleder, 2014) and that this regulation is mediated by HPA axis and ANS (Bierhaus et al., 2003; Richlin et al., 2004; Wolf et al., 2009). Therefore, inflammation is introduced here as another important, more downstream, stress-modulated pathway.

Acute Stressors and Inflammation

In response to acute stress, the requirement of a concerted activation and recovery of HPA axis and ANS pathways as proposed by Sapolsky et al. (2000) also and specifically applies to the regulation of innate immunity, specifically, inflammatory cells. Stress perception stimulates inflammatory activity through adrenergic receptors on immune cells (Padro & Sanders, 2014), leading to stimulation of the nuclear factor kappa-B (NF-kappaB), one of the central activators of inflammatory processes (Bierhaus et al., 2003; Richlin et al., 2004). Delayed HPA axis responding then down-regulates inflammatory activity through glucocorticoid receptor-mediated inhibition of NF-kappaB DNA binding activity (McKay & Cidlowski, 1999; Wolf et al., 2009). This mechanism leads to transient increases in plasma concentrations of inflammatory mediators, in particular interleukin-6 (IL-6) in humans (von Känel et al., 2006; Rohleder, 2014). These acute inflammatory stress responses are presumably adaptive in the short-term, as they do show recovery after a few hours. However, conditions such as loneliness, low self-compassion, and overweight are associated with a sensitization of IL-6 responses to repeated stress (Breines et al., 2014; McInnis et al., 2014; Rohleder, 2014). Altered acute stress reactivity, in particular lack of habituation, can be interpreted as a feature of allostatic load (McEwen & Stellar, 1993) and might therefore be a predictor of future disease. Translation of such acute alterations into long-term health declines, however, has not yet been systematically investigated (Rohleder, 2019).

Chronic and Distant Stressors and Inflammation

Inflammation as a stress-modulated pathway has also been investigated with regard to chronic stress or following distant stressors. One of the best examples of distant stressors is early life adversity, or childhood adversity. Miller, Chen, and Cole have convincingly demonstrated in an array of studies how different kinds of conditions of early human life can leave a long-lasting mark on the regulation of the inflammatory system. This gene expression pattern is called the Conserved Transcriptional Response to Adversity (CTRA; Cole, 2019). It is characterized by an upregulation of transcriptional mechanisms leading to inflammatory disinhibition, stimulated by beta-adrenergic signals, that is, the sympathetic part of the ANS, and by a downregulation of the suppressive impact of glucocorticoids. This pattern appears to be a consequence of long-term alterations of brain-to-immune communication, leads to inflammatory disinhibition, and is thus a prime candidate for explaining health effects of distant stressors. It has been found, for example, in adults who grew up in adverse conditions, for example, with low socioeconomic status (SES; Miller et al., 2009), and it was also shown to be less pronounced in individuals who had experienced better early life conditions such as maternal warmth (Chen et al., 2011). These findings at the cellular level correspond well with more general measures of inflammatory activity, for example, with findings of higher plasma concentrations of inflammatory molecules like IL-6 and C-reactive Protein (CRP) in association with early adversity (Danese et al., 2011).

Importantly, this pattern is also found in response to adversity experienced in adult life, for example chronic stress and adult trauma (Miller et al., 2008, 2014; Miller, Rohleder, & Cole, 2009). These findings highlight that chronic and distant stressors not only affect primary stress-modulated pathways such as the HPA axis and the ANS, but also that the translation into physical disease is mediated through at least one more downstream, stress-modulated pathway, inflammation. These findings highlight that it might be insufficient to solely focus on primary stress-modulated pathways when the goal is to understand the link between CNS states like stress and consequences in the periphery. A longitudinal study focusing on biological effects of caring for a family member with cancer observed that, over a 1-year period, there were almost no changes in HPA axis basal activity. Despite that, intra-cellular pathways regulating inflammation were severely affected, mainly through reduced gene-expression of anti-inflammatory factors such as inhibitory kappa-B and the glucocorticoid receptor (Rohleder et al., 2009). These changes were ultimately associated with higher plasma concentrations of CRP, underscoring the importance of going beyond primary stress-modulated pathways in the investigation of chronic stress effects on the body.

Conclusions

Taken together, stress is processed by the central nervous system, and communicated to the periphery of the body via different stress-modulated pathways. The primary stress-modulated pathways extending from the CNS to the periphery are the HPA axis and the ANS. Different conditions of stress—acute, short-lived, and chronic or distant stressors—affect these pathways in different ways. Acute stress is usually characterized by a concerted activation and deactivation of stress systems. The signal of activation and deactivation is carried through the organism and affects downstream pathways, of which inflammation was discussed here as one of the currently most important examples. While in a healthy organism exposed to “healthy doses” of stress, these pathways, and their activation and deactivation, are necessary for adaptation to environmental demands, repeated activation or alterations in response patterns are hypothesized to lead to long-term damage and allostatic load. However, empirical data connecting altered stress response patterns with long-term health is still scarce. In contrast to that, chronic or distant stressors exert more or less well-described effects on primary stress-modulated pathways, typically in the form of long-term alterations of basal activity patterns. These alterations are translated into potential organ damage through downstream pathways, such as inflammation. In the case of inflammation, altered regulation of inflammation by stress systems, and, consequently, increased activity of the inflammatory system, are well-described and predictive of long-term health.

References