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.

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

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.