This editorial highlights two elegant articles published recently about the stress response in health and disease: Agorastos and Chrousos [1] and de Kloet and Joels [2]. Chrousos, the senior author of the first paper, is arguably the world’s foremost expert on the stress system organization and the consequences of its dysregulation. The authors first define stress as a state of threatened homeostatic balance by a wide range of intrinsic or extrinsic, real or perceived challenges or stimuli. These are designated as stressors. This optimal homeostatic condition is maintained within a physiologic range by an extremely sophisticated stress system developed by living organisms, which influences energy redirection and multiple physiological adaptations to serve the organism’s self-regulation and adaptability. Repeated, short-lived, palpable stress states lead to adaptive responses and response habituations. In contrast, inadequate aversive, excessive, or prolonged stress often produces pathological alterations in behavior and physiology that significantly diminish the quality of life and perturb multiple physiological systems, leading to sequala such as premature coronary artery disease, stroke, diabetes, and osteoporosis that significantly shorten life.

Neuroendocrine responses to stress are key components of the stress response. They result in hypo- or hyperactivity of the overall stress system response, including impaired glucocorticoid and mineralocorticoid receptor system signaling, ultimately promoting cumulative changes in allostatic load, which lead to clinically significant disturbances in behavior and physiology. Agorastos and Chrousos’s article offers an expert and thorough overview of the organization and physiology of the human stress system and its reactivity, as well as the plethora of somatic effects of acute and chronic stress. It discusses a conceptual model of acute and chronic stress pathophysiology as a continuum in chronic disease development. The authors present an exceptional, comprehensive review of the organization of the human stress system, thoroughly reviewing the roles of peripheral mediators and central structures such as the amygdala, locus coeruleus, various brain stem constituents, central and peripheral inflammatory mediators, and multiple target tissues that become dysregulated when the stress system runs awry. They provide excellent descriptions of acute stress syndrome and acute sickness syndrome and then offer a detailed overview of the pathophysiology of the stress response. This section includes a comprehensive overview of the physical, behavioral, and emotional effects of acute, traumatic, and chronic stress.

Although much research addresses the acute and chronic manifestations of stress system activation, less is known about the transitional phase, in which acute stress becomes chronic to influence disease development. The most important factors affecting this probable chronic transition from hypercortisolemic states into hypocortisolemia are developmental timing, duration, frequency, nature, controllability, and subjective stressor appraisal [3]. In extreme cases, hyperactivity of the stress system is reflected in the symptom complex of melancholic depression. This state consists of anxiety, increased expectation of harm, feelings of worthlessness, insomnia, loss of appetite, inflammation, and activations of the HPA axis and the sympathetic nervous systems [4]. Hypocortisolism is most dramatically expressed in the syndrome of atypical depression, which is associated with lethargy, fatigue, feeling disconnected from self and others, increased sleep, and increased appetite [4].

de Kloet and Joels further broaden the relevance of Agorastos and Chrousos’s article by complementing it with concepts on coping style, vulnerability, resilience, and their circuitries and networks [2]. We are learning much about the neural structures and brain mediators that influence self-concept and self-esteem. Loss of self-esteem represents one of the significant stressors to which human beings are vulnerable and should be considered equally powerful a precipitant of severe distress as other forms of psychological and physical stress.

Three major networks make significant contributions to identity. The default mode network focuses on inward attention, emphasizing self-assessment and self-judgment [5]. In the context of an activated amygdala, as in melancholic depression, the sense of self is weakened and can be experienced as a sense of worthlessness. The central executive network, on the other hand, when activated, is associated with a diminution in the impact of the default mode network and biases attention towards working memory and other executive functions [6]. When associated with activations of the ventral striatum, this is often associated with feelings of grandiosity and great personal worth, manifested significantly in full-blown manic states [6,7,8]. The salience network is associated with a shift from the default mode network’s interior focus on the salience of external stimuli. This system of the three networks orchestrates a critical, potentially rapid change in one’s sense of self or identity [8].

The subgenual cingulate cortex of the anterior cingulate cortex estimates the likelihood of punishment or reward, restrains the amygdala, primes the ventral striatum, and plays a role in the calibration of self-esteem [4, 9, 10]. When it is hypoactive, as in depression, self-esteem is steeply diminished. The ventral striatum itself is vital to identity. Without the capacity to anticipate or experience pleasure, the likelihood of a good feeling about the self is profoundly diminished.

For example, the experience of getting caught up, such as craving and identifying with or being attached to attributes of ourselves, activates this circuit. Moreover, data support that the posterior cingulate cortex reduces in activity when we are not caught up in experience, whether being focused on a task or meditating [11].

Various aspects of the ventromedial prefrontal cortex (VMPFC) are activated when people contemplate various aspects of themselves and their lives, such as their traits, experiences, preferences, abilities, and goals [12]. Recent evidence suggests that this region may contribute to assigning personal value or significance to self-related contents: stimuli and mental representations that refer or relate to the self tend to be assigned unique value or significance, and the function of the VMPFC may precisely be to evaluate or represent such significance [12,13,14,15,16]. Several lines of evidence suggest that VMPFC activity during self-processing depends on the personal significance of self-related contents. First, increasing psychological distance from self-representation leads to decreased activation in the VMPFC. Second, the magnitude of VMPFC activation increases linearly with the personal importance attributed to self-representation [13]. Third, the activity of the VMPFC is modulated by individual differences in the interest placed on self-reflection. Lastly, the VMPFC responds to outer aspects of self with high personal value, such as possessions and being close to others. By assigning personal value to self-related contents, the VMPFC may play an important role in constructing, stabilizing, and modifying self-representations and ultimately guiding our choices and decisions [13, 17].

The brain’s most important mediator of identity is the anterior insula and its connections with sites such as the precuneus of the parietal lobe and the posterior cingulate cortex. The insula is only rudimentary in non-human primates and other animals [18, 19].

Craig provides many elegant lines of data on the critical role of the anterior insula in emotional awareness in many dimensions, including its cognitive components, as well as the influence of emotion in such domains as cognitions [19]. In addition, the anterior insula, which is responsible for the individual’s capacity to recognize images of themselves and for many other components of self-awareness, is also critical for awareness of the moment, time perception, perceptual space, decision-making, and cognitive and performance monitoring. As such, Craig suggests that the insula should be considered a potentially important neural correlate of consciousness [19].

The anterior portion of the human insula has evolved more than any other subdivision. It is virtually unique in containing von Economo neurons, which are the substrate for fast interconnections between such physically separated loci as the limbic and motor cortices and for emotional awareness [19, 20]. The loss of emotional awareness and self-conscious behaviors in patients with frontotemporal dementia that correlates with von Economo neuron degeneration supports this notion directly.

The insula generates many of the emotions associated with conscious happiness. Craig points out that mothers’s viewing their children activatea the left anterior insula. Greater activation on the left than the right is also associated with romantic love when either seeing or making a smile, attending to happy voices, hearing pleasant music, and in individuals experiencing joy. Activation of the left insula also correlates in females with self-reported orgasm ratings. In addition, the pathological dysfunction of any of these areas could significantly influence self-esteem in any respect, most pathologically in states of depression or mania [19].

The second paper by de Kloet and Joels extends the work of Chrousos’ group. It presents concepts regarding the cortisol switch between resilience and vulnerability, highlighting the contrasting role of the mineralocorticoid (MR) and glucocorticoid (GR) receptors. They emphasize that if the optimal balance between the activation of these receptor systems is altered, significant pathophysiology in the stress system response ensues. Their optimal balance promotes resilience in threats, adversity, and trauma.

Characteristics of MR modulation

de kloet and Joels note that the on switch for the stress response is initially affected by activation of the evolutionarily older MR receptor. MR activation serves as an on-switch in selecting an appropriate adaptive response. MR activation promotes neuroplasticity and neurogenesis and serves a neuroprotective function. MR effects on the brain also promote attention, vigilance, memory retrieval, risk assessment, response selection, and the selection of coping styles to save energy. If activation of the MR is excessive, a rigid, proactive coping style occurs characterized by low cortisol and high sympathetic output in response to social conflict. Thus, dysregulation of MR receptors potentially leads to cognitive inflexibility.

Moreover, it is of interest that this unusual dissociation of increased sympathetic outflow and decreased cortisol levels occurs in posttraumatic stress disorder (PTSD). To our knowledge, PTSD is the only entity where this dissociation occurs. Thus, spironolactone might help treat PTSD. In this regard, the antagonism of infralimbic MR prevents the stress-induced impairment of aversive memory extinction in rats.

de Kloet and Joels write that an MR gain of function variant is associated with improved stress handling and rapid peak responses of ACTH and cortisol. MR activation also results in an optimistic disposition, less rumination, and reduced hopelessness. Underactivity of the MR is associated with a diathesis to depression. In addition, decreased MR gene expression was found in the postmortem brains of patients with major depression. We have previously found that the chronic daily 3 months administration of imipramine to rats significantly increases MR mRNA expression in the hippocampus [21]. Thus, a decrease in the functional activity of the MR predisposes to depressive features. A decrease in the activation of the MR might also contribute to the hypercortisolism of depression. This dissociation of the MR and GR system characterizes a serious disease of adaptation.

Characteristics of GR activation

de Kloet and Joels state that one of the principal roles of GR activation during the stress response is to terminate it when it is no longer needed, which includes termination of the HPA axis activation and inflammatory components of the stress response.

Suppose the stressor is acknowledged as a threat to the safety or integrity of the organism. In this case, the GR becomes activated to promote further cognitive control and storage of the emotional memory of the experience, as well as ultimately bringing the stress response to a halt. The resultant hypercortisolism flattens the circadian pattern of HPA axis activation and downregulation of hippocampal GR receptors. Activation of GR receptors also sets metabolic and other physiologic concomitants of a concerted stress response into motion.

Chronically elevated cortisol levels via GR activation set hypertrophy into motion and increase amygdala neuroplasticity. Hypercortisolism also sets into motion emotional hyperactivity. In concert, there is atrophy in the hippocampus and multiple PFC areas. These cause significant abnormalities in cognitive flexibility and reward processing.

In integrating known information about the MR and GR systems, de Kloet and Joels state that, in many respects, they exert effects that are often the opposite of the other in orchestrating the normal response to stress that are each necessary. Moreover, dysregulation of the stress response occurs if the two systems are not in the correct balance. As one example, the MR system initiates the stress response, promotes the activity of multiple PFC sites, and promotes neuroplasticity and neurogenesis, inflammation, memory retrieval, risk assessment, and response selection. The GR system terminates the response when it is no longer needed, including the inflammatory component, and contributes to the consolidation of the emotional memory of the event rather than memory retrieval. In the context of chronic stress, sustained activation of GR receptors leads to hypertrophy of the amygdala, inhibition of multiple PFC sites, and a reduction in neuroplasticity and neurogenesis. An MR and GR system imbalance, such as occurs during chronic unrelieved stress, is pathogenic.

de Kloet and Joels pay tribute to Bruce McEwen, who first identified the MR in the hippocampus. They cite the recent work of George Chrousos’ group, another major contributor to our understanding of emotional and physical stress mechanisms and the consequences of their dysregulation.