Fig. 1.

The Brain Gets “Stuck”. The anticipation and/or perception of a stressor may trigger an alarm reaction causing arousal while a behavioral (vigilance, attention), autonomic (sympathetic nervous system) and neuroendocrine stress response develops. At the same the stressor is appraised for its controllability. While appraisal and stress response networks interact (Cabib et al., 2020; Douma and de Kloet, 2020), resources are shifted from the salience to the executive network underlying rationalization, selection of an appropriate coping style and contextualization to label the experience for memory storage (Cabib et al., 2020; Henckens et al., 2012, 2015; Hermans et al., 2014). If coping fails because of uncertainty about outcome, the stress response is reinforced and prolonged (in red). Upon repeated failure to cope with the stressor, the neurons that underlie emotional reactivity grow (amygdala, orbital frontal cortex), while hippocampus and medial PFC shrink and compromises their role in cognitive control (Wellman et al., 2020), a condition described by Bruce as ‘the brain gets stuck’ (McEwen, 2017; McEwen and Akil, 2020; McEwen et al., 2016). Under these ‘chronic stress' conditions a novel stimulus cannot be processed appropriately, which may lead to breakdown of adaptation, a condition that can be read from altered patterns of glucocorticoid secretion upon challenge by an acute stressor (McEwen, 1998, 2007; Papilloud et al., 2019; Tzanoulinou et al., 2020). If coping is adequate, because expectancy is rewarded and control is regained, the activated stress response system is extinguished, and adaptation promoted (Douma and de Kloet, 2020). Using fMRI, optogenetics and DREADD technology much progress has been made in recent years to understand how medial PFC neuronal ensembles gain control over stress- and emotional reactions, and how this control is translated top down into an altered pattern of neuroendocrine and behavioral responses; glucocorticoids integrate and coordinate in bottom up fashion the brain-body dialogue in stress-coping and adaptation (de Kloet et al., 2019; Herman et al., 2020; Lingg et al., 2020; Ulrich-Lai and Herman, 2009). GR seems involved in regulation of detection thresholds that are relevant for perception of sensory signals (Henkin and Daly, 1968; Obleser et al., 2021) and MR for the threshold or sensitivity of the stress response system; the balance in MR:GR-mediated actions is crucial for proper processing of information in the salience and executive networks (de Kloet et al., 1999, 2018; Joels et al., 2018; Wirz et al., 2017). MR activation facilitates retrieval processes, risk assessment and response selection; GR activation promotes rationalization and contextualization facilitating memory storage and behavioral adaptation (Oitzl and de Kloet, 1992; Roozendaal and McGaugh, 2011). Cartoon inspiration from discussions with Pieter Smelik, Nuno Sousa and Bruce McEwen. Green denotes that adequate coping extinguishes the stress response and promotes resilience, while red color denotes that failure to cope reinforces the stress response and leads to a crash of information processing. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)