Glucocorticoid-Mediated Developmental Programming of Vertebrate Stress Responsivity

Glucocorticoids, vertebrate steroid hormones produced by cells of the adrenal cortex or interrenal tissue, function dynamically to maintain homeostasis under constantly changing and occasionally stressful environmental conditions. They do so by binding and thereby activating nuclear receptor transcription factors, the Glucocorticoid and Mineralocorticoid Receptors (MR and GR, respectively). The GR, by virtue of its lower affinity for endogenous glucocorticoids (cortisol or corticosterone), is primarily responsible for transducing the dynamic signals conveyed by circadian and ultradian glucocorticoid oscillations as well as transient pulses produced in response to acute stress. These dynamics are important determinants of stress responsivity, and at the systemic level are produced by feedforward and feedback signaling along the hypothalamus-pituitary–adrenal/interrenal axis. Within receiving cells, GR signaling dynamics are controlled by the GR target gene and negative feedback regulator fkpb5. Chronic stress can alter signaling dynamics via imperfect physiological adaptation that changes systemic and/or cellular set points, resulting in chronically elevated cortisol levels and increased allostatic load, which undermines health and promotes development of disease. When this occurs during early development it can “program” the responsivity of the stress system, with persistent effects on allostatic load and disease susceptibility. An important question concerns the glucocorticoid-responsive gene regulatory network that contributes to such programming. Recent studies show that klf9, a ubiquitously expressed GR target gene that encodes a Krüppel-like transcription factor important for metabolic plasticity and neuronal differentiation, is a feedforward regulator of GR signaling impacting cellular glucocorticoid responsivity, suggesting that it may be a critical node in that regulatory network.

Future-Proofing Startups: Stress Management Principles Based on Adaptive Calibration Model and Active Inference Theory

In this paper, the Adaptive Calibration Model (ACM) and Active Inference Theory (AIT) are related to future-proofing startups. ACM encompasses the allocation of energy by the stress response system to alternative options for action, depending upon individuals’ life histories and changing external contexts. More broadly, within AIT, it is posited that humans survive by taking action to align their internal generative models with sensory inputs from external states. The first contribution of the paper is to address the need for future-proofing methods for startups by providing eight stress management principles based on ACM and AIT. Future-proofing methods are needed because, typically, nine out of ten startups do not survive. A second contribution is to relate ACM and AIT to startup life cycle stages. The third contribution is to provide practical examples that show the broader relevance ACM and AIT to organizational practice. These contributions go beyond previous literature concerned with entrepreneurial stress and organizational stress. In particular, rather than focusing on particular stressors, this paper is focused on the recalibrating/updating of startups’ stress responsivity patterns in relation to changes in the internal state of the startup and/or changes in the external state. Overall, the paper makes a contribution to relating physics of life constructs concerned with energy, action and ecological fitness to human organizations.

Effects of Biological Sex and Stress Exposure on Ventromedial Prefrontal Regulation of Mood-Related Behaviors

The ventral portion of the medial prefrontal cortex (vmPFC) regulates mood, sociability, and context-dependent behaviors. Consequently, altered vmPFC activity has been implicated in the biological basis of emotional disorders. Recent methodological advances have greatly enhanced the ability to investigate how specific prefrontal cell populations regulate mood-related behaviors, as well as the impact of long-term stress on vmPFC function. However, emerging preclinical data identify prominent sexual divergence in vmPFC behavioral regulation and stress responsivity. Notably, the rodent infralimbic cortex (IL), a vmPFC subregion critical for anti-depressant action, shows marked functional divergence between males and females. Accordingly, this review examines IL encoding and modulation of mood-related behaviors, including coping style, reward, and sociability, with a focus on sex-based outcomes. We also review how these processes are impacted by prolonged stress exposure. Collectively, the data suggest that chronic stress has sex-specific effects on IL excitatory/inhibitory balance that may account for sex differences in the prevalence and course of mood disorders.

Fathers' Heightened Stress Responses to Recounting their NICU Experiences Months after Discharge: A Mixed Methods Pilot Study

Objective The acute and traumatic events associated with having a newborn who requires admission to the neonatal intensive care unit (NICU) may elicit long-term concerns for parents postdischarge. Cognitive processing of taxing events influences recurring stress responses, which can be inferred via biomarkers such as salivary cortisol (sCort) and skin conductance (SC). In addition, personal narratives provide an important insight into individual perceptions and coping strategies. The current pilot study aimed to (1) test the hypotheses that fathers' sCort and SC would peak in response to stress induction and decrease during recovery, (2) examine associations among stress biomarkers and stress perceptions, (3) explore fathers' narratives using thematic analysis, and (4) integrate fathers' narrative themes with their stress responsivity. Study Design Using a convergent mixed methods approach, we enrolled 10 fathers of infants formerly cared for in NICU who underwent a Trier Social Stress Test including recounting their NICU experience months postdischarge. Stress responsivity was measured via sCort and SC, while stress perceptions were identified by using the Perceived Stress Scale and Distress Thermometer-Parent. Personal narratives were explored by using thematic analysis. Results The significant rise in fathers' sCort and SC in response to stress induction was reflected in narrative themes including loss, worry, and role strain. Subsequently, fathers' sCort and SC returned to baseline, which was illustrated by themes such as role strength, coping, and medical staff interactions. Fathers' stress measured by PSS was lower than that required for mental health referral, and did not correlate with stress biomarkers. Conclusion Salivary cortisol and skin conductance are useful biomarkers of paternal stress responsivity and recovery. Thematic analysis identified fathers' NICU stressors and coping strategies that mirrored their stress responsivity patterns. Further studies are needed to more broadly examine the sociodemographic variables that influence stress reactivity and perceptions in parents of infants formerly cared for in NICU. Key Points

Coordinated action of CRH and cortisol shapes acute stress-induced behavioural response in zebrafish

Introduction: The stress response mediated by the hypothalamus-pituitary-adrenal (HPA) axis activation is highly conserved in vertebrates. Hyperactivity is one such established acute stress response and corticotropin-releasing hormone (CRH), the primary step in HPA activation, signalling has been implicated in this stressor-mediated behaviour. However, whether CRH mediates the acute behavioural effects either alone or in conjunction with glucocorticoids (GCs) are far from clear. We hypothesized that the CRH receptor 1 (CRHR1)-mediated rise in GCs post-stress is necessary for the initiation and maintenance of acute stress-related behaviour. Methods: We first generated zebrafish (Danio rerio) with a mutation in the crhr1 gene (CRHR1-KO) to assess the function of CRH. The behavioural readout utilized for this study was the locomotor activity of larval zebrafish in response to acute light exposure, a protocol that freezes the larvae in response to the light stimulus. To test whether cortisol signalling is involved in the stress-mediated hyperactivity, we treated wildtype fish with metyrapone, an inhibitor of 11β-hydroxylase, to suppress cortisol production. The temporal role for cortisol signalling in the stress-related hyperactivity was tested using the glucocorticoid receptor (GRKO) and mineralocorticoid receptor (MRKO) knockout zebrafish mutants. Results: CRHR1-KO larvae did not increase cortisol, the principal GC in teleosts, post-stress, confirming a functional knockout. An acute stress resulted in the hyperactivity of the larvae in light at 15, 60 and 240 min post-stress and this was absent in CRHR1-KO larvae. Addition of metyrapone effectively blocked the attendant rise in cortisol post-stress; however, the stress-mediated hyperactivity was inhibited only at 60 min and 240 min but not at 15 min post-stress. Addition of human CRH peptide caused hyperactivity at 15 min and this response was also abolished in the CRHR1-KO mutants. The stress-induced hyperactivity was absent in the MRKO fish, while GRKO mutants showed transient effects. Conclusions: The results suggest that the stress-induced hyperactivity is induced by the CRH/CRHR1 system, while the temporal activation of cortisol production and the associated GR/MR signalling is essential for prolonging the stressor-induced hyperactivity. This study underscores the importance of systems-level analysis to assess stress responsivity.

The Effects of Social Stress on Memory: If, How and When

Physical stress, such as from the cold-pressor test, has been robustly associated with altered memory retrieval, but it is not yet clear whether the same happens following psychosocial stress. Studies using psychosocial stressors report mixed effects on memory, leading to uncertainty about the common cognitive impact of both forms of stress. The current study uses a stepped replication design, with four near-identical experiments, each differing by a single critical factor. In three experiments we induced psychosocial stress after participants encoded word stimuli, then assessed retrieval after a prolonged delay. These experiments found no group level influence of postencoding stress on recognition of neutral words or cued recall of word-pairs, but a small effect on recollection of semantically-related words. There was, however, some indication of positive relationships within the stress group between measures of stress (cortisol in experiment 1 and self-reported-anxiety in experiment 3) and recollection of single word stimuli. In the fourth experiment, we found that psychosocial stress immediately before retrieval did not influence word recognition. Overall, our findings demonstrate that psychosocial stress has a typically modest impact on memory, lower than previously claimed, but that individual differences in stress responsivity, particularly for tasks that tap recollection, may help to explain variability in previous findings.