AVP-eGFP was significantly upregulated by hypovolemia in the parvocellular division of the paraventricular nucleus in the transgenic rats.

Arginine vasopressin (AVP) is produced in the paraventricular (PVN) and supraoptic nuclei (SON). Peripheral AVP, which is secreted from the posterior pituitary, is produced in the magnocellular division of the PVN (mPVN) and SON. In addition, AVP is produced in the parvocellular division of the PVN (pPVN), where corticotrophin-releasing factor (CRF) is synthesized. These peptides synergistically modulate the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have revealed that the HPA axis was activated by hypovolemia. However, the detailed dynamics of AVP in the pPVN under hypovolemic state has not been elucidated. Here, we evaluated the effects of hypovolemia and hyperosmolality on the hypothalamus, using AVP-enhanced green fluorescent protein (eGFP) transgenic rats. Polyethylene glycol (PEG) or 3% hypertonic saline (HTN) was intraperitoneally administered to develop hypovolemia or hyperosmolality. AVP-eGFP intensity was robustly upregulated at 3 and 6 h after intraperitoneal administration of PEG or HTN in the mPVN. While in the pPVN, eGFP intensity was significantly increased at 6 h after intraperitoneal administration of PEG with significant induction of Fos-immunoreactive (-ir) neurons. Consistently, eGFP mRNA, AVP hnRNA, and CRF mRNA in the pPVN and plasma AVP and corticosterone were significantly increased at 6 h after intraperitoneal administration of PEG. The results suggest that AVP and CRF syntheses in the pPVN were activated by hypovolemia, resulting in the activation of the HPA axis.

Pituitary-Adrenal Responses and Glucocorticoid Receptor Expression in Critically Ill Patients with COVID-19.

The hypothalamus-pituitary-adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged sword; whereas inflammation that is timely and of appropriate magnitude is beneficial, exuberant systemic inflammation incites tissue damage with potentially devastating consequences. Apart from its beneficial cardiovascular and metabolic effects, cortisol exerts a significant immunoregulatory role, a major attribute being that it restrains the excessive inflammatory reaction, thereby preventing unwanted tissue damage. In this review, we will discuss the role of the HPA axis in the normal stress response and in critical illness, especially in critically ill patients with coronavirus disease 2019 (COVID-19). Finally, a chapter will be dedicated to the findings from clinical studies in critical illness and COVID-19 on the expression of the mediator of glucocorticoid actions, the glucocorticoid receptor (GCR).

Does dehydroepiandrosterone sulfate have a role in COVID-19 prognosis and treatment?

The pathophysiology of COVID comprises an exaggerated pro-inflammatory response. Hypothalamic-pituitary-adrenal (HPA) axis has a crucial role in various inflammatory conditions and modulated immunological response. Limited evidence is available regarding the incidence and the effect of HPA dysfunction in COVID-19. Although the cortisol levels have only been estimated in a few studies, the dehydroepiandrosterone sulfate (DHEAS) release from the adrenal gland has not been explored yet. In this mini review, the authors discuss the role of dehydroepiandrosterone (DHEA) and DHEAS in the acute stress response and immunological modulation. Various effects of DHEAS have been demonstrated in different diseases. The specific inhibitory effect of DHEA on interleukin 6 (IL-6) could be of paramount importance in COVID-19. Further, DHEA supplementation has already been proposed in inflammatory conditions, like rheumatoid arthritis. DHEAS levels in COVID-19 may help to understand the HPA axis dysfunction as well as the possibility of repurposing DHEA as a drug for mitigating the pro-inflammatory COVID-19.

Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia.

Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies.

Impact of loneliness on diurnal cortisol in youth.

Loneliness is associated with multiple forms of psychopathology in youth. However, we do not yet know how loneliness gets "under the skin" in ways that may impact the long-term health and development of early adolescents. In particular, loneliness may influence youths' patterns of diurnal cortisol, an index of hypothalamic-pituitary-adrenal (HPA) axis functioning and a central predictor of health across the lifespan. The current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, or COVID-19) pandemic represents a salient period in which to study the consequences of loneliness, as recent work has provided evidence that the physical-distancing measures put in place to contain the virus have resulted in greater loneliness, particularly among youth. Thus, the current study aimed to examine the prospective association between loneliness during the COVID-19 pandemic and diurnal cortisol in early adolescents. We found that greater loneliness was associated with higher levels of cortisol at waking and a blunted cortisol awakening response (CAR). These results held even when controlling for covariates that can influence diurnal trajectories of cortisol. Critically, this pattern of HPA-axis functioning increases risk for adverse mental and physical health outcomes across adolescence and into adulthood. This study is the first to examine the prospective association between loneliness and diurnal cortisol in early adolescence, and the first to identify mechanisms that contribute to biological markers of distress during the COVID-19 pandemic. Findings underscore the importance of developing and distributing strategies to mitigate feelings of loneliness among youth.

Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior.

The fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

Testicular Atrophy and Hypothalamic Pathology in COVID-19: Possibility of the Incidence of Male Infertility and HPG Axis Abnormalities.

Coronavirus disease 2019 (COVID-19), which resulted from the pandemic outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a massive inflammatory cytokine storm leading to multi-organ damage including that of the brain and testes. While the lungs, heart, and brain are identified as the main targets of SARS-CoV-2-mediated pathogenesis, reports on its testicular infections have been a subject of debate. The brain and testes are physiologically synchronized by the action of gonadotropins and sex steroid hormones. Though the evidence for the presence of the viral particles in the testicular biopsies and semen samples from COVID-19 patients are highly limited, the occurrence of testicular pathology due to abrupt inflammatory responses and hyperthermia has incresingly been evident. The reduced level of testosterone production in COVID-19 is associated with altered secretion of gonadotropins. Moreover, hypothalamic pathology which results from SARS-CoV-2 infection of the brain is also evident in COVID-19 cases. This article revisits and supports the key reports on testicular abnormalities and pathological signatures in the hypothalamus of COVID-19 patients and emphasizes that testicular pathology resulting from inflammation and oxidative stress might lead to infertility in a significant portion of COVID-19 survivors. Further investigations are required to monitor the reproductive health parameters and HPG axis abnormalities related to secondary pathological complications in COVID-19 patients and survivors.

Cortisol level dysregulation and its prevalence-Is it nature's alarm clock?

This review examines the stress hormone cortisol which plays an important role in regulating and supporting different bodily functions. Disruption in cortisol production has an impact on health and this review looks at a wide range of papers where cortisol has been indicated as a factor in numerous chronic conditions-especially those which are classed as "noncommunicable diseases" (NCDs). Timely detection, screening, and treatment for NCDs are vital to address the growing problem of NCDs worldwide-this would have health and socioeconomic benefits. Interestingly, many of the papers highlight the pro-inflammatory consequences of cortisol dysregulation and its deleterious effects on the body. This is particularly relevant given the recent findings concerning COVID-19 where pro-inflammatory cytokines have been implicated in severe inflammation.

Cytokine Storm in COVID19: A Neural Hypothesis.

Cytokine storm in COVID-19 is characterized by an excessive inflammatory response to SARS-CoV-2 that is caused by a dysregulated immune system of the host. We are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of nucleus tractus solitarius (NTS) may be responsible for the cytokine storm in COVID 19. The inflamed NTS may result in a dysregulated cholinergic anti-inflammatory pathway and hypothalamic-pituitary-adrenal axis.