[Stress and depression-a neurobiological perspective]. / Stress und Depression ­ eine neurobiologische Perspektive.

Depression is a common and often very debilitating disease causing a high number of years lost to disability worldwide. Mortality rates are high due to suicide and depression-associated somatic disorders, which seem to have a bidirectional connection. Depression is considered to be stress associated. Adverse life events such as losses, interpersonal conflicts, financial issues, unemployment, and loneliness are often found in the patient history. Also childhood maltreatment is a known risk factor. Chronic stress can cause maladaptive changes in different neurobiological systems and may contribute to the development of depression. Relevant changes have been described in the stress-response and immune systems of persons with depression and those with childhood trauma or abuse. Psychotherapy and antidepressants are both effective, and current treatment guidelines recommend their combination in severe depressive episodes.

Unbiased multitissue transcriptomic analysis reveals complex neuroendocrine regulatory networks mediated by spinal cord injury-induced immunodeficiency.

BACKGROUND: Spinal cord injury (SCI), which causes loss of sensory and motor function in the body below the level of injury, is a devastating disease of the central nervous system. SCI leads to severe secondary immunosuppression, called SCI-induced immunodeficiency syndrome (SCI-IDS), which is characterized by increased susceptibility to infection and further exacerbates neurological dysfunction. Several studies have suggested that SCI-IDS is an independent risk factor for poor neurological prognosis. SCI-IDS predominantly occurs following injury above the T5 levels and eventually leads to systemic immune failure, possibly via the sympathetic-adrenal medullary axis and the hypothalamic‒pituitary‒adrenal (HPA) axis. However, the mechanism remains unclear. METHODS AND OBJECTIVES: The concentrations of adrenocorticotropic hormone and cortisol in plasma, as well as changes in sympathetic activity (blood pressure and catecholamine levels in plasma), were assessed in rats in the high-level (T3) spinal cord injury (T3-SCI) group and the low-level (T10) spinal cord injury (T10-SCI) group. Second, the differential regulation of the gene network between the sympathetic-adrenal medullary axis and the HPA axis was explored by histology and multitissue transcriptomics, and the neuroendocrine-immune network associated with SCI-IDS was further elucidated. RESULTS: The spleen and thymus gland, which are secondary immune organs, were significantly atrophied in rats in the T3-SCI group, and the white pulp of the spleen was significantly atrophied. The level of cortisol, which is mediated by the adrenal glands, was markedly elevated, but norepinephrine levels were markedly decreased. There was no difference in adrenocorticotropic hormone expression between any of the groups. The transcriptome analysis results showed that the downregulated differentially expressed genes (DEGs) in the T3-SCI group were enriched in the GO term immunoregulation, indicating that splenic immune function was markedly impaired after high-level SCI. The upregulated DEGs in the hypothalamus (hub genes: Nod2, Serpine1, Cebpb, Nfkbil1, Ripk2, Zfp36, Traf6, Akap8, Gfer, Cxcl10, Tnfaip3, Icam1, Fcgr2b, Ager, Dusp10, and Mapkapk2) were significantly enriched in inflammatory pathways, and the downregulated genes (hub genes: Grm4, Nmu, P2ry12, rt1-bb1, Oprm1, Zfhx2, Gpr83, and Chrm2) were enriched in pathways related to inhibitory Gi-mediated G protein-coupled receptor (Gi-GPCR) neurons and neuropeptide changes. The upregulated genes in the adrenal glands (hub genes: Ciart, per2, per3, cry1, and cry2) were enriched in cortisol secretion and circadian rhythm changes, and the downregulated genes (hub genes: IL7r, rt1-bb, rt1-bb1, rt1-da, rt1-ba, cd74, cxcr3, vcam1, ccl5, bin1, and IL8) were significantly enriched in MHC-mediated immune responses. CONCLUSIONS: To explore the possible mechanism underlying SCI-IDS, this study assessed the differential regulation of the gene network associated with neuroendocrine immunity after SCI. Progressive neuroinflammation spreads after injury, and neurotransmission through Gi-mediated G protein-coupled receptors in the HPA axis and neuropeptide production by the hypothalamus are inhibited. Disruption of the connection between the hypothalamus and the adrenal glands causes autonomous regulation of the adrenal glands, disturbance of circadian rhythm and finally hypercortisolemia, leading to general suppression of peripheral adaptive immunity. Neuraxial nerve inflammation caused by SCI persists indefinitely, blocking nerve repair; persistent system-wide immunosuppression in the periphery results in increased susceptibility to infection, leading to poor neurological prognosis.

Characterising approaches to steroid therapy in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2.

AIM: We describe approaches to steroid therapy use in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and examine the association between steroid therapy and key clinical markers of severity. METHODS: We conducted a retrospective review of children (<18 years) admitted to a tertiary paediatric hospital in the UK with PIMS-TS. We collected data on if and why steroid therapy was used; the duration, type and dosing of steroids prescribed; and approaches to hypothalamo-pituitary-adrenal (HPA) axis monitoring, if performed. We examined associations between steroid exposure/total steroid dose (mg/m2 /day) and paediatric intensive care unit admission, mechanical ventilation and inotropic support. RESULTS: Steroid therapy was commenced in most children (84.9%, n = 104) with a median total daily steroid dose (hydrocortisone equivalent) of 271.0 mg/m2 /day (interquartile range 232.5-355.5) and treatment length of 26.0 days (interquartile range 19.0-32.0). Dosing regimens predominantly involved a short course of high-dose methylprednisolone followed by tapering oral prednisolone. Basal and/or dynamic testing of the HPA axis was conducted in a minority (11.8%, n = 15) and was normal. Duration of steroid therapy correlated positively with durations of paediatric intensive care unit admission (r = 0.407, P < 0.001) and mechanical ventilation (r = 0.797, P < 0.001). A greater proportion of children receiving steroid therapy also received inotropic support compared to those that did not receive steroid therapy (71.4% vs. 45.5%, P = 0.025). CONCLUSION: Prolonged, high-dose steroid therapy is often used in the management of severe PIMS-TS with the potential for HPA axis suppression and should be withdrawn carefully.

PITUITARY FUNCTIONS AFTER RECOVERY FROM COVID-19.

Context: Injury and functional disorders in pituitary gland after COVID-19 still need elucidation. Objective: To investigate pituitary functions, particularly hypothalamic pituitary adrenal (HPA) axis after COVID-19 infection. Methods: This study was conducted at a university hospital between May and October 2021. Patients who had COVID-19, were enrolled as study group, three months after recovery. Participants who do not have COVID-19 diagnosis, with similar characteristics were included as control group. Blood samples were taken on the morning at 08 AM. Adrenal stimulation test was performed with 1 µg of ACTH (Synacthen). Results: The study group included 50 patients and control group was 49 cases. One (2%) out of the 50 patients with 8 a.m. serum cortisol below 5 µg/dL. Low serum ACTH levels were detected in 7 (14%) participants in patient group. Stimulation with 1 µg of ACTH (Synacthen) test was performed for 2 (4%) of 50 patients with serum cortisol below 10 µg/dL. Both patients achieved a peak cortisol of over 12.5 µg/dL after stimulation. Standard deviation (SD) score for insulin like growh factor-1 (IGF-1) was lower than -2 SD for age and gender in 7 (14%) patients. TSH levels was mildly increased in five (10%) patients. There was no significant difference in baseline pituitary hormone levels in study and control groups. Conclusion: Basal pituitary hormone levels and HPA axes were found to be preserved and competently functioning in patients who experienced mild/moderate COVID-19. However, symptoms observed after COVID-19 episode were evident in substantial amount of patients in this study and these symptoms were not associated with changes in pituitary gland function.

Stress system dysfunction revealed by integrating reactivity of stress pathways to psychological stress in lean and overweight/obese men.

Although the patterns of response within the sympathoadrenal medullary (SAM) system and hypothalamo-pituitary adrenal (HPA) axis are interesting and important in their own accord, the overall response to acute psychological stress involves reactivity of both pathways. We tested the hypothesis that consideration of the integrated response of these pathways may reveal dysregulation of the stress systems, which is not evident when considering either system alone. Age-matched lean and overweight/obese men were subjected to a Trier Social Stress Test and reactivity of the SAM system (salivary α-amylase, systolic blood pressure, diastolic blood pressure, and heart rate) and the HPA axis (salivary cortisol) were measured. Relative reactivity of SAM system and HPA axis was calculated as the ratio between the measures from each pathway. Although analysis of reactivity of individual stress pathways showed no evidence of dysfunction in overweight/obese compared with lean men, analysis of HPA/SAM reactivity revealed significantly lower cortisol over systolic blood pressure (CoSBP) and cortisol over diastolic blood pressure (CoDBP) reactivity in overweight/obese compared with lean men. Other measures of HPA/SAM reactivity and all measures of SAM/HPA reactivity were unaltered in overweight/obese compared with lean men. These findings suggest that the cortisol response per unit of blood pressure response is blunted in men with elevated adiposity. Furthermore, these findings support a notion of a coordinated overall approach to activation of the stress pathways with the degree of activation in one pathway being related to the degree of activation in the other.

The Adrenergic Nerve Network in Cancer.

The central and autonomic nervous systems interact and converge to build up an adrenergic nerve network capable of promoting cancer. While a local adrenergic sympathetic innervation in peripheral solid tumors influences cancer and stromal cell behavior, the brain can participate to the development of cancer through an intermixed dysregulation of the sympathoadrenal system, adrenergic neurons, and the hypothalamo-pituitary-adrenal axis. A deeper understanding of the adrenergic nerve circuitry within the brain and tumors and its interactions with the microenvironment should enable elucidation of original mechanisms of cancer and novel therapeutic strategies.

Giving a good start to a new life via maternal brain allostatic adaptations in pregnancy.

Successful pregnancy requires adjustments to multiple maternal homeostatic mechanisms, governed by the maternal brain to support and enable survival of the growing fetus and placenta. Such adjustments fit the concept of allostasis (stability through change) and have a cost: allostatic load. Allostasis is driven by ovarian, anterior pituitary, placental and feto-placental hormones acting on the maternal brain to promote adaptations that support the pregnancy and protect the fetus. Many women carry an existing allostatic load into pregnancy, from socio-economic circumstances, poor mental health and in 'developed' countries, also from obesity. These pregnancies have poorer outcomes indicating negative interactions (failing allostasis) between pre-pregnancy and pregnancy allostatic loads. Use of animal models, such as adult prenatally stressed female offspring with abnormal neuroendocrine, metabolic and behavioural phenotypes, to probe gene expression changes, and epigenetic mechanisms in the maternal brain in adverse pregnancies are discussed, with the prospect of ameliorating poor pregnancy outcomes.

Interactions of body temperature and nutritional status on hypothalamo-pituitary-adrenal axis activity in pre-thermoregulatory eastern bluebird chicks (Sialia sialis).

Early life experiences can affect the function of the hypothalamo-pituitary-adrenal (HPA) axis of vertebrates, with potential fitness consequences later in life. In altricial species, for example, variation in parental behavior, e.g. brooding or feeding, can modify the activity of the HPA axis of the young by altering their exposure to noxious stimuli as the young develop in the nest. We have shown that a drop in the body temperature of eastern bluebird (Sialia sialis) chicks, such as occurs when females are away from the nest, elevates their blood corticosterone levels. If repeated during the early days of their development, cooling bouts also reduce the chicks' later corticosterone secretion in response to handling. Thus, variation in maternal behavior has the capacity to shape the function of the chicks' HPA axis. To better understand how maternal absence from the nest activates the HPA axis of bluebird chicks, we experimentally mimicked the cooling that occurs when the female is away from the nest, and investigated a) the age at which the HPA axis becomes capable of responding to cooling by increasing corticosterone secretion, b) whether corticosterone secretion remains elevated throughout long periods of cooling, and c) whether fasting (also potentially associated with maternal absence) interacts with cooling to affect corticosterone secretion. Cooling for 18 min significantly elevated circulating corticosterone levels of chicks as young as 4 days post-hatch, indicating that their HPA axis is sensitive to cooling very early in life. Corticosterone levels remained elevated throughout longer bouts of cooling. However, a 1-hr period of fasting had no effect on corticosterone secretion, regardless of whether chicks were cooled or not. Collectively, these data demonstrate that variation in maternal brooding behavior can substantially modify the corticosterone profiles of chicks during early postnatal development, and that chick temperature is likely the main driver of this.

Pro-inflammatory immune-to-brain signaling is involved in neuroendocrine responses to acute emotional stress.

Activation of the hypothalamo-pituitary-adrenal (HPA) axis by inflammatory stressors (e.g., bacterial lipopolysaccharide) is thought to involve vascular transduction of circulating cytokines, with perivascular macrophages (PVMs) along with endothelia, effecting activation of HPA control circuitry via inducible (cyclooxygenase-2- or COX-2-dependent) prostaglandin synthesis. To test the stressor-specificity of this mechanism, we examined whether ablation of PVMs or pharmacologic blockade of COX activity affected HPA responses to a representative emotional stressor, restraint. Exposing rats to a single 30min acute restraint episode provoked increased plasma levels of at least one proinflammatory cytokine, IL-6, microglial activation and multiple indices of cerebrovascular activation, including COX-2 expression and increased brain prostaglandin E2 levels at 0-2h after stress. Pretreatment with the nonselective COX inhibitor, indomethacin, either icv (10µg in 5µl) or iv (1mg/kg) significantly reduced restraint-induced Fos expression in the paraventricular hypothalamic nucleus (PVH) by 45%, relative to vehicle-injected controls. A 75% reduction of the PVH activational response was seen in rats exposed to acute restraint 5-7days after ablation of brain PVMs by icv injection of liposomes encapsulating the bisphosphonate drug, clodronate. Basal plasma levels of ACTH and corticosterone were not altered in clodronate liposome-injected rats, but the peak magnitude of restraint-induced HPA secretory responses was substantially reduced, relative to animals pretreated with saline-filled liposomes. These findings support an unexpectedly prominent role for inducible prostaglandin synthesis by PVMs in HPA responses to acute restraint, a prototypic emotional stressor.

Effects of neuro-immuno-modulation on healing of wound combined with local radiation injury in rats.

PURPOSE: To investigate effects of neuro-immuno-modulation on wound healing by observing changes of cytokines and hypothalamic-pituitary-adrenal (HPA) axis hormones in acute stress reaction in rats with wound and combined local radiation injury. METHODS: Sixty female Wistar rats (weighting 200 ± 20 g) were randomly divided into normal control group, wound group and combined wound-local radiation (CWR) group (25 Gy local radiation post wound), 20 rats in each group. Contents of IL-1ß, IL-6 and IFN-γ and IL-4 in serum were measured and changes of adrenocorticotropic hormone (ACTH) and glucocorticoid (GC) in serum were analyzed by using enzyme-linked immunosorbent assay and radioimmunologic assay, respectively at different time points post wound and radiation. RESULTS: (1) The level of IFN-γ, one of the Th1 cell cytokines increased significantly at 14 d post CWR, which was markedly higher than that in control group and wound group. However, the level of IL-4, IL-1ß and IL-6, one of the Th2 cell cytokines, did not show obvious change. (2) Ratio of Th1/Th2 (IFN-γ/IL-4) in wound group and CWR group increased significantly at 7 d after wound and radiation, which suggested that Th1/Th2 balance drifted to Th1 immune response. The ratio of Th1/Th2 in wound group returned to the normal level up to 14 d after the wound and radiation, while the Th1/Th2 ratio in CWR group increased persistently and was much higher than that in control and wound groups. (3) Level of serous ACTH and GC in CWR group increased at 3 d post wound and radiation, and among them, level of GC showed statistically significant increase, which was much higher than that in control and wound groups. CONCLUSION: Level of serous neurohormone GC in rats increased significantly immediately after wound and radiation; while the level of IFN-γ showed significant increase only up to 14 d after wound and radiation, and the Th1/Th2 imbalance sustained till 28 d post wound and radiation. In order to reduce acute damage caused by CWR, organic immune system and nerve system showed up a marked regulate effects simultaneously and mutually. Nonetheless, the excessive stress induced by CWR causes disturbance of immunoregulation, which is one of the key reasons for delayed wound healing in CWR.

Use of day 1 early morning cortisol to predict the need for glucocorticoid replacement after pituitary surgery.

BACKGROUND: Assessment of adrenal reserve in patients who have undergone pituitary surgery is crucial. However, there is no clear consensus with regards to the type and timing of the test that should be used in the immediate post-operative period. Recently, there has been increased interest in measuring post-operative cortisol levels. We present our data utilising day 1 post-operative early morning cortisol as a tool to assess adrenal reserve in steroid-naive patients. METHODS: A retrospective analysis of endoscopic pituitary surgery undertaken over a 2-year period. 82 patients underwent 84 surgeries in total. Patients who were already on glucocorticoids pre-operatively and patients with Cushing's disease, pituitary apoplexy and those without follow-up data were excluded, leaving a study group of 44 patients with 45 operations. A 9am day 1 post-operative cortisol value of > 400 nmol/L was taken as an indicator of adequate adrenal reserve. All the patients were reassessed at 6 weeks with a standard short synacthen test (SST) using 250 micrograms of intravenous synacthen. RESULTS: 22 out of 45 patients had a cortisol value of > 400 nmol/L on day 1 post-operatively and were discharged without glucocorticoid supplementation. Of these, only 2 patients subsequently failed the SST when reassessed at 6-8 weeks. The remaining 23 patients had a cortisol value of < 400 nmol/L on day 1 post-operatively and were discharged on hydrocortisone 10 mg twice daily. At 6-8 weeks, nine continued to show suboptimal stimulated cortisol levels whereas the remaining fourteen patients showed adequate adrenal reserve. The 9 am cortisol value had high specificity (81.8%) and positive predictive value (90.9%) for integrity of the HPA axis. Sensitivity was 58.8% and negative predictive value was 39.1%. CONCLUSION: A day 1 post-operative early morning cortisol is a useful tool to predict adrenal reserve post-pituitary surgery, enabling clinicians to avoid unnecessary blanket glucocorticoid replacement.

A blurring of life-history lines: Immune function, molt and reproduction in a highly stable environment.

Rufous-collared sparrows (Zonotrichia capensis peruviensis) from valleys in the Atacama Desert of Chile, live in an extremely stable environment, and exhibit overlap in molt and reproduction, with valley-specific differences in the proportion of birds engaged in both. To better understand the mechanistic pathways underlying the timing of life-history transitions, we examined the relationships among baseline and stress-induced levels of corticosterone (CORT), testosterone, and bacteria-killing ability of the blood plasma (BKA), as well as haemosporidian parasite infections and the genetic structure of two groups of sparrows from separate valleys over the course of a year. Birds neither molting nor breeding had the lowest BKA, but there were no differences among the other three categories of molt-reproductive stage. BKA varied over the year, with birds in May/June exhibiting significantly lower levels of BKA than the rest of the year. We also documented differences in the direction of the relationship between CORT and BKA at different times during the year. The direction of these relationships coincides with some trends in molt and reproductive stage, but differs enough to indicate that these birds exhibit individual-level plasticity, or population-level variability, in coordinating hypothalamo-pituitary-adrenal axis activity with life-history stage. We found weak preliminary evidence for genetic differentiation between the two populations, but not enough to indicate genetic isolation. No birds were infected with haemosporidia, which may be indicative of reduced parasite pressure in deserts. The data suggest that these birds may not trade off among different life-history components, but rather are able to invest in multiple life-history components based on their condition.

Role of cortisol in patients at risk for psychosis mental state and psychopathological correlates: A systematic review.

During recent decades, much evidence has been accumulated concerning the neuroendocrine basis of schizophrenia. Recently, research has focused on stress hormones, with cortisol being the most widely researched, during the prodromal phase of psychosis. Thus, the present study aims to systematically review the evidence concerning the role of cortisol in patients at risk for psychosis mental state and its associations with psychopathological correlates. We systematically reviewed the published reports referring to both 'at clinical risk for psychosis' and 'at genetic risk for psychosis' mental state. Sixteen studies were identified. A trend towards increased cortisol levels in saliva emerged. Findings concerning cortisol levels in the blood were minimal and less consistent. The longitudinal studies, though with divergent results, hinted towards upregulation of cortisol secretion prior to psychotic conversion. Regarding cortisol's reactivity, evaluated through neuroendocrine, psychosocial and naturalistic stressors, the findings were minimal and divergent. The hypothesized relation of psychotic symptomatology with cortisol in subjects at risk for psychosis was not confirmed by the majority of the studies. On the contrary, the anxiety parameter and stress-intolerance index were both positively associated with cortisol. In conclusion, the published reports related to the evaluation of cortisol levels/function at prodrome are hitherto minimal. Although the evidence favors cortisol's participation in the pathophysiology of psychosis, the exact cause-effect sequence and the intertwining of cortisol with psychopathology are still unclear.

Environmentally relevant bouts of cooling stimulate corticosterone secretion in free-living eastern bluebird (Sialia sialis) nestlings: potential links between maternal behavior and corticosterone exposure in offspring.

In vertebrates, exposure to stressful stimuli or to elevated glucocorticoids early in development can contribute to phenotypic variation that may have significant fitness consequences. In species with altricial young, offspring may be partially buffered from elevations in glucocorticoids by a period of low glucocorticoid responsiveness to stressors coupled with high levels of parental care. Because altricial young depend heavily on their parents for warmth, parental brooding behavior could buffer offspring from glucocorticoid exposure associated with cooling. We studied eastern bluebirds (Sialia sialis) with two goals: (1) to determine whether an experimental drop in body temperature such as that which might occur when a brooding female is off the nest was sufficient to stimulate glucocorticoid secretion in young chicks, and (2) to examine the extent to which chicks experienced such bouts of cooling in the field. We subjected chicks to treatments simulating nest temperatures while females were brooding or absent from the nest. We also recorded chick surface temperatures and ambient temperatures at nests during the first week of the brood period. Reductions of surface temperature of less than 10°C significantly elevated corticosterone secretion in chicks as young as 5days old, and thermal and hormonal responses of chicks to cooling increased in an age-dependent manner. One quarter of broods experienced repeated, natural bouts of cooling of this magnitude or greater in the nest. Our data suggest that natural variations in maternal brooding patterns can result in differential exposure of offspring to glucocorticoids, and this may have important phenotypic consequences later in life.

Activities of the hypothalamo-pituitary-adrenal axis and autonomic nervous system following a strong earthquake.

This study aimed to investigate the effects of post-traumatic stress, caused by a strong earthquake, on the hypothalamo-pituitary-adrenal axis (HPA) and autonomous nervous system activity (ANS). Activities of the HPA (as salivary cortisol) and ANS (as heart-rate variability [HRV]) were measured following the 2020 Elazig (Türkiye) earthquake (6.8 Richter Scale, classified as strong). A total of 227 participants (103 men (45%) and 124 women (%55)) provided saliva samples twice, namely, 1 week and 6 weeks after the earthquake. Of these participants, HRV was measured in 51 participants by 5 min continuous electrocardiogram (ECG) recording. Frequency- and time-domain parameters of the HRV were calculated to assess the activity of ANS and low/high frequency (LF/HF) ratio was used as surrogate for sympathovagal balance. Salivary cortisol levels decreased from week 1 towards week 6 (17.40 ± 1.48 and 15.32 ± 1.37 ng/mL, respectively, p < 0.05). There were no gender differences (17.99 ± 2.63 and 16.90 ± 1.60 ng/mL, respectively for females and males, p > 0.05) for salivary cortisol levels. There were no differences in time- and frequency domain parameters of the HRV including LF/HF ratio (2.95 ± 0.38 ms2 and 3.60 ± 0.70 ms2 , respectively for week 1 and 6, p > 0.05). The data show that HPA axis activity, but not that of the ANS, remains higher 1 week after the earthquake but decreases afterwards towards the sixth week, suggesting that the HPA axis might be responsible for the long-term effects of a traumatic event like a strong earthquake.

Female baboon adrenal zona fasciculata and zona reticularis regulatory and functional proteins decrease across the life course.

Debate exists on life-course adrenocortical zonal function trajectories. Rapid, phasic blood steroid concentration changes, such as circadian rhythms and acute stress responses, complicate quantification. To avoid pitfalls and account for life-stage changes in adrenocortical activity indices, we quantified zonae fasciculata (ZF) and reticularis (ZR) across the life-course, by immunohistochemistry of key regulatory and functional proteins. In 28 female baboon adrenals (7.5-22.1 years), we quantified 12 key proteins involved in cell metabolism, division, proliferation, steroidogenesis (including steroid acute regulatory protein, StAR), oxidative stress, and glucocorticoid and mitochondrial function. Life-course abundance of ten ZF proteins decreased with age. Cell cycle inhibitor and oxidative stress markers increased. Seven of the 12 proteins changed in the same direction for ZR and ZF. Importantly, ZF StAR decreased, while ZR StAR was unchanged. Findings indicate ZF function decreased, and less markedly ZR function, with age. Causes and aging consequences of these changes remain to be determined.

Evaluation of the hypothalamo-pituitary-adrenal axis during the post-COVID-19 period in patients treated with steroids during the illness.

Objective: COVID-19 is a multisystem immunoinflammatory disorder, and the hypothalamo-pituitary-adrenal (HPA) axis may be affected by SARS-CoV-2 as well as by steroid treatment during the illness. Information on the HPA axis after recovering from COVID-19, especially in those treated with steroids, is sparse. Hence, this study was performed to evaluate the hypothalamo-pituitary-adrenal axis during the post-COVID-19 period in patients treated with steroids during the illness. Subject and methods: This prospective study involved 60 patients aged 18-60 years who had recovered from moderate or severe COVID-19 and had received steroid treatment during the illness. The HPA axis was assessed with a low-dose (1 mcg) adrenocorticotropic hormone stimulation test at 3, 6 and 9 months in the post-COVID period. Results: The HPA axis was suppressed in 31.66% of the patients at 3 months and 5% at 6 months; however, all patients recovered at 9 months. Cumulative steroid use during the illness was inversely correlated with stimulated cortisol at 3 months in the post-COVID period. Fatigue was present in 58.33% of the patients at 3 months and was more prevalent in those with HPA axis suppression. Conclusion: Nearly one-third of the patients with moderate to severe COVID-19 who were treated with steroids had suppressed HPA axis at 3 months, with gradual recovery over a period of 9 months. Cumulative steroid equivalent dose, but not disease severity, was predictive of HPA axis suppression at 3 months.

Mapping of corticotropin-releasing factor, receptors, and binding protein mRNA in the chicken telencephalon throughout development.

Understanding the neural mechanisms that regulate the stress response is critical to know how animals adapt to a changing world and is one of the key factors to be considered for improving animal welfare. Corticotropin-releasing factor (CRF) is crucial for regulating physiological and endocrine responses, triggering the activation of the sympathetic nervous system and the hypothalamo-pituitary-adrenal axis (HPA) during stress. In mammals, several telencephalic areas, such as the amygdala and the hippocampus, regulate the autonomic system and the HPA responses. These centers include subpopulations of CRF containing neurons that, by way of CRF receptors, play modulatory roles in the emotional and cognitive aspects of stress. CRF binding protein also plays a role, buffering extracellular CRF and regulating its availability. CRF role in activation of the HPA is evolutionary conserved in vertebrates, highlighting the relevance of this system to help animals cope with adversity. However, knowledge on CRF systems in the avian telencephalon is very limited, and no information exists on detailed expression of CRF receptors and binding protein. Knowing that the stress response changes with age, with important variations during the first week posthatching, the aim of this study was to analyze mRNA expression of CRF, CRF receptors 1 and 2, and CRF binding protein in chicken telencephalon throughout embryonic and early posthatching development, using in situ hybridization. Our results demonstrate an early expression of CRF and its receptors in pallial areas regulating sensory processing, sensorimotor integration and cognition, and a late expression in subpallial areas regulating the stress response. However, CRF buffering system develops earlier in the subpallium than in the pallium. These results help to understand the mechanisms underlying the negative effects of noise and light during prehatching stages in chicken, and suggest that stress regulation becomes more sophisticated with age.

The stimulatory effects of glucagon on cortisol and GH secretion occur independently from FGF-21.

PURPOSE: Glucagon stimulation test (GST) is used to assess the hypothalamo-pituitary-adrenal (HPA) and growth hormone (GH) axes with an incompletely defined mechanism. We aimed to assess if glucagon acted through fibroblast growth factor-21 (FGF-21) to stimulate cortisol and GH secretion. The secondary outcome was to determine the relationship of FGF-21 with variable GH responses to GST in obesity. METHODS: A total of 26 healthy participants; 11 obese (body mass index (BMI) > 30 kg/m2) and 15 leans (BMI < 25 kg/m2) were included. Basal pituitary and target hormone levels were measured and GST was performed. During GST, glucose, insulin, cortisol, GH, and FGF-21 responses were measured. RESULTS: The mean age of the participants was 26.3±3.6 years. Glucagon resulted in significant increases in FGF-21, glucose, insulin, cortisol, and GH levels. The levels of basal cortisol, GH, FGF-21, and IGF-1 were similar in the two groups. The peak GH and area under the curve (AUC)(GH) responses to GST in the obese group were lower than those of the normal-weight group with a different pattern of response. There were no differences between the groups in terms of peak cortisol, AUC(cortisol), peak insulin, AUC(insulin), peak FGF-21, and AUC(FGF21). Obesity was associated with significantly increased glucose and insulin responses and slightly decreased FGF-21 response to glucagon. CONCLUSION: Obesity was associated with blunted and delayed GH, but preserved cortisol responses to GST. This is the first study showing that glucagon stimulates the HPA and GH axis independently from FGF-21. The delayed GH response to GST in obesity does not seem to be related to FGF-21.

The gut microbiota-brain axis, psychobiotics and its influence on brain and behaviour: A systematic review.

The gut microbiota is the set of microorganisms present in the gut, and it is connected to the central nervous system via the gut-brain axis. Despite there is not a definitive description of the eubiotic microbiota architecture, numerous studies have demonstrated its involvement in human behaviour and its relationship with several pathologies. This is a systematic review about the association between dysbiosis on the gut microbiota and the presence of neurological or neuropsychiatric diseases such as cognitive impairment, Alzheimer's disease, Parkinson's disease, ADHD, and depression. Furthermore, this study analyzes the potential benefits of psychobiotics supplementation for these pathologies. Searches were conducted in the electronic databases PubMed and PsycINFO. 17 articles were included in this review, the majority were published after 2019. The results showed that gut dysbiosis predicts the development of these pathologies and influences their pathogenesis. In addition, it was found that different psychobiotics, mainly dietary fibers and probiotics of the Lactobacillus family, improved different cognitive functions such as cognitive performance and induce a reduced cortisol response. Improvement in different cognitive functions is possible when understanding gut microbiota-brain axis, enteric nervous system, neural-immune system, neuroendocrine system, and central nervous system's relationship.