A Rapid Release of Corticosteroid-Binding Globulin from the Liver Restrains the Glucocorticoid Hormone Response to Acute Stress

A strict control of glucocorticoid hormone responses to stress is essential for health. In blood, glucocorticoid hormones are for the largest part bound to corticosteroid-binding globulin (CBG), and just a minor fraction of hormone is free. Only free glucocorticoid hormone is able to exert biological effects, but little is known about its regulation during stress. We found, using a dual-probe in vivo microdialysis method, that in rats, the forced-swim stress-induced rise in free corticosterone (its major glucocorticoid hormone) is strikingly similar in the blood and in target compartments such as the subcutaneous tissue and the brain. However, in all compartments, the free corticosterone response was delayed by 20–30 min as compared with the total corticosterone response in the blood. We discovered that CBG is the key player in this delay. Swim stress evoked a fast (within 5 min) and profound rise in CBG protein and binding capacity in the blood through a release of the protein from the liver. Thus, the increase in circulating CBG levels after stress restrains the rise in free corticosterone concentrations for approximately 20 min in the face of mounting total hormone levels in the circulation. The stress-induced increase in CBG seems to be specific for moderate and strong stressors. Both restraint stress and forced swimming caused an increase in circulating CBG, whereas its levels were not affected by mild novelty stress. Our data uncover a new, highly dynamic role for CBG in the regulation of glucocorticoid hormone physiology after acute stress

Continuous Free Cortisol Profiles – Circadian Rhythms in Healthy Men

The pituitary-adrenal axis had historically been considered a representative model for circadian rhythms. A recently developed portable collection device provided the opportunity to evaluate free cortisol profiles using the microdialysis approach in individuals free to conduct their day-to-day activities in their own surroundings. Methods Two separate experiments were conducted in healthy male volunteers – ten-minutely total and subcutaneous free cortisol were measured for 24-hour period in one and twenty-minutely subcutaneous free cortisol for 72 consecutive hours in free-living individuals in the other experiment. Results The characteristic circadian rhythm was evident in both serum total and subcutaneous free cortisol with the lowest levels being achieved and maintained in the hours surrounding sleep onset with peak levels occurring in every individual around waking. In all free-living individuals, the circadian rhythm was consistent across 72-hours despite a wide range of activities. All participants also showed increased cortisol following the consumption of lunch. The lowest levels during all 24 hour periods were observed during the hours following lights switch-off, at the onset of sleep Conclusions This is the first study to show up to three consecutive 24-hour measurements of subcutaneous free cortisol in healthy individuals. This, we believe is a landmark study that paves the way for ambulatory monitoring of free cortisol profiles continuously up to a period of 72 hours in a free-living individual going about their day to day activities whether in health or in diseases involving the HPA axis

Continuous Free Cortisol Profiles in Healthy Men - Validation of Microdialysis Method

Abstract Context In humans, approximately 95% of circulating cortisol is bound to corticosteroid-binding globulin and albumin. It is only the free fraction that is biologically active and can activate signalling pathways via glucocorticoid hormone receptors in cells. Microdialysis is a well-established technique that enables the sampling of molecules in different compartments of the body, including extracellular fluid. This is the first study validating a rapid sampling microdialysis method measuring free cortisol in the subcutaneous and blood compartments of healthy volunteers. Methods Healthy non-smoking volunteers (42 men; age 18-24 years; BMI 18-25 kg/m2) received placebo (saline), 250 µg Synacthen or 1 mg dexamethasone with ten minutely sampling to measure total and free cortisol (subcutaneous, intravenous and saliva) for an hour before and 4 hours after administration. Results Following stimulation by Synacthen, total serum cortisol and free cortisol in both compartments rose significantly, achieving and maintaining maximum levels between 2 and 3 hours following the stimulus. A decline in cortisol levels was evident after the administration of dexamethasone or placebo, but there was a clear pulsatile activity around lunchtime in the latter group which was prominent in the blood compartment (total and free cortisol). There was good correlation between serum total and free cortisol (SC and intravenous) in the Synacthen and dexamethasone groups with no significant delay (less than 5 minutes) between total and free cortisol. Conclusions This seminal study demonstrated the dynamic responses of total blood cortisol and microdialysis derived free cortisol in blood, subcutaneous tissue and saliva in man. </jats:sec

Exercise Improves Cognitive Responses to Psychological Stress through Enhancement of Epigenetic Mechanisms and Gene Expression in the Dentate Gyrus

Background We have shown previously that exercise benefits stress resistance and stress coping capabilities. Furthermore, we reported recently that epigenetic changes related to gene transcription are involved in memory formation of stressful events. In view of the enhanced coping capabilities in exercised subjects we investigated epigenetic, gene expression and behavioral changes in 4-weeks voluntarily exercised rats. Methodology/Principal Findings Exercised and control rats coped differently when exposed to a novel environment. Whereas the control rats explored the new cage for the complete 30-min period, exercised animals only did so during the first 15 min after which they returned to sleeping or resting behavior. Both groups of animals showed similar behavioral responses in the initial forced swim session. When re-tested 24 h later however the exercised rats showed significantly more immobility behavior and less struggling and swimming. If rats were killed at 2 h after novelty or the initial swim test, i.e. at the peak of histone H3 phospho-acetylation and c-Fos induction, then the exercised rats showed a significantly higher number of dentate granule neurons expressing the histone modifications and immediate-early gene induction. Conclusions/Significance Thus, irrespective of the behavioral response in the novel cage or initial forced swim session, the impact of the event at the dentate gyrus level was greater in exercised rats than in control animals. Furthermore, in view of our concept that the neuronal response in the dentate gyrus after forced swimming is involved in memory formation of the stressful event, the observations in exercised rats of enhanced neuronal responses as well as higher immobility responses in the re-test are consistent with the reportedly improved cognitive performance in these animals. Thus, improved stress coping in exercised subjects seems to involve enhanced cognitive capabilities possibly resulting from distinct epigenetic mechanisms in dentate gyrus neurons

Interactions between corticotropin-releasing hormone and serotonin: implications for the aetiology and treatment of anxiety disorders

Taken by traveling photographer Albert J. Ewing, ca. 1896-1912, this photograph shows an infant wearing a white gown, standing in front of a hanging backdrop. There is an illegible note etched on the right side of the glass plate negative. Like most of Ewing's work, it was likely taken in southeastern Ohio or central West Virginia. Born in 1870 in Washington County, Ohio, near Marietta, Ewing most likely began his photography career in the 1890s. The 1910 US Census and a 1912-1913 directory list him as a photographer. A negative signed "Ewing Brothers" and a picture with his younger brother, Frank, indicate that Frank may have joined the business. After 1916, directories list Albert as a salesman. He died in 1934. The Ewing Collection consists of 5,055 glass plate negatives, each individually housed and numbered. Additionally, the collection includes approximately 450 modern contact prints made from the glass plate negatives. Subjects include infants and young children, elderly people, families, school and religious groups, animals and rural scenes. In 1982, the Ohio Historical Society (now the Ohio History Connection) received the collection, still housed in the original dry plate negative boxes purchased by Albert J. Ewing. A selection of the original glass plate negatives were exhibited for the first time in 2013 at the Ohio Historical Center