Despite decades of research, we still lack a complete understanding of what factors influence the transition of the necessary and adaptive acute stress response to what has become known as chronic stress. This gap in knowledge has illuminated the necessity for studies that examine the thresholds between these two sides of the stress response. Here, we determine how repeated exposure to acute stressors influences physiological and behavioral responses. In this repeated measures study, house sparrows ( Passer domesticus ) were exposed to a chronic stress protocol. We took physiological and behavioral measurements before, during, and after the protocol. Blood samples were used to assess four aspects of hypothalamic-pituitary-adrenal (HPA) axis function: baseline corticosterone, stress-induced corticosterone, negative feedback, and the maximal capacity to secrete corticosterone. We also assessed bacterial killing capacity and changes in uric acid concentration. Neophobia trials were used to assess behavioral changes throughout the protocol. We found no significant changes in HPA axis regulation in any of the four aspects we tested. However, we found that uric acid concentrations and neophobia significantly decreased after only four days of the chronic stress protocol, while bacterial killing capacity did not decrease until after eight days of exposure. These results indicate that different components of the stress response can be impacted by chronic stress on different timescales. Our results further indicate the importance of assessing multiple aspects of both physiology and behavior in order to understand how exposure to chronic stress may influence ability to cope with future challenges.
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Repeated stimulation of the HPA axis alters white blood cell count without increasing oxidative stress or inflammatory cytokines in fasting elephant seal pups
ABSTRACT The hypothalamic–pituitary–adrenal (HPA) axis controls the release of glucocorticoids, which regulate immune and inflammatory function by modulating cytokines, white blood cells and oxidative stress via glucocorticoid receptor (GR) signaling. Although the response to HPA activation is well characterized in many species, little is known about the impacts of HPA activation during extreme physiological conditions. Hence, we challenged 18 simultaneously fasting and developing elephant seal pups with daily intramuscular injections of adrenocorticotropin (ACTH), a GR antagonist (RU486), or a combination of the two (ACTH+RU486) for 4 days. We collected blood at baseline, 2 h and 4 days after the beginning of treatment. ACTH and ACTH+RU486 elevated serum aldosterone and cortisol at 2 h, with effects diminishing at 4 days. RU486 alone induced a compensatory increase in aldosterone, but not cortisol, at 4 days. ACTH decreased neutrophils at 2 h, while decreasing lymphocytes and increasing the neutrophil:lymphocyte ratio at 4 days. These effects were abolished by RU486. Despite alterations in white blood cells, there was no effect of ACTH or RU486 on transforming growth factor-β or interleukin-6 levels; however, both cytokines decreased with the 4 day fasting progression. Similarly, ACTH did not impact protein oxidation, lipid peroxidation or antioxidant enzymes, but plasma isoprostanes and catalase activity decreased while glutathione peroxidase increased with fasting progression. These data demonstrate differential acute (2 h) and chronic (4 days) modulatory effects of HPA activation on white blood cells and that the chronic effect is mediated, at least in part, by GR. These results also underscore elephant seals' extraordinary resistance to oxidative stress derived from repeated HPA activation.
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- Award ID(s):
- 1907155
- NSF-PAR ID:
- 10300887
- Date Published:
- Journal Name:
- Journal of Experimental Biology
- Volume:
- 224
- Issue:
- 18
- ISSN:
- 0022-0949
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Cocaine is a highly abused drug that causes psychiatric and neurological problems. Its entry into neurons could alter cell-biochemistry and contribute in the manifestation of early pathological symptoms. We have previously shown the acute cocaine effects in rat C6 astroglia-like cells and found that these cells were highly sensitive to cocaine in terms of manifesting certain pathologies known to underlie psychological disorders. The present study was aimed to discern acute cocaine effects on the early onset of various changes in Neuro-2a (N2a) cells. Whole-cell patch-clamp recording of differentiated cells displayed the functional voltage-gated Na+and K+channels, which demonstrated the neuronal characteristics of the cells. Treatment of these cells with acute cocaine (1 h) at in vivo (nM to μM) and in vitro (mM) concentrations revealed that the cells remained almost 100% viable. Cocaine administration at 6.25 μM or 4 mM doses significantly reduced the inward currents but had no significant effect on outward currents, indicating the Na+channel-blocking activity of cocaine. While no morphological change was observed at in vivo doses, treatment at in vitro doses altered the morphology, damaged the neurites, and induced cytoplasmic vacuoles; furthermore, general mitochondrial activity and membrane potential were significantly decreased. Mitochondrial dysfunction enabled the cells switch to anaerobic glycolysis, evidenced by dose-dependent increases in lactate and H2S, resulting unaltered ATP level in the cells. Further investigation on the mechanism of action unfolded that the cell’s resistance to cocaine was through the activation of nuclear factor E2-related factor-2 (
Nrf-2 ) gene and subsequent increase of antioxidants (glutathione [GSH], catalase and GSH peroxidase [GPx]). The data clearly indicate that the cells employed a detoxifying strategy against cocaine. On a broader perspective, we envision that extrapolating the knowledge of neuronal resistance to central nervous system (CNS) diseases could delay their onset or progression. -
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Rationale The grey seal,
Halichoerus grypus Mirounga angustirostris δ 13C andδ 15N values are affected by starvation, but the precise effects of fasting associated with lactation and post‐weaning fast in seals remain poorly understood.Methods To examine the effect of lactation and post‐weaning fast on stable isotope ratios in GS and NES, blood and hair were sampled from 21 GS mother‐pup pairs on the Isle of May and on 22 weaned NES pups at Año Nuevo State Reserve during their respective breeding seasons. Milk samples were also collected from GS mothers. Stable isotope measurements were performed with an isotope ratio mass spectrometer coupled to an N‐C elemental analyser.
Results Changes in stable isotope ratios in blood components during fasting were similar and weak between GS and NES mothers especially in blood cells (GS:
Δ 15N = 0.05‰,Δ 13C = 0.02‰; NES:Δ 15N = 0.1‰,Δ 13C = 0.1‰). GS showed a15N discrimination factor between maternal and pup blood cells and milk, but not for13C. The strongest relationship between the isotopic compositions of the mother and the pup was observed in the blood cells.Conclusions Isotopic consequences of lactation, fasting, and growth seem limited in NES and GS, especially in medium‐term integrator tissues of feeding activity such as blood cells. Stable isotope ratios in the blood of pups and mothers are correlated. We observed a subtle mother‐to‐pup fractionation factor. Our results suggest that pup blood cells are mostly relevant for exploring the ecology of female seals.
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In this study, we investigated the effects of weak static magnetic fields (SMFs) on HT‐1080 human fibrosarcoma cells. Exposures to SMFs for four consecutive days were varied from 0.5 to 600 µT for treated units, while exposures to control units were held at 45 µT. Growth rates were measured by comparing cell counts, whereas membrane potentials, mitochondrial calcium, mitochondrial superoxide (O2−), nitric oxide (NO), hydrogen peroxide (H2O2), intercellular pH, and oxidative stress were measured by using fluorescent dyes. The relative cell growth rates vary with the angle of the SMFs. Increases in the magnitude of the SMFs increased concentrations of mitochondrial calcium and membrane potential and decreased intracellular pH. H2O2, an important reactive oxygen species (ROS), increases at 100 and 200 µT, decreases at 300 and 400 µT and increases again at 500 and 600 µT. Overall, oxidative stress increases slightly with increasing SMFs, while superoxide and NO concentrations decrease. These results indicate that weak SMFs can accelerate and inhibit cell growth rates and induce alterations in ROS. Changes in ROS and oxidative stress are important for various cell functions. Calcium influx into mitochondria was one of the initial steps into the corresponding changes. Bioelectromagnetics. 2021. © 2021 Bioelectromagnetics Society
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Abstract Problem Disruption in homeostatic feedback loops between inflammatory mediators and the hypothalamic‐pituitary‐adrenal (HPA) axis is a key mechanism linking chronic stress to inflammation and adverse health outcomes, including those occurring during pregnancy. In particular, alterations in glucocorticoid sensitivity may occur as a result of chronic stress, including that due to racial discrimination, and may be implicated in the persistent adverse maternal and infant health outcomes experienced by African Americans. While there are a few large‐scale studies in human pregnancy that measure both cytokines and HPA axis hormones, to our knowledge, none directly measure glucocorticoid sensitivity at the cellular level, especially in an African American population.
Method of study We measured the full range of the dexamethasone (DEX) dose‐response suppression of TNF‐α in first‐trimester blood samples from 408 African American women and estimated leukocyte cell type contribution to the production of TNF‐α.
Results The mean (SD) DEX level needed to inhibit TNF‐α production by 50% (ie, DEX IC50) was 9.8 (5.8) nmol/L. Monocytes appeared to be the main driver of Uninhibited TNF‐α production, but monocyte counts explained only 14% of the variation. Monocyte counts were only weakly correlated with the DEX IC50(
r = −.11,P < .05). Moreover, there was no statistically significant correlation between the DEX IC50and circulating pro‐inflammatory (CRP, IL‐6, IFN‐γ) or anti‐inflammatory (IL‐10) mediators (P > .05).Conclusion These findings challenge some prior assumptions and position this comprehensive study of glucocorticoid sensitivity as an important anchor point in the growing recognition of interindividual variation in maternal HPA axis regulation and inflammatory responses.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1242/jeb.243198
