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Psychoneuroendocrinology Apr 2019An organism's capacity to cope with stressful experiences is dependent on its ability to appropriately engage central and peripheral systems, such as the...
An organism's capacity to cope with stressful experiences is dependent on its ability to appropriately engage central and peripheral systems, such as the hypothalamic-pituitary-adrenal (HPA) axis, to adapt to changing environmental demands. The HPA axis is a primary neuroendocrine mediator of neural and behavioral responses to stress, and dysfunction of this system is linked to increased risk for developing mental health disorders such as depression, anxiety, and post-traumatic stress disorder. However, the mechanisms by which dysregulated HPA function results in abnormal behavioral responses to stress are poorly understood. Here, we tested how corticosterone (CORT)-induced HPA axis disruption affects behavioral responses to stress in male C57BL/6 N mice, and probed correlates of these behaviors in the brain. We show that chronic HPA disruption blunts acute stress-induced grooming and rearing behaviors in the open field test, effects which were accompanied by decreased FOS immunoreactivity in the paraventricular nucleus of the hypothalamus (PVH) and paraventricular nucleus of the thalamus (PVT). Blockade of CORT secretion with metyrapone injection prior to acute stress did not recapitulate the effects of chronic HPA disruption on open field behavior, and acute CORT replacement did not rescue normal behavioral stress responses following chronic HPA disruption. This suggests that under acute conditions, CORT is not necessary for these responses normally, nor sufficient to rescue the deficits of chronic HPA dysregulation. Together, these findings support the hypothesis that chronic HPA dysregulation causes adaptation in stress-related brain circuits and demonstrate that these changes can influence an organism's behavioral response to stress exposure.
Topics: Animals; Anxiety; Anxiety Disorders; Corticosterone; Depression; Depressive Disorder; Disease Models, Animal; Hypothalamo-Hypophyseal System; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Neurosecretory Systems; Pituitary Gland; Pituitary-Adrenal System; Stress, Psychological
PubMed: 30594817
DOI: 10.1016/j.psyneuen.2018.12.010 -
Nature Communications Nov 2021Chronic stress induces adaptive changes in the brain via the cumulative action of glucocorticoids, which is associated with mood disorders. Here we show that repeated...
Chronic stress induces adaptive changes in the brain via the cumulative action of glucocorticoids, which is associated with mood disorders. Here we show that repeated daily five-minute restraint resolves pre-existing stress-induced depressive-like behavior in mice. Repeated injection of glucocorticoids in low doses mimics the anti-depressive effects of short-term stress. Repeated exposure to short-term stress and injection of glucocorticoids activate neurons in largely overlapping regions of the brain, as shown by c-Fos staining, and reverse distinct stress-induced gene expression profiles. Chemogenetic inhibition of neurons in the prelimbic cortex projecting to the nucleus accumbens, basolateral amygdala, or bed nucleus of the stria terminalis results in anti-depressive effects similarly to short-term stress exposure, while only inhibition of neurons in the prelimbic cortex projecting to the bed nucleus of the stria terminalis rescues defective glucocorticoid release. In summary, we show that short-term stress can reverse adaptively altered stress gains and resolve stress-induced depressive-like behavior.
Topics: Aggression; Animals; Brain; Corticosterone; Depressive Disorder; Female; Gene Expression Profiling; Male; Mice, Inbred C57BL; Mice, Inbred ICR; Pregnancy; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins c-fos; Receptors, Mineralocorticoid; Restraint, Physical; Stress, Psychological; Time Factors; Mice
PubMed: 34795225
DOI: 10.1038/s41467-021-26968-4 -
Glia Nov 2019Low level sarin nerve gas and other anti-cholinesterase agents have been implicated in Gulf War illness (GWI), a chronic multi-symptom disorder characterized by... (Review)
Review
Low level sarin nerve gas and other anti-cholinesterase agents have been implicated in Gulf War illness (GWI), a chronic multi-symptom disorder characterized by cognitive, pain and fatigue symptoms that continues to afflict roughly 32% of veterans from the 1990-1991 Gulf War. How disrupting cholinergic synaptic transmission could produce chronic illness is unclear, but recent research indicates that acetylcholine also mediates communication between axons and oligodendrocytes. Here we investigated the hypothesis that oligodendrocyte development is disrupted by Gulf War agents, by experiments using the sarin-surrogate acetylcholinesterase inhibitor, diisopropyl fluorophosphate (DFP). The effects of corticosterone, which is used in some GWI animal models, were also investigated. The data show that DFP decreased both the number of mature and dividing oligodendrocytes in the rat prefrontal cortex (PFC), but differences were found between PFC and corpus callosum. The differences seen between the PFC and corpus callosum likely reflect the higher percentage of proliferating oligodendroglia in the adult PFC. In cell culture, DFP also decreased oligodendrocyte survival through a non-cholinergic mechanism. Corticosterone promoted maturation of oligodendrocytes, and when used in combination with DFP it had protective effects by increasing the pool of mature oligodendrocytes and decreasing proliferation. Cell culture studies indicate direct effects of both DFP and corticosterone on OPCs, and by comparison with in vivo results, we conclude that in addition to direct effects, systemic effects and interruption of neuron-glia interactions contribute to the detrimental effects of GW agents on oligodendrocytes. Our results demonstrate that oligodendrocytes are an important component of the pathophysiology of GWI.
Topics: Animals; Brain; Cholinesterase Inhibitors; Corticosterone; Gulf War; Humans; Neurons; Oligodendroglia
PubMed: 31339622
DOI: 10.1002/glia.23668 -
Acta Physiologica (Oxford, England) Jun 2018After stress, the brain is exposed to waves of stress mediators, including corticosterone (in rodents) and cortisol (in humans). Corticosteroid hormones affect neuronal... (Review)
Review
After stress, the brain is exposed to waves of stress mediators, including corticosterone (in rodents) and cortisol (in humans). Corticosteroid hormones affect neuronal physiology in two time-domains: rapid, non-genomic actions primarily via mineralocorticoid receptors; and delayed genomic effects via glucocorticoid receptors. In parallel, cognitive processing is affected by stress hormones. Directly after stress, emotional behaviour involving the amygdala is strongly facilitated with cognitively a strong emphasis on the "now" and "self," at the cost of higher cognitive processing. This enables the organism to quickly and adequately respond to the situation at hand. Several hours later, emotional circuits are dampened while functions related to the prefrontal cortex and hippocampus are promoted. This allows the individual to rationalize the stressful event and place it in the right context, which is beneficial in the long run. The brain's response to stress depends on an individual's genetic background in interaction with life events. Studies in rodents point to the possibility to prevent or reverse long-term consequences of early life adversity on cognitive processing, by normalizing the balance between the two receptor types for corticosteroid hormones at a critical moment just before the onset of puberty.
Topics: Animals; Brain; Corticosterone; Humans; Neurons; Receptors, Glucocorticoid; Stress, Physiological; Stress, Psychological
PubMed: 29575542
DOI: 10.1111/apha.13066 -
Biomolecular Concepts Apr 2022Microglial activation in the central nervous system (CNS) has been associated with brain damage and neurodegenerative disorders. Ochratoxin A (OTA) is a mycotoxin that...
Microglial activation in the central nervous system (CNS) has been associated with brain damage and neurodegenerative disorders. Ochratoxin A (OTA) is a mycotoxin that occurs naturally in food and feed and has been associated with neurotoxicity, while corticosteroids are CNS' physiological function modulators. This study examined how OTA affected microglia activation and how corticosteroids influenced microglial neuroinflammation. Murine microglial cells (BV-2) were stimulated by OTA, and the potentiation effects on OTA-induced inflammation were determined by corticosterone pre-treatment. Expressions of pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS) were determined. Phosphorylation of mitogen-activated protein kinases (MAPKs) was analyzed by western blotting. OTA significantly increased the mRNA expression of IL-6, TNF-α, IL-1β, and iNOS and also elevated IL-6 and NO levels. Corticosterone pre-treatment enhanced the neuroinflammatory response to OTA in a mineralocorticoid receptor (MR)-dependent mechanism, which is associated with increases in extracellular signal-regulated kinase (ERK) and p38 MAPK activation. In response to OTA, microglial cells produced pro-inflammatory cytokines and NO, while corticosterone increased OTA-induced ERK and p38 MAPK phosphorylation via MR. Findings indicated the direct role of OTA in microglia activation and neuroinflammatory response and suggested that low corticosterone concentrations in the brain exacerbated neurodegeneration.
Topics: Animals; Corticosterone; Inflammation; Interleukin-6; Lipopolysaccharides; Mice; Microglia; NF-kappa B; Ochratoxins; Tumor Necrosis Factor-alpha; p38 Mitogen-Activated Protein Kinases
PubMed: 35437979
DOI: 10.1515/bmc-2022-0017 -
International Journal of Molecular... Feb 2023The aim of the experiment was to test the effect of an elevated level of glucocorticoids on the mouse hippocampal transcriptome after 12 h of treatment with...
The aim of the experiment was to test the effect of an elevated level of glucocorticoids on the mouse hippocampal transcriptome after 12 h of treatment with corticosterone that was administered during an active phase of the circadian cycle. Additionally, we also tested the circadian changes in gene expression and the decay time of transcriptomic response to corticosterone. Gene expression was analyzed using microarrays. Obtained results show that transcriptomic responses to glucocorticoids are heterogeneous in terms of the decay time with some genes displaying persistent changes in expression during 9 h of rest. We have also found a considerable overlap between genes regulated by corticosterone and genes implicated previously in stress response. The examples of such genes are , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . This indicates that the applied model is a useful tool for the investigation of mechanisms underlying the stress response.
Topics: Mice; Animals; Corticosterone; Glucocorticoids; Hippocampus; Gene Expression Profiling; Transcriptome
PubMed: 36769150
DOI: 10.3390/ijms24032828 -
Analytical Biochemistry Feb 2019Endogenous glucocorticoids modulate airway and lung inflammation in various respiratory diseases and after exposure to airborne contaminants. Although bronchoalveolar...
Endogenous glucocorticoids modulate airway and lung inflammation in various respiratory diseases and after exposure to airborne contaminants. Although bronchoalveolar lavage fluid (BALF) is commonly used to evaluate the inflammatory and immune response in the lungs, limited information is available on determination of endogenous glucocorticoid levels in BALF. Here we describe a simple method to determine corticosterone in BALF, and evaluate the relationship between BALF and plasma corticosterone.
Topics: Animals; Bronchoalveolar Lavage Fluid; Corticosterone; Glucocorticoids; Immunoassay; Liquid-Liquid Extraction; Lung; Male; Rats; Rats, Inbred F344
PubMed: 30529217
DOI: 10.1016/j.ab.2018.12.005 -
International Journal of Molecular... Nov 2022Exogenous corticosterone administration reduces GABAergic transmission and impairs its 5-HT receptor-dependent modulation in the rat dorsal raphe nucleus (DRN), but it...
Restraint Stress and Repeated Corticosterone Administration Differentially Affect Neuronal Excitability, Synaptic Transmission and 5-HT Receptor Reactivity in the Dorsal Raphe Nucleus of Young Adult Male Rats.
Exogenous corticosterone administration reduces GABAergic transmission and impairs its 5-HT receptor-dependent modulation in the rat dorsal raphe nucleus (DRN), but it is largely unknown how neuronal functions of the DRN are affected by repeated physical and psychological stress. This study compared the effects of repeated restraint stress and corticosterone injections on DRN neuronal excitability, spontaneous synaptic transmission, and its 5-HT receptor-dependent modulation. Male Wistar rats received corticosterone injections for 7 or 14 days or were restrained for 10 min twice daily for 3 days. Repeated restraint stress and repeated corticosterone administration evoked similar changes in performance in the forced swim test. They increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) recorded from DRN neurons. In contrast to the treatment with corticosterone, restraint stress-induced changes in sEPSC kinetics and decreased intrinsic excitability of DRN neurons did not modify inhibitory transmission. Repeated injections of the 5-HT receptor antagonist SB 269970 ameliorated the effects of restraint on excitability and sEPSC frequency but did not restore the altered kinetics of sEPSCs. Thus, repeated restraint stress and repeated corticosterone administration differ in consequences for the intrinsic excitability of DRN projection neurons and their excitatory and inhibitory synaptic inputs. Effects of repeated restraint stress on DRN neurons can be partially abrogated by blocking the 5-HT receptor.
Topics: Rats; Male; Animals; Dorsal Raphe Nucleus; Corticosterone; Serotonin; Inhibitory Postsynaptic Potentials; Rats, Wistar; Synaptic Transmission; Neurons
PubMed: 36430779
DOI: 10.3390/ijms232214303 -
International Journal of Molecular... Apr 2023The circadian rhythms evolved to anticipate and cope with cyclic changes in environmental conditions. This adaptive function is currently compromised by increasing... (Review)
Review
The circadian rhythms evolved to anticipate and cope with cyclic changes in environmental conditions. This adaptive function is currently compromised by increasing levels of artificial light at night (ALAN), which can represent a risk for the development of diseases of civilisation. The causal links are not completely understood, and this featured review focuses on the chronodisruption of the neuroendocrine control of physiology and behaviour by dim ALAN. The published data indicate that low levels of ALAN (2-5 lux) can attenuate the molecular mechanisms generating circadian rhythms in the central oscillator, eliminate the rhythmic changes in dominant hormonal signals, such as melatonin, testosterone and vasopressin, and interfere with the circadian rhythm of the dominant glucocorticoid corticosterone in rodents. These changes are associated with a disturbed daily pattern of metabolic changes and behavioural rhythms in activity and food and water intake. The increasing levels of ALAN require the identification of the pathways mediating possible negative consequences on health to design effective mitigation strategies to eliminate or minimise the effects of light pollution.
Topics: Light Pollution; Circadian Rhythm; Melatonin; Corticosterone; Testosterone
PubMed: 37108420
DOI: 10.3390/ijms24087255 -
Molecules (Basel, Switzerland) Jul 2018Glucosylation of the 21-hydroxyl group of glucocorticoid changes its solubility into hydrophilicity from hydrophobicity and, as with glucocorticoid glucuronides as a...
Glucosylation of the 21-hydroxyl group of glucocorticoid changes its solubility into hydrophilicity from hydrophobicity and, as with glucocorticoid glucuronides as a moving object in vivo, it is conceivable that it exhibits the same behavior. Therefore, glucosylation to the 21-hydroxyl group while maintaining the 11-hydroxyl group is particularly important, and glucosylation of corticosterone was confirmed by high-resolution mass spectrometry and 1D (¹H and C) and 2D (COSY, ROESY, HSQC-DEPT and HMBC) NMR. Moreover, the difference in bioactivity between corticosterone and corticosterone 21-glucoside was investigated in vitro. Corticosterone 21-glucoside showed greater neuroprotective effects against H₂O₂-induced cell death and reactive oxygen species (ROS) compared with corticosterone. These results for the first time demonstrate that bioconversion of corticosterone through the region-selective glucosylation of a novel compound can present structural potential for developing new neuroprotective agents.
Topics: Cell Line, Tumor; Cell Survival; Chromatography, High Pressure Liquid; Corticosterone; Glucocorticoids; Glucosides; Glucosyltransferases; Glycosylation; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Reactive Oxygen Species
PubMed: 30029555
DOI: 10.3390/molecules23071783