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Duyvesteyn E, Vizcarra VS, Waight E, Balbuena E, Hablitz LM. Biological Fluid Flows: Signaling Mediums for Circadian Timing. J Biol Rhythms 2025; 40:234-248. [PMID: 40145493 DOI: 10.1177/07487304251323318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
While there is extensive literature on both the neuronal circuitry of rhythms and the intracellular molecular clock, there is a large component of signaling that has been understudied: interstitial fluid (ISF)-fluid that surrounds the cells in the extracellular space of tissue. In this review, we highlight evidence in the circadian literature supporting ISF signaling as key to circadian synchronization and entrainment and propose new mechanisms of how fluid movement between the brain and periphery may act as zeitgebers by examining the main ISF pathways of the body, focusing on circadian regulation of the glymphatic and lymphatic systems. We identify key pieces of circadian research that point to ISF as an important timing medium, expand on the basics of cerebrospinal fluid (CSF) and ISF production, and outline the basic structure and function of the glymphatic and lymphatic systems.
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Affiliation(s)
- Evalien Duyvesteyn
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Velia S Vizcarra
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Emma Waight
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Estephanie Balbuena
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Lauren M Hablitz
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
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2
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Adebayo OG, Ben-Azu B, Aduema W, Oyebanjo OT, Modo E, Ndidiamaka IP, Eleazer SE, Enya JI, Ajayi AM. Ginkgolide B as a biopsychosocial treatment salvages repeated restraint stress-induced amygdalar anomalies in mice. IBRO Neurosci Rep 2025; 18:66-77. [PMID: 39844942 PMCID: PMC11750493 DOI: 10.1016/j.ibneur.2024.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/24/2025] Open
Abstract
From preclinical and clinical findings, it has been shown that the amygdala is a critical mediator of stress and primary target for stress effects in the brain. We investigated the neuroprotective effect of Ginkgolide B (GB) in repeated restraint stress-induced behavioral deficit and amygdalar inflammation in mice. Mice were orally pre-treated with GB 20 mg/kg 1 h prior to 4 h restraint stress for 21 consecutive days. Behavioural deficit and serum and amygdalar biochemical changes were estimated using spectrophotometric and ELISA techniques. The results showed that GB pre-treatment inhibited spatial memory deficit, renounces neuropsychiatric phenotypes and metabolic redox activity by augmenting the endogenous antioxidant system via Nrf2 levels in the mice. The HPA axis activity impaired by the restraint stress induction was abated with marked reduction of corticosterone, hypertrophy of the adrenal gland and blood glucose level. Meanwhile, our data further reveals that GB pre-treatment inhibited the release of neuroinflammatory mediators (MPO, TNF-α, IL-6, MAPK, COX-2) and elevated CREB production via activation of BDNF protein. Further, the acetylcholinesterase activity was inhibited while the level of glutamate release remains unchanged in the amygdala of the restraint mice. The GB treatment also up-regulate the release of BCL-2 proteins. This study suggests that GB could be considered as a therapeutic agent in the management of memory impairment, neuropsychiatric phenotypes and neuropathological alterations.
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Affiliation(s)
- Olusegun G. Adebayo
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Osun State University, Osogbo, Osun State, Nigeria
- Neurosciences and Oral Physiology Unit, Department of Physiology, Faculty of Basic Medical Sciences, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
| | - Benneth Ben-Azu
- DELSU Joint Canada-Israel Neuroscience and Biopsychiatry Laboratory, Department of Pharmacology, Faculty of Basic Medical Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria
| | - Wadioni Aduema
- Department of Physiology, Faculty of Basic Medical Sciences, Bayelsa Medical University, Yenagoa, Bayelsa State, Nigeria
| | - Oyetola T. Oyebanjo
- Neurosciences and Oral Physiology Unit, Department of Physiology, Faculty of Basic Medical Sciences, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
- Department of Physiology, Faculty of Basic Medical Sciences, Babcock University, Ilishan-Remo, Nigeria
| | - Emmanuel U. Modo
- Department of Biochemistry, Faculty of Sciences, Delta State University, Abraka, Delta State, Nigeria
| | | | - Spiff E. Eleazer
- Department of Physiology, Faculty of Basic Medical Sciences, PAMO University of Medical Sciences, Port-Harcourt, River State, Nigeria
| | - Joseph Igbo Enya
- Department of Anatomy, Faculty of Basic Medical Sciences, Babcock University, Ilishan-Remo, Nigeria
| | - Abayomi M. Ajayi
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo State, Nigeria
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3
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Dolgacheva LP, Zinchenko VP, Nadeev AD, Goncharov NV. Serotonergic Regulation in Alzheimer's Disease. Int J Mol Sci 2025; 26:5218. [PMID: 40508026 PMCID: PMC12154332 DOI: 10.3390/ijms26115218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 05/18/2025] [Accepted: 05/27/2025] [Indexed: 06/16/2025] Open
Abstract
Serotonin (5-HT) is a neurotransmitter that also plays an important role in the regulation of vascular tone and angiogenesis. This review focuses on the involvement of the 5-HT system in pathological processes leading to the development of Alzheimer's disease (AD). There is evidence that damage or dysfunction of the 5-HT system contributes to the development of AD, and different subtypes of 5-HT receptors are a potential target for the treatment of AD. A link has been established between AD, depression, stress, and 5-HT deficiency in the brain. There are new data on the role of circadian rhythms in modulating stress, depression, and the 5-HT system; amyloid β (Aβ) plaque clearance; and AD progression. Circadian disruption inhibits Aβ plaque clearance and modulates AD progression. The properties and functions of 5-HT, its receptors, and serotonergic neurons are presented. Special attention is paid to the central role of 5-HT in brain development, including neurite outgrowth, regulation of somatic morphology, motility, synaptogenesis, control of dendritic spine shape and density, neuronal plasticity determining its role in network regeneration, and changes in innervation after brain damage. The results of different studies indicate that the interaction of amyloid β oligomers (AβO) with mitochondria is a sufficient trigger for AD-related neurodegeneration. The action of 5-HT leads to an improvement in mitochondrial quality and the restoration of brain areas after traumatic brain injury, chronic stress, or developmental disorders in AD. The role of a healthy lifestyle and drugs acting on serotonin receptors in the prevention and treatment of AD is discussed.
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Affiliation(s)
- Lyudmila P. Dolgacheva
- Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institute of Cell Biophysics of the Russian Academy of Sciences, Pushchino 142290, Russia (V.P.Z.)
| | - Valery P. Zinchenko
- Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institute of Cell Biophysics of the Russian Academy of Sciences, Pushchino 142290, Russia (V.P.Z.)
| | - Alexander D. Nadeev
- Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institute of Cell Biophysics of the Russian Academy of Sciences, Pushchino 142290, Russia (V.P.Z.)
| | - Nikolay V. Goncharov
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg 194223, Russia
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Al-Khanaty A, Guduguntla AN, Lawrentschuk N, Bolton D, Eapen R. Adrenal Anatomy and Physiology. Urol Clin North Am 2025; 52:169-179. [PMID: 40250885 DOI: 10.1016/j.ucl.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2025]
Abstract
The adrenal glands are paired endocrine organs that play a vital role in maintaining homeostasis by regulating blood pressure, metabolism, electrolyte balance, and the body's response to stress. Each gland comprises the adrenal cortex, which produces steroid hormones, and the adrenal medulla, responsible for catecholamine synthesis. The cortex is further divided into three functional zones, the zona glomerulosa (mineralocorticoids), zona fasciculata (glucocorticoids), and zona reticularis (androgens), while the medulla secretes adrenaline, noradrenaline, and dopamine under sympathetic control. This article aims to provide a comprehensive overview of the adrenal glands, including their anatomical structure, embryological development, vascular supply, microscopic architecture, and physiological function. Additionally, the historical evolution of adrenal research and the impact of modern molecular advancements are discussed. Understanding the anatomy and function of adrenal gland is crucial for diagnosing and managing adrenal disorders, including hormonal deficiencies, hypersecretion syndromes, and adrenal neoplasms.
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Affiliation(s)
- Abdullah Al-Khanaty
- Department of Urology, Austin Health, 145 Studley Road, Heidelberg, Victoria 3084, Australia
| | - Arjun N Guduguntla
- Department of Urology, Austin Health, University of Melbourne, 145 Studley Road, Heidelberg, Victoria 3084, Australia
| | - Nathan Lawrentschuk
- Department of Urology, Royal Melbourne Hospital, University of Melbourne; Department of Urology, Peter MacCallum Centre, 300 Grattan Street, Parkville, Victoria 3052, Australia
| | - Damien Bolton
- Department of Urology, Austin Health, University of Melbourne, 145 Studley Road, Heidelberg, Victoria 3084, Australia
| | - Renu Eapen
- Department of Urology, Austin Health, University of Melbourne, 145 Studley Road, Heidelberg, Victoria 3084, Australia; Department of Urology, Peter MacCallum Centre, 145 Studley Road, Heidelberg, Victoria 3084, Australia.
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Berry NT, Anderson T, Rhea CK, Wideman L. Optimization of Serum and Salivary Cortisol Interpolation for Time-Dependent Modeling Frameworks in Healthy Adult Males. Sports (Basel) 2025; 13:112. [PMID: 40278738 PMCID: PMC12030809 DOI: 10.3390/sports13040112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/27/2025] [Accepted: 04/02/2025] [Indexed: 04/26/2025] Open
Abstract
Cortisol is an important marker of hypothalamic-pituitary-adrenal function and follows robust circadian and diurnal rhythms. However, biomarker sampling protocols can be labor-intensive and cost-prohibitive. OBJECTIVES Explore analytical approaches that can handle differing biological sampling frequencies to maximize these data in more detailed and time-dependent analyses. METHODS Healthy adult males [N = 8; 26.1 (±3.1) years; 176.4 (±8.6) cm; 73.1 (±12.0) kg)] completed two 24 h admissions: one at rest and one including a high-intensity exercise session on the cycle ergometer. Serum and salivary cortisol were sampled every 60 and 120 min, respectively. Six alternative sampling profiles were defined by downsampling from the observed data and creating two intermittent sampling profiles. A polynomial (1-6 degrees) validation process was performed, and interpolation was conducted to match the observed data. Model fit and performance were assessed using the coefficient of determination (R2) and the root mean square error (RMSE), as well as an examination of the equivalence, via two one-sided t-tests (TOST), of 24 h cortisol output between the observed and interpolated data. RESULTS Mean serum cortisol output was higher than salivary cortisol (p < 0.001), and no effect was observed for condition (p = 0.61). Second- and third-degree polynomial regressions were determined to be the optimal models for fitting salivary. TOST tests determined that serum data and estimated 24 h output from these models (with interpolation) provided statistically similar estimates to the observed data (p < 0.05). CONCLUSIONS Second- and third-degree polynomial fits of salivary and serum cortisol provide a reasonable means for interpolation without introducing bias into estimates of 24 h output. This allows researchers to sample biomarkers at biologically relevant frequencies and subsequently match necessary sampling frequencies during the data processing stage of various machine learning workflows.
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Affiliation(s)
- Nathaniel T. Berry
- Department of Kinesiology, University of North Carolina at Greensboro, Greensboro, NC 27412, USA;
| | - Travis Anderson
- Department of Kinesiology, University of North Carolina at Greensboro, Greensboro, NC 27412, USA;
| | - Christopher K. Rhea
- Ellmer College of Health Sciences, Old Dominion University, Norfolk, VA 23529, USA;
| | - Laurie Wideman
- Department of Kinesiology, University of North Carolina at Greensboro, Greensboro, NC 27412, USA;
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Tapp ZM, Ghosh AK, Obrietan KH, Pyter LM. Mechanistic insights into chemotherapy-induced circadian disruption using rodent models. Trends Neurosci 2025; 48:283-296. [PMID: 39843333 PMCID: PMC11981850 DOI: 10.1016/j.tins.2024.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 12/06/2024] [Accepted: 12/31/2024] [Indexed: 01/24/2025]
Abstract
Chemotherapy treatment can significantly increase the survival of patients with cancer, but it also causes collateral damage in the body that can lead to treatment dose reductions and can reduce patient quality of life. One understudied side effect of chemotherapy is circadian disruption, which is associated with lasting biological and behavioral toxicities. Mechanisms of how chemotherapy alters circadian rhythms remain largely unknown, although leveraging rodent models may provide insights into causes and consequences of this disruption. Here, we review physiological, molecular, and behavioral evidence of central and peripheral circadian disruption in various rodent models of chemotherapy and discuss possible mechanisms driving these circadian disruptions. Overall, restoring circadian rhythms following treatment-induced disruptions may be a novel target by which to improve the health and quality of life of survivors.
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Affiliation(s)
- Zoe M Tapp
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA
| | - Amiya K Ghosh
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA
| | - Karl H Obrietan
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA
| | - Leah M Pyter
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA; Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, USA.
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7
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Zhang HY, Li KY, Wang YL, Wei CJ, Gao YX, Ren-Zhou, Zhong YB, Yin ZJ, Ren DL. ROS regulates circadian rhythms by modulating Ezh2 interactions with clock proteins. Redox Biol 2025; 81:103526. [PMID: 39952198 PMCID: PMC11875201 DOI: 10.1016/j.redox.2025.103526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 02/01/2025] [Indexed: 02/17/2025] Open
Abstract
Redox imbalance induced by the accumulation of reactive oxygen species (ROS) accelerates age-related processes, often accompanied by a decrease in circadian rhythm amplitude. However, the underlying mechanisms by which ROS modulate circadian rhythms remain poorly understood. In this study, we found that ROS disrupt circadian rhythms in both zebrafish, as indicated by changes in diurnal behavior and clock gene expression, and in a human cell model. Using weighted gene co-expression network analysis (WGCNA) and machine learning approaches (RF, LASSO, SVM), EZH2 was identified as a key gene involved in regulating circadian rhythms under oxidative stress conditions. To further investigate the role of EZH2, we employed ezh2-/- mutants, Morpholino injection, and overexpression treatment and discovered that EZH2 is crucial in mediating the effect of ROS on circadian rhythms. Furthermore, EZH2 interacts with the CLOCK-BMAL1 complex to regulate the transcription of clock genes, as demonstrated through co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. Our study revealed that ROS disrupt circadian rhythms by regulating the interaction between EZH2 and the CLOCK-BMAL1 complex, shedding light on the molecular mechanisms of circadian rhythm disruption under oxidative stress and suggesting potential targets for age-related and circadian disorders.
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Affiliation(s)
- Hao-Yi Zhang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Ke-Yun Li
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Yi-Li Wang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Chun-Jiao Wei
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Yu-Xuan Gao
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Ren-Zhou
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Ying-Bin Zhong
- School of Biology & Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu, 215000, China
| | - Zong-Jun Yin
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Da-Long Ren
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China.
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8
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Tofani GSS, Clarke G, Cryan JF. I "Gut" Rhythm: the microbiota as a modulator of the stress response and circadian rhythms. FEBS J 2025; 292:1454-1479. [PMID: 39841560 PMCID: PMC11927059 DOI: 10.1111/febs.17400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 11/20/2024] [Accepted: 01/07/2025] [Indexed: 01/24/2025]
Abstract
Modern habits are becoming more and more disruptive to health. As our days are often filled with circadian disruption and stress exposures, we need to understand how our responses to these external stimuli are shaped and how their mediators can be targeted to promote health. A growing body of research demonstrates the role of the gut microbiota in influencing brain function and behavior. The stress response and circadian rhythms, which are essential to maintaining appropriate responses to the environment, are known to be impacted by the gut microbiota. Gut microbes have been shown to alter the host's response to stress and modulate circadian rhythmicity. Although studies demonstrated strong links between the gut microbiota, circadian rhythms and the stress response, such studies were conducted in an independent manner not conducive to understanding the interface between these factors. Due to the interconnected nature of the stress response and circadian rhythms, in this review we explore how the gut microbiota may play a role in regulating the integration of stress and circadian signals in mammals and the consequences for brain health and disease.
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Affiliation(s)
- Gabriel S. S. Tofani
- APC MicrobiomeUniversity College CorkIreland
- Department of Anatomy & NeuroscienceUniversity College CorkIreland
| | - Gerard Clarke
- APC MicrobiomeUniversity College CorkIreland
- Department of Psychiatry & Neurobehavioural ScienceUniversity College CorkIreland
| | - John F. Cryan
- APC MicrobiomeUniversity College CorkIreland
- Department of Anatomy & NeuroscienceUniversity College CorkIreland
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9
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Li W, Liu H, Zheng J, Wang D, Wang Z, Hong M, Zhou Y. Kaempferol modulates ɑ2M secretion in bone marrow-derived macrophages by downregulating GR/PER1-mediated lipid metabolism to attenuate the emotional stress-aggravated metastasis of prostate cancer. JOURNAL OF ETHNOPHARMACOLOGY 2025; 339:119162. [PMID: 39603396 DOI: 10.1016/j.jep.2024.119162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/09/2024] [Accepted: 11/25/2024] [Indexed: 11/29/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Prostate cancer patients often suffer from depression during androgen deprivation therapy. Chaihu-Shugan-San (CSS) can prevent prostate cancer metastasis caused by chronic unpredictable mild stress (CUMS), but its active ingredients and molecular mechanism remain unelucidated. AIM OF STUDY This study aims to explore the potential targets and molecular mechanisms of CSS in the treatment of emotional stress-aggravated metastasis of prostate cancer. RESULTS Stress induces nuclear translocation of GR, initiating the transcription of PER1, which leads to an enhanced lipid metabolism and decreased secretion of α2M in BMDMs. CSS, a classical Traditional Chinese Medicine (TCM) formula for alleviating depression, can improve prostate cancer metastasis caused by CUMS. Of the active ingredients in CSS, kaempferol demonstrated the highest potency for enhancing α2M secretion in BMDMs and inhibiting prostate cancer cell migration. Kaempferol also inhibited nuclear translocation of GR and the GR/PER1 pathway in Per1-overexpressed BMDMs. CONCLUSIONS These findings reveal that emotional stress-aggravated prostate cancer growth and metastasis rely on the GR/PER1 pathway and lipid metabolism, as the suppression of this pathway ultimately leads to an increase in α2M secretion in BMDMs and inhibition of PC-3 cell metastasis.
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Affiliation(s)
- Wei Li
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Hao Liu
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jie Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Department of Pharmacology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Dechao Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Zhiying Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Min Hong
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yuxin Zhou
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
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10
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Fitzgerald LS, Reynoso Spurrier CS, Lau NJ, Melamed MD, Burnett LA, Meyer GA, Gui C, Hevener AL, Sanford JA, Schenk S. Markers of mitochondrial function and oxidative metabolism in female skeletal muscle do not display intrinsic circadian regulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.08.631231. [PMID: 39868315 PMCID: PMC11761028 DOI: 10.1101/2025.01.08.631231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Mitochondria are key regulators of metabolism and ATP supply in skeletal muscle, while circadian rhythms influence many physiological processes. However, whether mitochondrial function is intrinsically regulated in a circadian manner in mouse skeletal muscle is inadequately understood. Accordingly, we measured post-absorptive transcript abundance of markers of mitochondrial biogenesis, dynamics, and metabolism (extensor digitorum longus [EDL], soleus, gastrocnemius), protein abundance of electron transport chain complexes (EDL and soleus), enzymatic activity of SDH (tibialis anterior and plantaris), and maximum uncoupled respiration (tibialis anterior) in different skeletal muscles from female C57BL/6NJ mice at four zeitgeber times (ZT), ZT 1, 7, 13, and 19. Our findings demonstrate that markers of mitochondrial function and oxidative metabolism do not display intrinsic time-of-day regulation at the gene, protein, enzymatic, or functional level. The core-clock genes Bmal1 and Dbp exhibited intrinsic circadian rhythmicity in skeletal muscle (i.e., EDL, soleus, gastrocnemius) and circadian amplitude varied by muscle type. These findings demonstrate that female mouse skeletal muscle does not display circadian regulation of markers of mitochondrial function or oxidative metabolism over 24 hours.
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11
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Tofani GSS, Leigh SJ, Gheorghe CE, Bastiaanssen TFS, Wilmes L, Sen P, Clarke G, Cryan JF. Gut microbiota regulates stress responsivity via the circadian system. Cell Metab 2025; 37:138-153.e5. [PMID: 39504963 DOI: 10.1016/j.cmet.2024.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 04/12/2024] [Accepted: 10/02/2024] [Indexed: 11/08/2024]
Abstract
Stress and circadian systems are interconnected through the hypothalamic-pituitary-adrenal (HPA) axis to maintain responses to external stimuli. Yet, the mechanisms of how such signals are orchestrated remain unknown. Here, we uncover the gut microbiota as a regulator of HPA-axis rhythmicity. Microbial depletion disturbs the brain transcriptome and metabolome in stress-responding pathways in the hippocampus and amygdala across the day. This is coupled with a dysregulation of the circadian pacemaker in the brain that results in perturbed glucocorticoid rhythmicity. The resulting hyper-activation of the HPA axis at the sleep/wake transition drives time-of-day-specific impairments of the stress response and stress-sensitive behaviors. Finally, microbiota transplantation confirmed that diurnal oscillations of gut microbes underlie altered glucocorticoid secretion and that L. reuteri is a candidate strain for such effects. Our data offer compelling evidence that the microbiota regulates stress responsiveness in a circadian manner and is necessary to respond adaptively to stressors throughout the day.
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Affiliation(s)
- Gabriel S S Tofani
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
| | - Sarah-Jane Leigh
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Psychiatry & Neurobehavioral Sciences, University College Cork, Cork, Ireland
| | - Cassandra E Gheorghe
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Psychiatry & Neurobehavioral Sciences, University College Cork, Cork, Ireland
| | - Thomaz F S Bastiaanssen
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
| | - Lars Wilmes
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry & Neurobehavioral Sciences, University College Cork, Cork, Ireland
| | - Paromita Sen
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Psychiatry & Neurobehavioral Sciences, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.
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12
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Fitzgerald LS, Bremner SN, Ward SR, Cho Y, Schenk S. Intrinsic Skeletal Muscle Function and Contraction-Stimulated Glucose Uptake Do Not Vary by Time-of-Day in Mice. FUNCTION 2024; 5:zqae035. [PMID: 39134511 PMCID: PMC11873798 DOI: 10.1093/function/zqae035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 07/13/2024] [Accepted: 08/01/2024] [Indexed: 08/21/2024] Open
Abstract
A growing body of data suggests that skeletal muscle contractile function and glucose metabolism vary by time-of-day, with chronobiological effects on intrinsic skeletal muscle properties being proposed as the underlying mediator. However, no studies have directly investigated intrinsic contractile function or glucose metabolism in skeletal muscle over a 24 h circadian cycle. To address this, we assessed intrinsic contractile function and endurance, as well as contraction-stimulated glucose uptake, in isolated extensor digitorum longus and soleus from mice at 4 times-of-day (zeitgeber times 1, 7, 13, 19). Significantly, though both muscles demonstrated circadian-related changes in gene expression, there were no differences between the 4 time points in intrinsic contractile function, endurance, and contraction-stimulated glucose uptake, regardless of sex. Overall, these results suggest that time-of-day variation in exercise performance and the glycemia-reducing benefits of exercise are not due to chronobiological effects on intrinsic muscle function or contraction-stimulated glucose uptake.
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Affiliation(s)
- Liam S Fitzgerald
- Department of Orthopaedic Surgery, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
- Biomedical Sciences Graduate Program, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
- Medical Scientist Training Program, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Shannon N Bremner
- Department of Orthopaedic Surgery, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Samuel R Ward
- Department of Orthopaedic Surgery, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
- Department of Radiology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Yoshitake Cho
- Division of Cardiovascular Medicine—Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Simon Schenk
- Department of Orthopaedic Surgery, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
- Biomedical Sciences Graduate Program, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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13
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Welter H, Kreitmair N, Schneider M, Schneider J, Petkov S, Stepanov Y, Köhn FM, Pickl U, Trottmann M, Fröhlich T, Behr R, Mayerhofer A. Dexamethasone is a regulator of clock genes in testicular peritubular cells. Andrology 2024. [PMID: 39506194 DOI: 10.1111/andr.13788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 09/06/2024] [Accepted: 10/10/2024] [Indexed: 11/08/2024]
Abstract
BACKGROUND We recently found that peritubular cells of the human testis are a dominant site of expression of the glucocorticoid receptor (GR; encoded by NR3C1). Activation of GR by dexamethasone (Dex) strongly influences the phenotype of cultured human testicular peritubular cells (HTPCs), causing massive changes of their proteome and secretome. As glucocorticoids (GC) are also known to set the internal clock of peripheral organs by regulating clock genes, we tested such an influence of Dex in HTPCs. METHODS We performed cellular studies with HTPCs and immortalized nonhuman primate (Callithrix jacchus; Cj)-derived peritubular cells, organotypic incubations of testicular fragments of Cj, qPCR and proteomic, as well as immunohistochemical studies. RESULTS Basal clock gene expression levels, when monitored by qPCR under standard culture conditions, showed alterations over 24 h, suggesting an endogenous circadian rhythm, especially for BMAL1. Dex (1 µM) when added to cells, caused a strong and significant increase of PER1, followed by elevations of BMAL1, and other clock genes. This action was observed as early as 4 h after the addition of Dex. Immunohistochemistry and data mining revealed GR in testicular peritubular cells and other somatic cells of Cj, in situ. We therefore performed organotypic incubations of testicular fragments of Cj (n = 3) and found that upon addition of Dex (1 µM), mRNA levels of BMAL1 and PER1 also increased in samples of two out of three animals after 6 h. Mass spectrometry did, however, not reveal significant alterations of the testicular proteome, possibly due to the short time point and/or the fact that the somatic GR-expressing cells represent only a small portion of the testis. In support for this assumption, Dex (1 µM; 6 h) significantly increased mRNA levels of BMAL1 and PER1 in Cj-derived immortalized testicular peritubular cells. CONCLUSION The results indicate that an internal clock system likely exists in peritubular cells of the testis and that Dex, via testicular GR expressed by peritubular cells and other somatic cells, is a strong regulator of this system. In a physiological situation, GC thus may be important regulators of the testicular clock, while in a situation of prolonged stress or GC-medication, derangements in clock gene expression may result.
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Affiliation(s)
- Harald Welter
- Biomedical Center, Cell Biology, Anatomy III, Faculty of Medicine, Ludwig Maximilian University of Munich, Planegg-Martinsried, Munich, Germany
| | - Nicole Kreitmair
- Biomedical Center, Cell Biology, Anatomy III, Faculty of Medicine, Ludwig Maximilian University of Munich, Planegg-Martinsried, Munich, Germany
| | - Michaela Schneider
- Biomedical Center, Cell Biology, Anatomy III, Faculty of Medicine, Ludwig Maximilian University of Munich, Planegg-Martinsried, Munich, Germany
| | - Julia Schneider
- Biomedical Center, Cell Biology, Anatomy III, Faculty of Medicine, Ludwig Maximilian University of Munich, Planegg-Martinsried, Munich, Germany
| | - Stoyan Petkov
- Platform Degenerative Diseases, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany
| | - Youli Stepanov
- Laboratory for Functional Genome Analysis LAFUGA, Gene Center, Ludwig Maximilian University of Munich, München, Germany
| | | | | | | | - Thomas Fröhlich
- Laboratory for Functional Genome Analysis LAFUGA, Gene Center, Ludwig Maximilian University of Munich, München, Germany
| | - Rüdiger Behr
- Platform Degenerative Diseases, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany
| | - Artur Mayerhofer
- Biomedical Center, Cell Biology, Anatomy III, Faculty of Medicine, Ludwig Maximilian University of Munich, Planegg-Martinsried, Munich, Germany
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14
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Harvey-Carroll J, Stevenson TJ, Bussière LF, Spencer KA. Pre-natal exposure to glucocorticoids causes changes in developmental circadian clock gene expression and post-natal behaviour in the Japanese quail. Horm Behav 2024; 163:105562. [PMID: 38810363 DOI: 10.1016/j.yhbeh.2024.105562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 05/11/2024] [Accepted: 05/13/2024] [Indexed: 05/31/2024]
Abstract
The embryonic environment is critical in shaping developmental trajectories and consequently post-natal phenotypes. Exposure to elevated stress hormones during this developmental stage is known to alter a variety of post-natal phenotypic traits, and it has been suggested that pre-natal stress can have long term effects on the circadian rhythm of glucocorticoid hormone production. Despite the importance of the circadian system, the potential impact of developmental glucocorticoid exposure on circadian clock genes, has not yet been fully explored. Here, we showed that pre-natal exposure to corticosterone (CORT, a key glucocorticoid) resulted in a significant upregulation of two key hypothalamic circadian clock genes during the embryonic period in the Japanese quail (Coturnix japonica). Altered expression was still present 10 days into post-natal life for both genes, but then disappeared by post-natal day 28. At post-natal day 28, however, diel rhythms of eating and resting were influenced by exposure to pre-natal CORT. Males exposed to pre-natal CORT featured an earlier acrophase, alongside spending a higher proportion of time feeding. Females exposed to pre-natal CORT featured a less pronounced shift in acrophase and spent less time eating. Both males and females exposed to pre-natal CORT spent less time inactive during the day. Pre-natal CORT males appeared to feature a delay in peak activity levels. Our novel data suggest that these circadian clock genes and aspects of diurnal behaviours are highly susceptible to glucocorticoid disruption during embryonic development, and these effects are persistent across developmental stages, at least into early post-natal life.
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Affiliation(s)
- Jessica Harvey-Carroll
- School of Psychology and Neuroscience, University of St Andrews, Scotland; Department of Biological and Environmental Sciences & Gothenburg Global Biodiversity Centre, University of Gothenburg, Sweden.
| | - Tyler J Stevenson
- Institute of Biodiversity, Animal Health & Comparative Medicine, University of Glasgow, United Kingdom of Great Britain and Northern Ireland
| | - Luc F Bussière
- Department of Biological and Environmental Sciences & Gothenburg Global Biodiversity Centre, University of Gothenburg, Sweden
| | - Karen A Spencer
- School of Psychology and Neuroscience, University of St Andrews, Scotland
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15
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Luo X, Liu Y, Balck A, Klein C, Fleming RMT. Identification of metabolites reproducibly associated with Parkinson's Disease via meta-analysis and computational modelling. NPJ Parkinsons Dis 2024; 10:126. [PMID: 38951523 PMCID: PMC11217404 DOI: 10.1038/s41531-024-00732-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 05/30/2024] [Indexed: 07/03/2024] Open
Abstract
Many studies have reported metabolomic analysis of different bio-specimens from Parkinson's disease (PD) patients. However, inconsistencies in reported metabolite concentration changes make it difficult to draw conclusions as to the role of metabolism in the occurrence or development of Parkinson's disease. We reviewed the literature on metabolomic analysis of PD patients. From 74 studies that passed quality control metrics, 928 metabolites were identified with significant changes in PD patients, but only 190 were replicated with the same changes in more than one study. Of these metabolites, 60 exclusively increased, such as 3-methoxytyrosine and glycine, 54 exclusively decreased, such as pantothenic acid and caffeine, and 76 inconsistently changed in concentration in PD versus control subjects, such as ornithine and tyrosine. A genome-scale metabolic model of PD and corresponding metabolic map linking most of the replicated metabolites enabled a better understanding of the dysfunctional pathways of PD and the prediction of additional potential metabolic markers from pathways with consistent metabolite changes to target in future studies.
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Affiliation(s)
- Xi Luo
- School of Medicine, University of Galway, University Rd, Galway, Ireland
| | - Yanjun Liu
- School of Medicine, University of Galway, University Rd, Galway, Ireland
| | - Alexander Balck
- Institute of Neurogenetics and Department of Neurology, University of Luebeck and University Hospital Schleswig-Holstein, Luebeck, Germany
| | - Christine Klein
- Institute of Neurogenetics and Department of Neurology, University of Luebeck and University Hospital Schleswig-Holstein, Luebeck, Germany
| | - Ronan M T Fleming
- School of Medicine, University of Galway, University Rd, Galway, Ireland.
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands.
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16
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Tikhomirov R, Oakley RH, Anderson C, Xiang Y, Al-Othman S, Smith M, Yaar S, Torre E, Li J, Wilson LR, Goulding DR, Donaldson I, Harno E, Soattin L, Shiels HA, Morris GM, Zhang H, Boyett MR, Cidlowski JA, Mesirca P, Mangoni ME, D’Souza A. Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility. Circ Res 2024; 134:1306-1326. [PMID: 38533639 PMCID: PMC11081863 DOI: 10.1161/circresaha.123.323464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 02/15/2024] [Accepted: 03/13/2024] [Indexed: 03/28/2024]
Abstract
BACKGROUND Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the morning. Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the underlying mechanisms are not understood. We investigated the recruitment of transcription factors that underpins transcriptional rhythms in ion channels and assessed whether this mechanism was pertinent to the heart's intrinsic diurnal susceptibility to VA. METHODS AND RESULTS Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte nuclei at the beginning of the animals' inactive (ZT0) and active (ZT12) periods revealed differentially accessible chromatin sites annotating to rhythmically transcribed ion channels and distinct transcription factor binding motifs in these regions. Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) in open chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular, electrophysiological, and in silico biophysically-detailed modeling approaches demonstrated GR-mediated transcriptional control of ion channels (including Scn5a underlying the cardiac Na+ current, Kcnh2 underlying the rapid delayed rectifier K+ current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA. Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts. CONCLUSIONS Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the ZT12 surge in glucocorticoids to intrinsic VA propensity at this time.
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Affiliation(s)
- Roman Tikhomirov
- Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom
- Myocardial Function Section, National Heart and Lung Institute, Imperial College London, United Kingdom (R.T., M.S., A.D.)
| | - Robert H. Oakley
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (R.H.O., J.L., L.R.W., D.R.G., J.A.C.)
| | - Cali Anderson
- Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom
| | - Yirong Xiang
- Department of Physics and Astronomy (Y.X., H.Z.), The University of Manchester, United Kingdom
| | - Sami Al-Othman
- Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom
| | - Matthew Smith
- Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom
- Myocardial Function Section, National Heart and Lung Institute, Imperial College London, United Kingdom (R.T., M.S., A.D.)
| | - Sana Yaar
- Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom
| | - Eleonora Torre
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), F-34094 Montpellier France (E.T., P.M., M.E.M.)
| | - Jianying Li
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (R.H.O., J.L., L.R.W., D.R.G., J.A.C.)
| | - Leslie R. Wilson
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (R.H.O., J.L., L.R.W., D.R.G., J.A.C.)
| | - David R. Goulding
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (R.H.O., J.L., L.R.W., D.R.G., J.A.C.)
| | - Ian Donaldson
- Bioinformatics Core Facility (I.D.), The University of Manchester, United Kingdom
| | - Erika Harno
- Division of Diabetes, Endocrinology and Gastroenterology (E.H.), The University of Manchester, United Kingdom
| | - Luca Soattin
- Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom
| | - Holly A. Shiels
- Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom
| | - Gwilym M. Morris
- Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom
- Department of Cardiology, John Hunter Hospital, Newcastle, NSW, Australia (G.M.M.)
| | - Henggui Zhang
- Department of Physics and Astronomy (Y.X., H.Z.), The University of Manchester, United Kingdom
| | - Mark R. Boyett
- Faculty of Life Sciences, University of Bradford, United Kingdom (M.R.B.)
| | - John A. Cidlowski
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (R.H.O., J.L., L.R.W., D.R.G., J.A.C.)
| | - Pietro Mesirca
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), F-34094 Montpellier France (E.T., P.M., M.E.M.)
| | - Matteo E. Mangoni
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), F-34094 Montpellier France (E.T., P.M., M.E.M.)
| | - Alicia D’Souza
- Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom
- Myocardial Function Section, National Heart and Lung Institute, Imperial College London, United Kingdom (R.T., M.S., A.D.)
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17
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Lee HB, Shams S, Dang Thi VH, Boyum GE, Modhurima R, Hall EM, Green IK, Cervantes EM, Miguez FE, Clark KJ. Key HPI axis receptors facilitate light adaptive behavior in larval zebrafish. Sci Rep 2024; 14:7759. [PMID: 38565594 PMCID: PMC10987622 DOI: 10.1038/s41598-024-57707-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024] Open
Abstract
The vertebrate stress response (SR) is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and contributes to generating context appropriate physiological and behavioral changes. Although the HPA axis plays vital roles both in stressful and basal conditions, research has focused on the response under stress. To understand broader roles of the HPA axis in a changing environment, we characterized an adaptive behavior of larval zebrafish during ambient illumination changes. Genetic abrogation of glucocorticoid receptor (nr3c1) decreased basal locomotor activity in light and darkness. Some key HPI axis receptors (mc2r [ACTH receptor], nr3c1), but not nr3c2 (mineralocorticoid receptor), were required to adapt to light more efficiently but became dispensable when longer illumination was provided. Such light adaptation was more efficient in dimmer light. Our findings show that the HPI axis contributes to the SR, facilitating the phasic response and maintaining an adapted basal state, and that certain adaptations occur without HPI axis activity.
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Affiliation(s)
- Han B Lee
- Department of Neurology, Mayo Clinic, Rochester, MN, USA
| | - Soaleha Shams
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Viet Ha Dang Thi
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Grace E Boyum
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Rodsy Modhurima
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Emma M Hall
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Izzabella K Green
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | | | | | - Karl J Clark
- Department of Neurology, Mayo Clinic, Rochester, MN, USA.
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
- Neuroscience, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA.
- Department of Animal Science, Texas A&M University, College Station, TX, USA.
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18
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Molcan L, Babarikova K, Cvikova D, Kincelova N, Kubincova L, Mauer Sutovska H. Artificial light at night suppresses the day-night cardiovascular variability: evidence from humans and rats. Pflugers Arch 2024; 476:295-306. [PMID: 38177874 PMCID: PMC10847188 DOI: 10.1007/s00424-023-02901-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/06/2024]
Abstract
Artificial light at night (ALAN) affects most of the population. Through the retinohypothalamic tract, ALAN modulates the activity of the central circadian oscillator and, consequently, various physiological systems, including the cardiovascular one. We summarised the current knowledge about the effects of ALAN on the cardiovascular system in diurnal and nocturnal animals. Based on published data, ALAN reduces the day-night variability of the blood pressure and heart rate in diurnal and nocturnal animals by increasing the nocturnal values of cardiovascular variables in diurnal animals and decreasing them in nocturnal animals. The effects of ALAN on the cardiovascular system are mainly transmitted through the autonomic nervous system. ALAN is also considered a stress-inducing factor, as glucocorticoid and glucose level changes indicate. Moreover, in nocturnal rats, ALAN increases the pressure response to load. In addition, ALAN induces molecular changes in the heart and blood vessels. Changes in the cardiovascular system significantly depend on the duration of ALAN exposure. To some extent, alterations in physical activity can explain the changes observed in the cardiovascular system after ALAN exposure. Although ALAN acts differently on nocturnal and diurnal animals, we can conclude that both exhibit a weakened circadian coordination among physiological systems, which increases the risk of future cardiovascular complications and reduces the ability to anticipate stress.
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Affiliation(s)
- Lubos Molcan
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, Bratislava, Slovakia
| | - Katarina Babarikova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, Bratislava, Slovakia
| | - Diana Cvikova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, Bratislava, Slovakia
| | - Natalia Kincelova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, Bratislava, Slovakia
| | - Lenka Kubincova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, Bratislava, Slovakia
| | - Hana Mauer Sutovska
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, Bratislava, Slovakia.
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19
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Aukema RJ, Baglot SL, Scheufen J, Lightfoot SH, Hill MN. Circadian Influence on Acute Stress-induced Changes in Cortico-limbic Endocannabinoid Levels in Adult Male Rats. Neuroscience 2024; 537:84-92. [PMID: 38006961 DOI: 10.1016/j.neuroscience.2023.11.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 11/17/2023] [Accepted: 11/20/2023] [Indexed: 11/27/2023]
Abstract
The endocannabinoid (eCB) system plays an important role in regulating the stress response, including glucocorticoid release and the generation of avoidance behaviour. Its two major ligands, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), are dynamically influenced by psychological stress to gate the generation of the stress response and facilitate recovery upon stress termination. Many biological systems exhibit circadian "daily" rhythms, including glucocorticoids and endocannabinoids, and the behavioural and endocrine impact of stress is modulated by the time of day. Nonetheless, most preclinical experiments investigating the interaction between stress and endocannabinoids occur in the light, "inactive" phase. We therefore tested if circadian phase influences stress-induced changes in eCB levels in the hippocampus (HIP), prefrontal cortex (PFC), and amygdala (AMY). Adult male rats were exposed to 15 min swim stress or immediately euthanized, and brains were collected. Testing occurred either early in the light or early in the dark phase of their cycle to compare circadian effects. We found that overall, stress decreased AEA in the AMY and HIP, with an effect in the PFC dependent on the time of day. Conversely, stress increased 2-AG in the AMY, with an effect in the PFC and HIP dependent on the time of day. This suggests that stress has a similar overall impact on eCB levels regardless of circadian phase, but that subtle differences may occur depending on the brain region, especially the PFC.
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Affiliation(s)
- Robert J Aukema
- Hotchkiss Brain Institute, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada; Mathison Centre for Mental Health, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Samantha L Baglot
- Hotchkiss Brain Institute, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada; Mathison Centre for Mental Health, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Jessica Scheufen
- Hotchkiss Brain Institute, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada; Mathison Centre for Mental Health, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Savannah Hm Lightfoot
- Hotchkiss Brain Institute, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada; Mathison Centre for Mental Health, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Matthew N Hill
- Hotchkiss Brain Institute, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada; Mathison Centre for Mental Health, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada; Department of Cell Biology and Anatomy, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada; Department of Psychiatry, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
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20
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Li Y, Lu L, Androulakis IP. The Physiological and Pharmacological Significance of the Circadian Timing of the HPA Axis: A Mathematical Modeling Approach. J Pharm Sci 2024; 113:33-46. [PMID: 37597751 PMCID: PMC10840710 DOI: 10.1016/j.xphs.2023.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 08/02/2023] [Accepted: 08/02/2023] [Indexed: 08/21/2023]
Abstract
As a potent endogenous regulator of homeostasis, the circadian time-keeping system synchronizes internal physiology to periodic changes in the external environment to enhance survival. Adapting endogenous rhythms to the external time is accomplished hierarchically with the central pacemaker located in the suprachiasmatic nucleus (SCN) signaling the hypothalamus-pituitary-adrenal (HPA) axis to release hormones, notably cortisol, which help maintain the body's circadian rhythm. Given the essential role of HPA-releasing hormones in regulating physiological functions, including immune response, cell cycle, and energy metabolism, their daily variation is critical for the proper function of the circadian timing system. In this review, we focus on cortisol and key fundamental properties of the HPA axis and highlight their importance in controlling circadian dynamics. We demonstrate how systems-driven, mathematical modeling of the HPA axis complements experimental findings, enhances our understanding of complex physiological systems, helps predict potential mechanisms of action, and elucidates the consequences of circadian disruption. Finally, we outline the implications of circadian regulation in the context of personalized chronotherapy. Focusing on the chrono-pharmacology of synthetic glucocorticoids, we review the challenges and opportunities associated with moving toward personalized therapies that capitalize on circadian rhythms.
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Affiliation(s)
- Yannuo Li
- Chemical & Biochemical Engineering Department, Piscataway, NJ 08854, USA
| | - Lingjun Lu
- Chemical & Biochemical Engineering Department, Piscataway, NJ 08854, USA
| | - Ioannis P Androulakis
- Chemical & Biochemical Engineering Department, Piscataway, NJ 08854, USA; Biomedical Engineering Department, Rutgers University, Piscataway, NJ 08540, USA.
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21
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Jimeno B, Gerritsma Y, Mulder E, Verhulst S. Glucocorticoid receptor expression in blood, but not across brain regions, reveals long-term effects of early life adversity in zebra finches. Physiol Behav 2023; 271:114310. [PMID: 37543106 DOI: 10.1016/j.physbeh.2023.114310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 05/12/2023] [Accepted: 07/28/2023] [Indexed: 08/07/2023]
Abstract
Early-life environment can affect organisms for life on many levels. The glucocorticoid receptor (GR) gene has a pivotal role mediating organismal physiological and behavioral responses to environmental change, and is sensitive to early-life environmental conditions and epigenetic programming. Longitudinal studies require non-lethal sampling of peripheral tissues (e.g. blood), but this approach is dependent on the extent to which GR expression in peripheral tissues covaries with GR expression in central tissues. To test for the long-term effects of early life adversity on GR expression across brain and peripheral tissues, we manipulated developmental conditions of captive zebra finches (n = 45), rearing them in either benign or harsh conditions through manipulation of parental foraging costs. We measured relative GR mRNA expression in blood and five brain regions in adulthood: hippocampus, hypothalamus, amygdala, ventral striatum, and the nidopallium caudolaterale (analogous to the mammalian prefrontal cortex), using qPCR. We further tested whether GR expression was modulated by natal brood size (which affected growth), age at sampling, and sex. GR expression correlations among tissues varied widely in magnitude and direction, ranging from -0.27 to +0.80, indicating that our understanding of developmental effects on GR expression and associated phenotypes needs to be region specific rather than organism wide. A more consistent pattern was that GR expression increased with age in blood, ventral striatum and hippocampus; GR expression was independent of age in other tissues. Developmental treatment did not affect GR expression in any of the tissues measured directly, but in blood and ventral striatum of adult females we found a positive correlation between nestling mass and GR expression. Thus, GR expression in blood was affected by early life conditions as reflected in growth in adult females, a pattern also found in one brain tissue, but not ubiquitous across brain regions. These results point at sex-dependent physiological constraints during development, shaping early life effects on GR expression in females only. Further study is required to investigate whether these tissue-dependent effects more generally reflect tissue-dependent long-term effects of early life adversity. This, together with investigating the physiological consequences of GR expression levels on individual performance and coping abilities, will be fundamental towards understanding the mechanisms mediating long-term impacts of early life, and the extent to which these can be quantified through non-lethal sampling.
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Affiliation(s)
- Blanca Jimeno
- Instituto de Investigación en Recursos Cinegéticos (IREC), CSIC-UCLM-JCCM, Ronda de Toledo 12, 13005 Ciudad Real; Instituto Pirenaico de Ecologia (IPE), CSIC, Avda. Nuestra Señora de la Victoria, 16, Jaca, Spain.
| | - Yoran Gerritsma
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, the Netherlands
| | - Ellis Mulder
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, the Netherlands
| | - Simon Verhulst
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, the Netherlands
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22
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Lee H, Shams S, Dang Thi VH, Boyum G, Modhurima R, Hall E, Green I, Cervantes E, Miguez F, Clark K. The canonical HPA axis facilitates and maintains light adaptive behavior. RESEARCH SQUARE 2023:rs.3.rs-3240080. [PMID: 37720015 PMCID: PMC10503838 DOI: 10.21203/rs.3.rs-3240080/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2023]
Abstract
The vertebrate stress response (SR) is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and contributes to generating context appropriate physiological and behavioral changes. Although the HPA axis plays vital roles both in stressful and basal conditions, research has focused on the response under stress. To understand broader roles of the HPA axis in a changing environment, we characterized an adaptive behavior of larval zebrafish during ambient illumination changes. The glucocorticoid receptor (nr3c1) was necessary to maintain basal locomotor activity in light and darkness. The HPA axis was required to adapt to light more efficiently but became dispensable when longer illumination was provided. Light adaptation was more efficient in dimmer light and did not require the mineralocorticoid receptor (nr3c2). Our findings show that the HPA axis contributes to the SR at various stages, facilitating the phasic response and maintaining an adapted basal state, and that certain adaptations occur without HPA axis activity.
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23
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Bering T, Blancas-Velazquez AS, Rath MF. Circadian Clock Genes Are Regulated by Rhythmic Corticosterone at Physiological Levels in the Rat Hippocampus. Neuroendocrinology 2023; 113:1076-1090. [PMID: 37517388 PMCID: PMC10614510 DOI: 10.1159/000533151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/10/2023] [Indexed: 08/01/2023]
Abstract
INTRODUCTION In the hippocampus, clock gene expression is important for memory and mood; however, the signaling mechanism controlling clock gene expression in the hippocampus is unknown. Recent findings suggest that circadian glucocorticoid rhythms driven by the suprachiasmatic nucleus (SCN) control rhythmic clock gene expression in neurons; in addition, dexamethasone modulates hippocampal clock gene expression. We therefore hypothesized that oscillations of clock genes in the hippocampus could be driven by SCN-controlled circadian rhythms in glucocorticoids. METHODS Temporal profiles of hippocampal clock gene expression were established by quantitative reverse-transcription real-time PCR on rat hippocampi, while cellular distribution was established by in situ hybridization. To determine the effect of rhythmic glucocorticoids on hippocampal clock gene expression, the SCN was lesioned, adrenal glands removed and a 24 h exogenous corticosterone rhythm at physiological levels was reestablished by use of a programmable infusion pump. RESULTS Daily rhythms were detected for Per1, Per2, Bmal1, Nr1d1, and Dbp, while clock gene products were confirmed in both the hippocampus proper and the dentate gyrus. In sham controls, differential hippocampal expression of Per1 and Dbp between ZT3 and ZT15 was detectable. This rhythm was abolished by SCN lesion; however, reestablishing the natural rhythm in corticosterone restored differential rhythmic expression of both Per1 and Dbp. Further, a 6 h phase delay in the corticosterone profile caused a predictable shift in expression of Nr1d1. CONCLUSION Our data show that rhythmic corticosterone can drive hippocampal clock gene rhythms suggesting that the SCN regulates the circadian oscillator of the hippocampus by controlling the circadian rhythm in circulating glucocorticoids.
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Affiliation(s)
- Tenna Bering
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Copenhagen, Denmark
| | - Aurea Susana Blancas-Velazquez
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Copenhagen, Denmark
| | - Martin Fredensborg Rath
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Copenhagen, Denmark
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24
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Chbeir S, Carrión V. Resilience by design: How nature, nurture, environment, and microbiome mitigate stress and allostatic load. World J Psychiatry 2023; 13:144-159. [PMID: 37303926 PMCID: PMC10251360 DOI: 10.5498/wjp.v13.i5.144] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/11/2023] [Accepted: 04/17/2023] [Indexed: 05/19/2023] Open
Abstract
Resilience to psychological stress is defined as adaption to challenging life experiences and not the absence of adverse life events. Determinants of resilience include personality traits, genetic/epigenetic modifications of genes involved in the stress response, cognitive and behavioral flexibility, secure attachment with a caregiver, social and community support systems, nutrition and exercise, and alignment of circadian rhythm to the natural light/dark cycle. Therefore, resilience is a dynamic and flexible process that continually evolves by the intersection of different domains in human’s life; biological, social, and psychological. The objective of this minireview is to summarize the existing knowledge about the multitude factors and molecular alterations that result from resilience to stress response. Given the multiple contributing factors in building resilience, we set out a goal to identify which factors were most supportive of a causal role by the current literature. We focused on resilience-related molecular alterations resulting from mind-body homeostasis in connection with psychosocial and environmental factors. We conclude that there is no one causal factor that differentiates a resilient person from a vulnerable one. Instead, building resilience requires an intricate network of positive experiences and a healthy lifestyle that contribute to a balanced mind-body connection. Therefore, a holistic approach must be adopted in future research on stress response to address the multiple elements that promote resilience and prevent illnesses and psychopathology related to stress allostatic load.
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Affiliation(s)
- Souhad Chbeir
- Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, CA 94305, United States
| | - Victor Carrión
- Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, CA 94305, United States
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25
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Dantzer B. Frank Beach Award Winner: The centrality of the hypothalamic-pituitary-adrenal axis in dealing with environmental change across temporal scales. Horm Behav 2023; 150:105311. [PMID: 36707334 DOI: 10.1016/j.yhbeh.2023.105311] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 01/02/2023] [Accepted: 01/06/2023] [Indexed: 01/26/2023]
Abstract
Understanding if and how individuals and populations cope with environmental change is an enduring question in evolutionary ecology that has renewed importance given the pace of change in the Anthropocene. Two evolutionary strategies of coping with environmental change may be particularly important in rapidly changing environments: adaptive phenotypic plasticity and/or bet hedging. Adaptive plasticity could enable individuals to match their phenotypes to the expected environment if there is an accurate cue predicting the selective environment. Diversifying bet hedging involves the production of seemingly random phenotypes in an unpredictable environment, some of which may be adaptive. Here, I review the central role of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoids (GCs) in enabling vertebrates to cope with environmental change through adaptive plasticity and bet hedging. I first describe how the HPA axis mediates three types of adaptive plasticity to cope with environmental change (evasion, tolerance, recovery) over short timescales (e.g., 1-3 generations) before discussing how the implications of GCs on phenotype integration may depend upon the timescale under consideration. GCs can promote adaptive phenotypic integration, but their effects on phenotypic co-variation could also limit the dimensions of phenotypic space explored by animals over longer timescales. Finally, I discuss how organismal responses to environmental stressors can act as a bet hedging mechanism and therefore enhance evolvability by increasing genetic or phenotypic variability or reducing patterns of genetic and phenotypic co-variance. Together, this emphasizes the crucial role of the HPA axis in understanding fundamental questions in evolutionary ecology.
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Affiliation(s)
- Ben Dantzer
- Department of Psychology, University of Michigan, MI 48109 Ann Arbor, MI, USA; Department of Ecology and Evolutionary Biology, University of Michigan, MI 48109, Ann Arbor, MI, USA.
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26
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Circle(s) of Life: The Circadian Clock from Birth to Death. BIOLOGY 2023; 12:biology12030383. [PMID: 36979075 PMCID: PMC10045474 DOI: 10.3390/biology12030383] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/03/2023]
Abstract
Most lifeforms on earth use endogenous, so-called circadian clocks to adapt to 24-h cycles in environmental demands driven by the planet’s rotation around its axis. Interactions with the environment change over the course of a lifetime, and so does regulation of the circadian clock system. In this review, we summarize how circadian clocks develop in humans and experimental rodents during embryonic development, how they mature after birth and what changes occur during puberty, adolescence and with increasing age. Special emphasis is laid on the circadian regulation of reproductive systems as major organizers of life segments and life span. We discuss differences in sexes and outline potential areas for future research. Finally, potential options for medical applications of lifespan chronobiology are discussed.
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27
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Zimmer C, Taff CC, Ardia DR, Rosvall KA, Kallenberg C, Bentz AB, Taylor AR, Johnson LS, Vitousek MN. Gene expression in the female tree swallow brain is associated with inter- and intra-population variation in glucocorticoid levels. Horm Behav 2023; 147:105280. [PMID: 36403365 DOI: 10.1016/j.yhbeh.2022.105280] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 10/12/2022] [Accepted: 11/07/2022] [Indexed: 11/18/2022]
Abstract
Studies of the evolutionary causes and consequences of variation in circulating glucocorticoids (GCs) have begun to reveal how they are shaped by selection. Yet the extent to which variation in circulating hormones reflects variation in other important regulators of the hypothalamic-pituitary-adrenal (HPA) axis, and whether these relationships vary among populations inhabiting different environments, remain poorly studied. Here, we compare gene expression in the brain of female tree swallows (Tachycineta bicolor) from populations that breed in environments that differ in their unpredictability. We find evidence of inter-population variation in the expression of glucocorticoid and mineralocorticoid receptors in the hypothalamus, with the highest gene expression in a population from an extreme environment, and lower expression in a population from a more consistent environment as well as in birds breeding at an environmentally variable high-altitude site that are part of a population that inhabits a mixture of high and low altitude habitats. Within some populations, variation in circulating GCs predicted differences in gene expression, particularly in the hypothalamus. However, some patterns were present in all populations, whereas others were not. These results are consistent with the idea that some combination of local adaptation and phenotypic plasticity may modify components of the HPA axis affecting stress resilience. Our results also underscore that a comprehensive understanding of the function and evolution of the stress response cannot be gained from measuring circulating hormones alone, and that future studies that apply a more explicitly evolutionary approach to important regulatory traits are likely to provide significant insights.
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Affiliation(s)
- Cedric Zimmer
- Department of Ecology and Evolutionary Biology, Cornell University, Ithaca, NY 14853, USA; Laboratoire d'Ethologie Expérimentale et Comparée, LEEC, Université Sorbonne Paris Nord, UR 4443, 93430 Villetaneuse, France.
| | - Conor C Taff
- Department of Ecology and Evolutionary Biology, Cornell University, Ithaca, NY 14853, USA; Cornell Lab of Ornithology, Ithaca, NY 14850, USA
| | - Daniel R Ardia
- Department of Biology, Franklin and Marshall College, Lancaster, PA 17604, USA
| | - Kimberly A Rosvall
- Department of Biology, Indiana University Bloomington, Bloomington, IN 47405, USA
| | - Christine Kallenberg
- Department of Ecology and Evolutionary Biology, Cornell University, Ithaca, NY 14853, USA
| | - Alexandra B Bentz
- Department of Biology, Indiana University Bloomington, Bloomington, IN 47405, USA; Department of Biology, University of Oklahoma, Norman, OK 73019, USA
| | - Audrey R Taylor
- Biological Sciences, University of Alaska Anchorage, Anchorage, AK 99508, USA
| | - L Scott Johnson
- Department of Biological Sciences, Towson University, Towson, MD 21252, USA
| | - Maren N Vitousek
- Department of Ecology and Evolutionary Biology, Cornell University, Ithaca, NY 14853, USA; Cornell Lab of Ornithology, Ithaca, NY 14850, USA
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28
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Wong SD, Wright KP, Spencer RL, Vetter C, Hicks LM, Jenni OG, LeBourgeois MK. Development of the circadian system in early life: maternal and environmental factors. J Physiol Anthropol 2022; 41:22. [PMID: 35578354 PMCID: PMC9109407 DOI: 10.1186/s40101-022-00294-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 05/01/2022] [Indexed: 12/25/2022] Open
Abstract
In humans, an adaptable internal biological system generates circadian rhythms that maintain synchronicity of behavior and physiology with the changing demands of the 24-h environment. Development of the circadian system begins in utero and continues throughout the first few years of life. Maturation of the clock can be measured through sleep/wake patterns and hormone secretion. Circadian rhythms, by definition, can persist in the absence of environmental input; however, their ability to adjust to external time cues is vital for adaptation and entrainment to the environment. The significance of these external factors that influence the emergence of a stable circadian clock in the first years of life remain poorly understood. Infants raised in our post-modern world face adverse external circadian signals, such as artificial light and mistimed hormonal cues via breast milk, which may increase interference with the physiological mechanisms that promote circadian synchronization. This review describes the very early developmental stages of the clock and common circadian misalignment scenarios that make the developing circadian system more susceptible to conflicting time cues and temporal disorder between the maternal, fetal, infant, and peripheral clocks.
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29
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Rossiter A, Comyns TM, Sherwin I, Nevill AM, Campbell MJ, Warrington GD. Effects of long-haul transmeridian travel on physiological, sleep, perceptual and mood markers in Olympic team support staff. Chronobiol Int 2022; 39:1640-1655. [PMID: 36367300 DOI: 10.1080/07420528.2022.2139186] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The objective of this study was to holistically examine the impact of long-haul transmeridian travel (LHTT) on perceptual, mood, sleep and physiological markers in Olympic team support staff travelling to Japan for the 2020 Summer Olympic Games. An observational descriptive study design was used. Nine support staff members of the Irish Olympic team (2 M/7 F; age 34.3 ± 8.3 y (mean ±SD)) embarked on a long-haul (LH) eastward flight across eight time-zones from Ireland to Japan (approx. 24 h total travel time), to work at the Irish Team's 2020 Summer pre-Olympic Games camp, postponed to July 2021 due to Covid-19 pandemic. Perceived jet lag and travel fatigue symptoms, mood states and salivary markers for circadian rhythm and stress were assessed in the morning and evening during the week prior to travel as baseline (BL) measures and on days 1 to 8 (C1-C8) and day 15 (C15) post-travel. Night-time sleep (duration and quality) was monitored via actigraphy monitors and self-report sleep diaries. Participants perceived themselves to be significantly jet lagged for six days post-travel (p < .05). Morning sCort decreased by 66% on C1 and remained significantly lower than BL until C6 (p ≤ .03). On arrival participants perceived sleep to be worse than BL on arrival (C1, C2, C4, C5; p ≤ .04), with significantly shorter sleep duration (C2, C3, C6; p ≤ .01) and lower sleep efficiency (C2, C6; p ≤ .04) recorded by actigraphy, all normalizing by C7. Negative changes in mood states were evident in the evening time following LHTT, with significant elevations in confusion (C2, C3, p ≤ .02), fatigue (C2, C3; p ≤ .03) and depression (C3, C7; p < .05) and reduction in vigour (C2, C6, C7; p < .05). Following LHTT in an eastward direction across eight time-zones, it took seven days for perceived jet lag, physiological markers for circadian rhythm and sleep to normalize in Olympic team support staff. Despite alleviation of jet lag and fatigue and return of sleep to normal by C15, vigor remained low, indicating a "submerged" mood profile in these Olympic team support staff. These findings highlight the need to put strategies in place before and after LHTT for the Olympic Games to assist Olympic team support staff to maximize sleep, minimize stress and assist with expediating recovery from jet lag and travel fatigue, allowing them to perform optimally in supporting Olympic athletes in their final preparations for the Games.
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Affiliation(s)
- Antonia Rossiter
- Sport Ireland Institute, Sport Ireland Campus, Dublin, Ireland.,Department of Physical Education and Sport Science, University of Limerick, Limerick, Ireland.,Sport and Human Performance Research Centre, Health Research Institute, University of Limerick, Limerick, Ireland
| | - Thomas M Comyns
- Department of Physical Education and Sport Science, University of Limerick, Limerick, Ireland.,Sport and Human Performance Research Centre, Health Research Institute, University of Limerick, Limerick, Ireland
| | - Ian Sherwin
- Department of Physical Education and Sport Science, University of Limerick, Limerick, Ireland.,Sport and Human Performance Research Centre, Health Research Institute, University of Limerick, Limerick, Ireland
| | - Alan M Nevill
- Department of Physical Education and Sport Science, University of Limerick, Limerick, Ireland.,Faculty for Education Health and Wellbeing, University of Wolverhampton, Wolverhampton, UK
| | - Mark J Campbell
- Department of Physical Education and Sport Science, University of Limerick, Limerick, Ireland.,Lero, SFI Centre for Software Research, University of Limerick, Limerick, Ireland
| | - Giles D Warrington
- Department of Physical Education and Sport Science, University of Limerick, Limerick, Ireland.,Sport and Human Performance Research Centre, Health Research Institute, University of Limerick, Limerick, Ireland
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30
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Srinivasan M, Walker C. Circadian Clock, Glucocorticoids and NF-κB Signaling in Neuroinflammation- Implicating Glucocorticoid Induced Leucine Zipper as a Molecular Link. ASN Neuro 2022; 14:17590914221120190. [PMID: 36317290 PMCID: PMC9629546 DOI: 10.1177/17590914221120190] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Inflammation including neuroinflammation is considered a protective response and is directed to repair, regenerate, and restore damaged tissues in the central nervous system. Persistent inflammation due to chronic stress, age related accrual of free radicals, subclinical infections or other factors lead to reduced survival and increased neuronal death. Circadian abnormalities secondary to altered sleep/wake cycles is one of the earliest signs of neurodegenerative diseases. Brain specific or global deficiency of core circadian trans-activator brain and muscle ARNT (Arylhydrocarbon Receptor Nuclear Translocator)-like protein 1 (BMAL1) or that of the transrepressor REV-ERBα, impaired neural function and cognitive performance in rodents. Consistently, transcripts of inflammatory cytokines and host immune responses have been shown to exhibit diurnal variation, in parallel with the disruption of the circadian rhythm. Glucocorticoids that exhibit both a circadian rhythm similar to that of the core clock transactivator BMAL1 and tissue specific ultradian rhythm are critical in the control of neuroinflammation and re-establishment of homeostasis. It is widely accepted that the glucocorticoids suppress nuclear factor-kappa B (NF-κB) mediated transactivation and suppress inflammation. Recent mechanistic elucidations suggest that the core clock components also modulate NF-κB mediated transactivation in the brain and peripheral tissues. In this review we discuss evidence for interactions between the circadian clock components, glucocorticoids and NF-κB signaling responses in the brain and propose glucocorticoid induced leucine zipper (GILZ) encoded by Tsc22d3, as a molecular link that connect all three pathways in the maintenance of CNS homeostasis as well as in the pathogenesis of neuroinflammation-neurodegeneration.
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Affiliation(s)
- Mythily Srinivasan
- Department of Oral Pathology, Medicine and Radiology, Indiana University School of Dentistry, Indiana University Purdue University at Indianapolis, Indiana, USA,Provaidya LLC, Indiana Center for Biomedical Innovation, Indianapolis, Indiana, USA,Mythily Srinivasan, Oral Pathology, Radiology and Medicine, Indiana University School of Dentistry, Indianapolis, Indiana, United States; Provaidya LLC, Indiana Center for Biomedical Innovation, 1800 North Capitol Av, Indianapolis, IN 46202, United States.
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| | - Chandler Walker
- Department of Oral Pathology, Medicine and Radiology, Indiana University School of Dentistry, Indiana University Purdue University at Indianapolis, Indiana, USA,Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indiana University Purdue University at Indianapolis, Indiana, USA
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31
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Jimeno B, Zimmer C. Glucocorticoid receptor expression as an integrative measure to assess glucocorticoid plasticity and efficiency in evolutionary endocrinology: A perspective. Horm Behav 2022; 145:105240. [PMID: 35933849 DOI: 10.1016/j.yhbeh.2022.105240] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 11/17/2022]
Abstract
Organisms have to cope with the changes that take place in their environment in order to keep their physical and psychological stability. In vertebrates, the hypothalamic-pituitary-adrenal (HPA) axis plays a key role in mediating phenotypic adjustments to environmental changes, primarily by regulating glucocorticoids (GCs). Although circulating GCs have widely been used as proxy for individual health and fitness, our understanding of HPA regulation is still very limited, especially in free-living animals. Circulating GCs only exert their actions when they are bound to receptors, and therefore, GC receptors play a pivotal role mediating HPA regulation and GC downstream phenotypic changes. Because under challenging conditions GC actions (as well as negative feedback activation) occur mainly through binding to low-affinity glucocorticoid receptors (GR), we propose that GR activity, and in particular GR expression, may play a crucial role in GC regulation and dynamics, and be ultimately related to organismal capacity to appropriately respond to environmental changes. Thus, we suggest that GR expression will provide more comprehensive information of GC variation and function. To support this idea, we compile previous evidence demonstrating the fundamental role of GR on GC responses and the fine-tuning of circulating GCs. We also make predictions about the phenotypic differences in GC responsiveness - and ultimately HPA regulation capacity - associated with differences in GR expression, focusing on GC plasticity and efficiency. Finally, we discuss current priorities and limitations of integrating measures of GR expression into evolutionary endocrinology and ecology studies, and propose further research directions towards the use of GR expression and the study of the mechanisms regulating GR activity to gather information on coping strategies and stress resilience. Our goals are to provide an integrative perspective that will prompt reconsideration on the ecological and physiological interpretation of current GC measurements, and motivate further research on the role of GR in tuning individual responses to dynamic environments.
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Affiliation(s)
- Blanca Jimeno
- Instituto de Investigación en Recursos Cinegéticos (IREC), CSIC-UCLM-JCCM, Ronda de Toledo 12, 13005 Ciudad Real, Spain.
| | - Cedric Zimmer
- Laboratoire d'Ethologie Expérimentale et Comparée, LEEC, Université Sorbonne Paris Nord, UR 4443, 93430 Villetaneuse, France; Global Health and Infectious Disease Research Center, University of South Florida, 33612 Tampa, FL, USA
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32
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Schär S, Mürner-Lavanchy I, Schmidt SJ, Koenig J, Kaess M. Child maltreatment and hypothalamic-pituitary-adrenal axis functioning: A systematic review and meta-analysis. Front Neuroendocrinol 2022; 66:100987. [PMID: 35202606 DOI: 10.1016/j.yfrne.2022.100987] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 02/11/2022] [Accepted: 02/17/2022] [Indexed: 11/04/2022]
Abstract
Alterations in hypothalamic-pituitary-adrenal (HPA) axis and its effector hormone cortisol have been proposed as one possible mechanism linking child maltreatment experiences to health disparities. In this series of meta-analyses, we aimed to quantify the existing evidence on the effect of child maltreatment on various measures of HPA axis activity. The systematic literature search yielded 1,858 records, of which 87 studies (k = 132) were included. Using random-effects models, we found evidence for blunted cortisol stress reactivity in individuals exposed to child maltreatment. In contrast, no overall differences were found in any of the other HPA axis activity measures (including measures of daily activity, cortisol assessed in the context of pharmacological challenges and cumulative measures of cortisol secretion). The impact of several moderators (e.g., sex, psychopathology, study quality), the role of methodological shortcomings of existing studies, as well as potential directions for future research are discussed.
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Affiliation(s)
- Selina Schär
- University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland
| | - Ines Mürner-Lavanchy
- University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland
| | - Stefanie J Schmidt
- Department of Clinical Psychology and Psychotherapy, University of Bern, Bern, Switzerland
| | - Julian Koenig
- University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Cologne, Germany; Section for Experimental Child and Adolescent Psychiatry, Department of Child and Adolescent Psychiatry, Centre for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany
| | - Michael Kaess
- University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland; Clinic for Child and Adolescent Psychiatry, Centre for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany.
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33
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Yao Y, Silver R. Mutual Shaping of Circadian Body-Wide Synchronization by the Suprachiasmatic Nucleus and Circulating Steroids. Front Behav Neurosci 2022; 16:877256. [PMID: 35722187 PMCID: PMC9200072 DOI: 10.3389/fnbeh.2022.877256] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/11/2022] [Indexed: 11/18/2022] Open
Abstract
Background Steroids are lipid hormones that reach bodily tissues through the systemic circulation, and play a major role in reproduction, metabolism, and homeostasis. All of these functions and steroids themselves are under the regulation of the circadian timing system (CTS) and its cellular/molecular underpinnings. In health, cells throughout the body coordinate their daily activities to optimize responses to signals from the CTS and steroids. Misalignment of responses to these signals produces dysfunction and underlies many pathologies. Questions Addressed To explore relationships between the CTS and circulating steroids, we examine the brain clock located in the suprachiasmatic nucleus (SCN), the daily fluctuations in plasma steroids, the mechanisms producing regularly recurring fluctuations, and the actions of steroids on their receptors within the SCN. The goal is to understand the relationship between temporal control of steroid secretion and how rhythmic changes in steroids impact the SCN, which in turn modulate behavior and physiology. Evidence Surveyed The CTS is a multi-level organization producing recurrent feedback loops that operate on several time scales. We review the evidence showing that the CTS modulates the timing of secretions from the level of the hypothalamus to the steroidogenic gonadal and adrenal glands, and at specific sites within steroidogenic pathways. The SCN determines the timing of steroid hormones that then act on their cognate receptors within the brain clock. In addition, some compartments of the body-wide CTS are impacted by signals derived from food, stress, exercise etc. These in turn act on steroidogenesis to either align or misalign CTS oscillators. Finally this review provides a comprehensive exploration of the broad contribution of steroid receptors in the SCN and how these receptors in turn impact peripheral responses. Conclusion The hypothesis emerging from the recognition of steroid receptors in the SCN is that mutual shaping of responses occurs between the brain clock and fluctuating plasma steroid levels.
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Affiliation(s)
- Yifan Yao
- Department of Psychology, Columbia University, New York City, NY, United States
- *Correspondence: Yifan Yao,
| | - Rae Silver
- Department of Psychology, Columbia University, New York City, NY, United States
- Department of Neuroscience, Barnard College, New York City, NY, United States
- Department of Psychology, Barnard College, New York City, NY, United States
- Department of Pathology and Cell Biology, Graduate School, Columbia University Irving Medical Center, New York City, NY, United States
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Villegas E, Hartsock MJ, Aben BL, Lenahan KN, Hernández TD, Spencer RL. ASSOCIATION BETWEEN ALTERED CORTISOL PROFILES AND NEUROBEHAVIORAL IMPAIRMENT FOLLOWING mTBI IN COLLEGE STUDENTS. J Neurotrauma 2022; 39:809-820. [PMID: 35196881 DOI: 10.1089/neu.2021.0495] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Mild Traumatic Brain Injury (mTBI) is the most common form of TBI, accounting for over 2.5 million TBI cases in the United States annually. Identification of easily obtainable biomarkers that track strongly with mTBI symptoms may improve our understanding of biological factors that contribute to mTBI symptom profiles and long-term outcomes. Notably, some individuals with mTBI exhibit circadian disruptions and elevated stress sensitivity, which in other clinical groups often correlate with disrupted secretion of cortisol, a glucocorticoid hormone that coordinates circadian and stress physiology. Here, we sought to determine whether cortisol profiles could serve as a biomarker to complement the assessment of neurobehavioral sequelae following mTBI. We partnered with our on-campus health clinic to recruit college students seeking medical care following mTBI (n=46) and compared this population to a well-matched non-injured student control group (n=44). We collected data at an initial visit (shortly after injury in mTBI subjects) and one week later. At each visit, we evaluated neurobehavioral function using the Automated Neuropsychological Assessment Metric (ANAM). Our subjects then provided cortisol samples through at-home saliva collection. We observed strong coherence between ANAM subjective and objective measures, indicating significant multidimensional impairment in those with mTBI. Further, female mTBI subjects exhibited diminished neurobehavioral function compared to males. Regardless of sex, decreased amplitude of diurnal cortisol and a blunted cortisol awakening response predicted mTBI symptom severity and neurobehavioral impairment. Taken together, these findings suggest that salivary cortisol profiles may be a sensitive biomarker for studying underlying biological factors that impact mTBI outcomes.
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Affiliation(s)
- Eduardo Villegas
- University of Colorado Boulder, 1877, Psychology and Neuroscience, Boulder, Colorado, United States;
| | - Matthew J Hartsock
- University of Colorado Boulder, 1877, Psychology and Neuroscience, Boulder, Colorado, United States;
| | - Bo Llg Aben
- University of Colorado Boulder, 1877, Psychology and Neuroscience, Boulder, Colorado, United States;
| | - Kristen Nicole Lenahan
- University of Colorado Boulder, 1877, Psychology and Neuroscience, Boulder, Colorado, United States;
| | - Theresa Dea Hernández
- University of Colorado Boulder, 1877, Psychology and Neuroscience, Boulder, Colorado, United States;
| | - Robert L Spencer
- University of Colorado Boulder, 1877, Psychology and Neuroscience, Boulder, Colorado, United States;
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Bougea A, Stefanis L, Chrousos G. Stress system and related biomarkers in Parkinson's disease. Adv Clin Chem 2022; 111:177-215. [DOI: 10.1016/bs.acc.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
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Liška K, Sládek M, Houdek P, Shrestha N, Lužná V, Ralph MR, Sumová A. High Sensitivity of the Circadian Clock in the Hippocampal Dentate Gyrus to Glucocorticoid- and GSK3-Beta-Dependent Signals. Neuroendocrinology 2022; 112:384-398. [PMID: 34111876 DOI: 10.1159/000517689] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 06/07/2021] [Indexed: 11/19/2022]
Abstract
AIMS Circadian clocks in the hippocampus (HPC) align memory processing with appropriate time of day. Our study was aimed at ascertaining the specificity of glycogen synthase kinase 3-beta (GSK3β)- and glucocorticoid (GC)-dependent pathways in the entrainment of clocks in individual HPC regions, CA1-3, and dentate gyrus (DG). METHODS The role of GCs was addressed in vivo by comparing the effects of adrenalectomy (ADX) and subsequent dexamethasone (DEX) supplementation on clock gene expression profiles (Per1, Per2, Nr1d1, and Bmal1). In vitro the effects of DEX and the GSK3β inhibitor, CHIR-99021, were assessed from recordings of bioluminescence rhythms in HPC organotypic explants of mPER2Luc mice. RESULTS Circadian rhythms of clock gene expression in all HPC regions were abolished by ADX, and DEX injections to the rats rescued those rhythms in DG. The DEX treatment of the HPC explants significantly lengthened periods of the bioluminescence rhythms in all HPC regions with the most significant effect in DG. In contrast to DEX, CHIR-99021 significantly shortened the period of bioluminescence rhythm. Again, the effect was most significant in DG which lacks the endogenously inactivated (phosphorylated) form of GSK3β. Co-treatment of the explants with CHIR-99021 and DEX produced the CHIR-99021 response. Therefore, the GSK3β-mediated pathway had dominant effect on the clocks. CONCLUSION GSK3β- and GC-dependent pathways entrain the clock in individual HPC regions by modulating their periods in an opposite manner. The results provide novel insights into the mechanisms connecting the arousal state-relevant signals with temporal control of HPC-dependent memory and cognitive functions.
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Affiliation(s)
- Karolína Liška
- Laboratory of Biological Rhythms, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
- Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Martin Sládek
- Laboratory of Biological Rhythms, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
| | - Pavel Houdek
- Laboratory of Biological Rhythms, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
| | - Norzin Shrestha
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Vendula Lužná
- Laboratory of Biological Rhythms, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
| | - Martin R Ralph
- Department of Psychology, University of Toronto, Toronto, Ontario, Canada
| | - Alena Sumová
- Laboratory of Biological Rhythms, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
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Crislip GR, Johnston JG, Douma LG, Costello HM, Juffre A, Boyd K, Li W, Maugans CC, Gutierrez-Monreal M, Esser KA, Bryant AJ, Liu AC, Gumz ML. Circadian Rhythm Effects on the Molecular Regulation of Physiological Systems. Compr Physiol 2021; 12:2769-2798. [PMID: 34964116 PMCID: PMC11514412 DOI: 10.1002/cphy.c210011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Nearly every system within the body contains an intrinsic cellular circadian clock. The circadian clock contributes to the regulation of a variety of homeostatic processes in mammals through the regulation of gene expression. Circadian disruption of physiological systems is associated with pathophysiological disorders. Here, we review the current understanding of the molecular mechanisms contributing to the known circadian rhythms in physiological function. This article focuses on what is known in humans, along with discoveries made with cell and rodent models. In particular, the impact of circadian clock components in metabolic, cardiovascular, endocrine, musculoskeletal, immune, and central nervous systems are discussed. © 2021 American Physiological Society. Compr Physiol 11:1-30, 2021.
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Affiliation(s)
- G. Ryan Crislip
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
| | - Jermaine G. Johnston
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
| | | | - Hannah M. Costello
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
| | | | - Kyla Boyd
- Department of Biochemistry and Molecular Biology
| | - Wendy Li
- Department of Biochemistry and Molecular Biology
| | | | | | - Karyn A. Esser
- Department of Physiology and Functional Genomics
- Myology Institute
| | | | - Andrew C. Liu
- Department of Physiology and Functional Genomics
- Myology Institute
| | - Michelle L. Gumz
- Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation
- Department of Biochemistry and Molecular Biology
- Department of Physiology and Functional Genomics
- Center for Integrative Cardiovascular and Metabolic Disease
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Hartsock MJ, Strnad HK, Spencer RL. Iterative Metaplasticity Across Timescales: How Circadian, Ultradian, and Infradian Rhythms Modulate Memory Mechanisms. J Biol Rhythms 2021; 37:29-42. [PMID: 34781753 DOI: 10.1177/07487304211058256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Work in recent years has provided strong evidence for the modulation of memory function and neuroplasticity mechanisms across circadian (daily), ultradian (shorter-than-daily), and infradian (longer-than-daily) timescales. Despite rapid progress, however, the field has yet to adopt a general framework to describe the overarching role of biological rhythms in memory. To this end, Iyer and colleagues introduced the term iterative metaplasticity, which they define as the "gating of receptivity to subsequent signals that repeats on a cyclic timebase." The central concept is that the cyclic regulation of molecules involved in neuroplasticity may produce cycles in neuroplastic capacity-that is, the ability of neural cells to undergo activity-dependent change. Although Iyer and colleagues focus on the circadian timescale, we think their framework may be useful for understanding how biological rhythms influence memory more broadly. In this review, we provide examples and terminology to explain how the idea of iterative metaplasticity can be readily applied across circadian, ultradian, and infradian timescales. We suggest that iterative metaplasticity may not only support the temporal niching of neuroplasticity processes but also serve an essential role in the maintenance of memory function.
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Affiliation(s)
- Matthew J Hartsock
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado
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Vassiliadi DA, Vassiliou AG, Ilias I, Tsagarakis S, Kotanidou A, Dimopoulou I. Pituitary-Adrenal Responses and Glucocorticoid Receptor Expression in Critically Ill Patients with COVID-19. Int J Mol Sci 2021; 22:11473. [PMID: 34768903 PMCID: PMC8584241 DOI: 10.3390/ijms222111473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 12/15/2022] Open
Abstract
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).
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Affiliation(s)
- Dimitra A. Vassiliadi
- Department of Endocrinology, Diabetes and Metabolism, National Expertise Centre for Rare Endocrine Diseases, Evangelismos Hospital, 106 76 Athens, Greece; (D.A.V.); (S.T.)
| | - Alice G. Vassiliou
- First Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens, Evangelismos Hospital, 106 76 Athens, Greece; (A.G.V.); (A.K.)
| | - Ioannis Ilias
- Department of Endocrinology, Helena Venizelos Hospital, 115 21 Athens, Greece;
| | - Stylianos Tsagarakis
- Department of Endocrinology, Diabetes and Metabolism, National Expertise Centre for Rare Endocrine Diseases, Evangelismos Hospital, 106 76 Athens, Greece; (D.A.V.); (S.T.)
| | - Anastasia Kotanidou
- First Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens, Evangelismos Hospital, 106 76 Athens, Greece; (A.G.V.); (A.K.)
| | - Ioanna Dimopoulou
- First Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens, Evangelismos Hospital, 106 76 Athens, Greece; (A.G.V.); (A.K.)
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40
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The role of clock genes in sleep, stress and memory. Biochem Pharmacol 2021; 191:114493. [DOI: 10.1016/j.bcp.2021.114493] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 12/23/2022]
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Knoedler JR, Sáenz de Miera C, Subramani A, Denver RJ. An Intact Krüppel-like factor 9 Gene Is Required for Acute Liver Period 1 mRNA Response to Restraint Stress. Endocrinology 2021; 162:6255381. [PMID: 33904929 PMCID: PMC8312639 DOI: 10.1210/endocr/bqab083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Indexed: 12/14/2022]
Abstract
The clock protein period 1 (PER1) is a central component of the core transcription-translation feedback loop governing cell-autonomous circadian rhythms in animals. Transcription of Per1 is directly regulated by the glucocorticoid (GC) receptor (GR), and Per1 mRNA is induced by stressors or injection of GC. Circulating GCs may synchronize peripheral clocks with the central pacemaker located in the suprachiasmatic nucleus of the brain. Krüppel-like factor 9 (KLF9) is a zinc finger transcription factor that, like Per1, is directly regulated by liganded GR, and it associates in chromatin at clock and clock-output genes, including at Per1. We hypothesized that KLF9 modulates stressor-dependent Per1 transcription. We exposed wild-type (WT) and Klf9 null mice (Klf9-/-) of both sexes to 1 hour restraint stress, which caused similar 2- to 2.5-fold increases in plasma corticosterone (B) in each genotype and sex. Although WT mice of both sexes showed a 2-fold increase in liver Per1 mRNA level after restraint stress, this response was absent in Klf9-/- mice. However, injection of B in WT and Klf9-/- mice induced similar increases in Per1 mRNA. Our findings support that an intact Klf9 gene is required for liver Per1 mRNA responses to an acute stressor, but a possible role for GCs in this response requires further investigation.
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Affiliation(s)
- Joseph R Knoedler
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan 48109-2215, USA
- Current Affiliation: J. R. Knoedler’s current affiliation is the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Cristina Sáenz de Miera
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-1085, USA
- Current Affiliation: C. Sáenz de Miera’s current affiliation is the Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-2800, USA
| | - Arasakumar Subramani
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-1085, USA
| | - Robert J Denver
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan 48109-2215, USA
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-1085, USA
- Correspondence: Robert J. Denver, PhD, Department of Molecular, Cellular and Developmental Biology, 1105 North University Avenue, University of Michigan, Ann Arbor, MI 48109-1085, USA.
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The Effect of High-Intensity Exercise on Changes in Salivary and Serum Cortisol Proportion Dynamics. ENDOCRINES 2021. [DOI: 10.3390/endocrines2010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Typically, salivary cortisol is reported as 5–10% of total cortisol, but the stability of this proportion and the effect of exercise on the 24-h profile is unclear. Therefore, this study investigated the circadian rhythm of the proportion of serum cortisol represented by salivary cortisol, and the impact of acute high-intensity exercise. Recreationally trained males (n = 8, age = 25.7 ± 2.4 years, height = 174.7 ± 7.8 cm, mass = 69.8 ± 12.1 kg) completed two 24-h profiles (rest and exercise conditions) for serum (Q60) and salivary (Q120) cortisol. Exercise consisted of 5 × 30 s sprinting intervals on the cycle ergometer. Cortisol was assessed using commercially available assays. The proportion (Cprop) of serum cortisol (Cser) represented by salivary cortisol (Csal) was calculated as [Cprop = Csal/ Cser × 100]. Multilevel growth models tested for trends across the 24-h profile. The highest relation between Cser and Csal was observed at 08:00 AM (r = 0.90). The average Cprop was 5.95% and demonstrated a circadian profile characterized by a cubic model. Acute exercise did not alter Cser, Csal, or Cprop. Thus, the proportion of Cser represented by Csal changes across a 24-h period and should be accounted for if using salivary cortisol to reflect circadian output of cortisol.
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Elderbrock EK, Hau M, Greives TJ. Sex steroids modulate circadian behavioral rhythms in captive animals, but does this matter in the wild? Horm Behav 2021; 128:104900. [PMID: 33245879 DOI: 10.1016/j.yhbeh.2020.104900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 10/21/2020] [Accepted: 11/17/2020] [Indexed: 12/14/2022]
Abstract
Nearly all organisms alter physiological and behavioral activities across the twenty-four-hour day. Endogenous timekeeping mechanisms, which are responsive to environmental and internal cues, allow organisms to anticipate predictable environmental changes and time their daily activities. Among-individual variation in the chronotype, or phenotypic output of these timekeeping mechanisms (i.e. timing of daily behaviors), is often observed in organisms studied under naturalistic environmental conditions. The neuroendocrine system, including sex steroids, has been implicated in the regulation and modulation of endogenous clocks and their behavioral outputs. Numerous studies have found clear evidence that sex steroids modulate circadian and daily timing of activities in captive animals under controlled conditions. However, little is known about how sex steroids influence daily behavioral rhythms in wild organisms or what, if any, implication this may have for survival and reproductive fitness. Here we review the evidence that sex steroids modulate daily timing in vertebrates under controlled conditions. We then discuss how this relationship may be relevant for the reproductive success and fitness of wild organisms and discuss the limited evidence that sex steroids modulate circadian rhythms in wild organisms.
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Affiliation(s)
- Emily K Elderbrock
- North Dakota State University, Department of Biological Sciences, Fargo, ND, USA.
| | - Michaela Hau
- Max Planck Institute for Ornithology, Evolutionary Physiology Research Group, Seewiesen, Germany; University of Konstanz, Department of Biology, Konstanz, Germany
| | - Timothy J Greives
- North Dakota State University, Department of Biological Sciences, Fargo, ND, USA
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Quattrocelli M, Zelikovich AS, Salamone IM, Fischer JA, McNally EM. Mechanisms and Clinical Applications of Glucocorticoid Steroids in Muscular Dystrophy. J Neuromuscul Dis 2021; 8:39-52. [PMID: 33104035 PMCID: PMC7902991 DOI: 10.3233/jnd-200556] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Glucocorticoid steroids are widely used as immunomodulatory agents in acute and chronic conditions. Glucocorticoid steroids such as prednisone and deflazacort are recommended for treating Duchenne Muscular Dystrophy where their use prolongs ambulation and life expectancy. Despite this benefit, glucocorticoid use in Duchenne Muscular Dystrophy is also associated with significant adverse consequences including adrenal suppression, growth impairment, poor bone health and metabolic syndrome. For other forms of muscular dystrophy like the limb girdle dystrophies, glucocorticoids are not typically used. Here we review the experimental evidence supporting multiple mechanisms of glucocorticoid action in dystrophic muscle including their role in dampening inflammation and myofiber injury. We also discuss alternative dosing strategies as well as novel steroid agents that are in development and testing, with the goal to reduce adverse consequences of prolonged glucocorticoid exposure while maximizing beneficial outcomes.
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Affiliation(s)
- Mattia Quattrocelli
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.,Molecular Cardiovascular Biology Division, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Aaron S Zelikovich
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Isabella M Salamone
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Julie A Fischer
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Elizabeth M McNally
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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45
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Carol EE, Spencer RL, Mittal VA. Acute Physiological and Psychological Stress Response in Youth at Clinical High-Risk for Psychosis. Front Psychiatry 2021; 12:641762. [PMID: 33679489 PMCID: PMC7933586 DOI: 10.3389/fpsyt.2021.641762] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/01/2021] [Indexed: 12/19/2022] Open
Abstract
Deficits in stress-response systems are a characteristic of schizophrenia and psychosis spectrum illnesses, and recent evidence suggests that this impairment may be evident in those at clinical high-risk (CHR) for the development of a psychotic disorder. However, there is limited research specifically investigating biological and subjective stress reactivity in CHR individuals. In the present study, 38 CHR individuals and group of 38 control individuals participated in the Trier Social Stress Test (TSST), an experimentally induced psychosocial stressor. Changes in salivary cortisol and alpha amylase, as well as self-reported units of distress (SUDS), were evaluated. Interestingly, the TSST did not induce a change in cortisol levels in either group, though the CHR group did show higher overall cortisol levels throughout the TSST (pre-anticipation period through recovery period). However, indicative of an effective task manipulation, the TSST did illicit an increase in alpha amylase in both groups. CHR participants exhibited higher levels of subjective stress prior to the stressor compared to the control group and CHR SUDs did not significantly increase in response to the stressor. In contrast, the control group showed an increase in SUDS in response to the stressor. Notably, SUDS for the control group post task mirrored the levels CHR youth endorsed prior to the stressor. Taken together, these findings suggest that there may be a functional relationship between persistently elevated cortisol and chronic high levels of subjective distress in CHR individuals.
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Affiliation(s)
- Emily E Carol
- Laboratory for Early Psychosis (LEAP) Center, Psychotic Disorders Division, McLean Hospital and Harvard Medical School, Belmont, MA, United States
| | - Robert L Spencer
- Spener Neuroendocrinology Laboratory, Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, United States
| | - Vijay A Mittal
- Adolescent Development and Preventative Treatment Program, Departments of Psychology, Psychiatry, and Medical Social Sciences, Institute for Policy Research, Northwestern University, Evanston, IL, United States
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Savareh BA, Bashiri A, Hatef MM, Hatef B. Prediction of salivary cortisol level by electroencephalography features. ACTA ACUST UNITED AC 2020; 66:275-284. [PMID: 34062630 DOI: 10.1515/bmt-2020-0005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 11/23/2020] [Indexed: 11/15/2022]
Abstract
Change in cortisol affects brain EEG signals. So, the identification of the significant EEG features which are sensitized to cortisol concentration was the aim of the present study. From 468 participated healthy subjects, the salivary samples were taken to test the cortisol concentration and EEG signal recording was done simultaneously. Then, the subjects were categorized into three classes based on the salivary cortisol concentration (<5, 5-15 and >15 nmol/l). Some linear and nonlinear features extracted and finally, in order to investigate the relationship between cortisol level and EEG features, the following steps were taken on features in sequence: Genetic Algorithm, Neighboring Component Analysis, polyfit, artificial neural network and support vector machine classification. Two classifications were considered as following: state 1 categorized the subjects into three groups (three classes) and the second state put them into two groups (group 1: class 1 and 3, group 2: class 2). The best classification was done using ANN in the second state with the accuracy=94.1% while it was 92.7% in the first state. EEG features carefully predicted the cortisol level. This result is applicable to design the intelligence brain computer machines to control stress and brain performance.
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Affiliation(s)
- Behrouz Alizadeh Savareh
- National Agency for Strategic Research in Medical Education, Tehran, Iran.,Department of Health Information Management, School of Management and Medical Information Sciences, Health Human Resources Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Azadeh Bashiri
- Department of Health Information Management, School of Management and Medical Information Sciences, Health Human Resources Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Mehdi Hatef
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Boshra Hatef
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Islamic Republic of Iran
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47
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Borgi M, Collacchi B, Ortona E, Cirulli F. Stress and coping in women with breast cancer:unravelling the mechanisms to improve resilience. Neurosci Biobehav Rev 2020; 119:406-421. [PMID: 33086128 DOI: 10.1016/j.neubiorev.2020.10.011] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 10/01/2020] [Accepted: 10/13/2020] [Indexed: 12/15/2022]
Abstract
Breast cancer diagnosis, surgery, adjuvant therapies and survivorship can all be extremely stressful. In women, concerns about body image are common as a result of the disease and can affect interpersonal relationships, possibly leading to social isolation, increasing the likelihood for mood disorders. This is particularly relevant as women are at greater risk to develop anxiety and depressive symptoms in response to highly stressful situations. Here we address the mechanisms and the pathways activated as a result of stress and contributing to changes in the pathophysiology of breast cancer, as well as the potential of stress management factors and interventions in buffering the deleterious effects of chronic stress in a gender perspective. An improved understanding of the biological mechanisms linking stress-management resources to health-relevant biological processes in breast cancer patients could reveal novel therapeutic targets and help clarifying which psychosocial interventions can improve cancer outcomes, ultimately offering a unique opportunity to improve contemporary cancer treatments.
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Affiliation(s)
- Marta Borgi
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Barbara Collacchi
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Elena Ortona
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Francesca Cirulli
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
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48
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Bernard C. Circadian/multidien Molecular Oscillations and Rhythmicity of Epilepsy (MORE). Epilepsia 2020; 62 Suppl 1:S49-S68. [PMID: 33063860 DOI: 10.1111/epi.16716] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/15/2020] [Accepted: 09/15/2020] [Indexed: 12/26/2022]
Abstract
The occurrence of seizures at specific times of the day has been consistently observed for centuries in individuals with epilepsy. Electrophysiological recordings provide evidence that seizures have a higher probability of occurring at a given time during the night and day cycle in individuals with epilepsy here referred to as the seizure rush hour. Which mechanisms underlie such circadian rhythmicity of seizures? Why don't they occur every day at the same time? Which mechanisms may underlie their occurrence outside the rush hour? In this commentary, I present a hypothesis: MORE - Molecular Oscillations and Rhythmicity of Epilepsy, a conceptual framework to study and understand the mechanisms underlying the circadian rhythmicity of seizures and their probabilistic nature. The core of the hypothesis is the existence of ~24-hour oscillations of gene and protein expression throughout the body in different cells and organs. The orchestrated molecular oscillations control the rhythmicity of numerous body events, such as feeding and sleep. The concept developed here is that molecular oscillations may favor seizure genesis at preferred times, generating the condition for a seizure rush hour. However, the condition is not sufficient, as other factors are necessary for a seizure to occur. Studying these molecular oscillations may help us understand seizure genesis mechanisms and find new therapeutic targets and predictive biomarkers. The MORE hypothesis can be generalized to comorbidities and the slower multidien (week/month period) rhythmicity of seizures, a phenomenon addressed in another article in this issue of Epilepsia.
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Affiliation(s)
- Christophe Bernard
- Inserm, INS, Institut de Neurosciences des Systèmes, Aix Marseille Univ, Marseille, France
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49
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Præstholm SM, Correia CM, Grøntved L. Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism. Front Endocrinol (Lausanne) 2020; 11:572981. [PMID: 33133019 PMCID: PMC7578419 DOI: 10.3389/fendo.2020.572981] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/03/2020] [Indexed: 12/14/2022] Open
Abstract
Glucocorticoids (GCs) and the glucocorticoid receptor (GR) are important regulators of development, inflammation, stress response and metabolism, demonstrated in various diseases including Addison's disease, Cushing's syndrome and by the many side effects of prolonged clinical administration of GCs. These conditions include severe metabolic challenges in key metabolic organs like the liver. In the liver, GR is known to regulate the transcription of key enzymes in glucose and lipid metabolism and contribute to the regulation of circadian-expressed genes. Insights to the modes of GR regulation and the underlying functional mechanisms are key for understanding diseases and for the development of improved clinical uses of GCs. The activity and function of GR is regulated at numerous levels including ligand availability, interaction with heat shock protein (HSP) complexes, expression of GR isoforms and posttranslational modifications. Moreover, recent genomics studies show functional interaction with multiple transcription factors (TF) and coregulators in complex transcriptional networks controlling cell type-specific gene expression by GCs. In this review we describe the different regulatory steps important for GR activity and discuss how different TF interaction partners of GR selectively control hepatic gene transcription and metabolism.
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Affiliation(s)
| | | | - Lars Grøntved
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
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50
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Ibrahim SIA, Strong JA, Qualls KA, Ulrich-Lai YM, Zhang JM. Differential Regulation of the Glucocorticoid Receptor in a Rat Model of Inflammatory Pain. Anesth Analg 2020; 131:298-306. [PMID: 31990732 DOI: 10.1213/ane.0000000000004652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Anti-inflammatory corticosteroids are a common treatment for different conditions involving chronic pain and inflammation. Clinically used steroids target the glucocorticoid receptor (GR) for its anti-inflammatory effects. We previously reported that GR in sensory neurons may play central roles in some pain models and that GR immunoreactivity signal in dorsal root ganglia (DRG) decreased after local inflammation of the DRG (a model of low back pain). In the current study, we aimed to determine if similar changes in GR signal also exist in a skin inflammation model, the complete Freund's adjuvant (CFA) model (a model of peripheral inflammatory pain), in which the terminals of the sensory neurons rather than the somata are inflamed. METHODS A low dose of CFA was injected into the hind paw to establish the peripheral inflammation model in Sprague-Dawley rats of both sexes, as confirmed by measurements of behavior and paw swelling. Immunohistochemical and western blotting techniques were used to determine the expression pattern of the GR in the inflamed hind paw and the DRGs. Plasma corticosterone levels were measured with radioimmunoassay. RESULTS The immunohistochemical staining revealed that GR is widely expressed in the normal DRG and skin tissues. Paw injection with CFA caused upregulation of the GR in the skin tissue on postinjection day 1, mostly detected in the dermis area. However, paw inflammation significantly reduced the GR signal in the L5 DRG 1 day after the injection. The GR downregulation was still evident 14 days after CFA inflammation. On day 1, western blotting confirmed this downregulation and showed that it could also be observed in the contralateral L5 DRG, as well as in the L2 DRG (a level which does not innervate the paw). Plasma corticosterone levels were elevated in both sexes on day 14 after CFA compared to day 1, suggesting autologous downregulation of the GR by corticosterone may have contributed to the downregulation observed on day 14 but not day 1. CONCLUSIONS There are distinctive patterns of GR activation under different pain conditions, depending on the anatomical location. The observed downregulation of the GR in sensory neurons may have a significant impact on the use of steroids as treatment in these conditions and on the regulatory effects of endogenous glucocorticoids.
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Affiliation(s)
- Shaimaa I A Ibrahim
- From the Department of Anesthesiology, Pain Research Center.,Graduate Program in Molecular, Cellular, and Biochemical Pharmacology
| | | | - Katherine A Qualls
- From the Department of Anesthesiology, Pain Research Center.,Graduate Program in Molecular, Cellular, and Biochemical Pharmacology
| | - Yvonne M Ulrich-Lai
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jun-Ming Zhang
- From the Department of Anesthesiology, Pain Research Center
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