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Suglia SF, Hidalgo B, Baccarelli AA, Cardenas A, Damrauer S, Johnson A, Key K, Liang M, Magnani JW, Pate B, Sims M, Tajeu GS. Improving Cardiovascular Health Through the Consideration of Social Factors in Genetics and Genomics Research: A Scientific Statement From the American Heart Association. Circ Cardiovasc Qual Outcomes 2025; 18:e000138. [PMID: 40123498 DOI: 10.1161/hcq.0000000000000138] [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] [Indexed: 03/25/2025]
Abstract
Cardiovascular health (CVH) is affected by genetic, social, and genomic factors across the life course, yet little research has focused on the interrelationships among them. An extensive body of work has documented the impact of social determinants of health at both the structural and individual levels on CVH, highlighting pathways in which racism, housing, violence, and neighborhood environments adversely affect CVH and contribute to disparities in cardiovascular disease. Genetic factors have also been identified as contributors to risk for cardiovascular disease. Emerging evidence suggests that social factors can interact with genetic susceptibility to affect disease risk. Increasingly, social factors have been shown to affect epigenetic markers such as DNA methylation, which can regulate gene and protein expression. This is a potential biological mechanism through which exposure to poor social determinants of health becomes physically embodied at the molecular level, potentially contributing to the development of suboptimal CVH and chronic disease, thus reinforcing and propagating health disparities. The objective of this statement is to highlight and summarize key literature that has examined the joint associations between social, genetic, and genomic factors and CVH and cardiovascular disease.
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Arancibia M, Manterola M, Ríos U, Moya PR, Moran-Kneer J, Bustamante ML. The rs1360780 Variant of FKBP5: Genetic Variation, Epigenetic Regulation, and Behavioral Phenotypes. Genes (Basel) 2025; 16:325. [PMID: 40149476 PMCID: PMC11941772 DOI: 10.3390/genes16030325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 03/04/2025] [Accepted: 03/07/2025] [Indexed: 03/29/2025] Open
Abstract
FKBP5 has been of special scientific interest in the behavioral sciences since it has been involved in the pathophysiology of several mental disorders. It is a gene with pleiotropic effects which encodes the protein FKBP5, a cochaperone that decreases glucocorticoid receptor (GR) affinity for glucocorticoids by competing with FKBP4, altering the GR chaperone complex, and impairing GR activation. As a key modulator of the stress response, FKBP5 plays a critical role in regulating cortisol levels in the organism. The FKBP5 gene is regulated through a combination of transcriptional, epigenetic, post-transcriptional, and environmental mechanisms, as well as genetic polymorphisms that influence its transcription and stress responsiveness. Notably, the rs1360780 T-allele in FKBP5 significantly affects FKBP5 regulation and has been linked to stress-related disorders by influencing transcription and stress responsiveness. In this narrative review, we aim to provide an overview of the role played by the single-nucleotide polymorphism rs1360780 in the FKBP5 locus in gene expression, its epigenetic regulation, and the impact of early stress in its functioning. We discuss some brain regions with differential expression of FKBP5 and some behavioral phenotypes linked to the locus. The T-allele of rs1360780 is considered a risk variant, as it leads to high FKBP5 induction, which delays negative feedback and increases GR resistance. This results in states of relative hypercortisolemia and brain morphofunctional alterations, particularly in regions sensitive to glucocorticoid activity during critical periods of neurodevelopment. Additionally, exposure to childhood maltreatment is associated with demethylation of the glucocorticoid response elements of FKBP5, further increasing its expression levels. Among the psychological dimensions analyzed in which FKBP5 is involved are neurocognition, aggression, suicidality, and social cognition. At the level of mental disorders, the gene may play a role in the pathogenesis of post-traumatic stress disorder, depression, and bipolar disorder. In psychotic disorders, its role is less clear. This knowledge enhances the understanding of disease mechanisms that operate through psychopathological dimensions, and highlights the need to design specific, person-centered psychopharmacological and environmental therapeutic interventions.
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Affiliation(s)
- Marcelo Arancibia
- Department of Psychiatry, Faculty of Medicine, School of Medicine, Universidad de Valparaíso, Valparaíso 2360002, Chile; (M.A.)
- Center for Translational Studies in Stress and Mental Health (C-ESTRES), Faculty of Sciences, Universidad de Valparaíso, Valparaíso 2360102, Chile; (M.M.); (P.R.M.); (J.M.-K.)
- Program of Human Genetics, Biomedical Science Institute, Universidad de Chile, Independencia 8380453, Chile
| | - Marcia Manterola
- Center for Translational Studies in Stress and Mental Health (C-ESTRES), Faculty of Sciences, Universidad de Valparaíso, Valparaíso 2360102, Chile; (M.M.); (P.R.M.); (J.M.-K.)
- Program of Human Genetics, Biomedical Science Institute, Universidad de Chile, Independencia 8380453, Chile
| | - Ulises Ríos
- Department of Psychiatry, Faculty of Medicine, School of Medicine, Universidad de Valparaíso, Valparaíso 2360002, Chile; (M.A.)
- Center for Translational Studies in Stress and Mental Health (C-ESTRES), Faculty of Sciences, Universidad de Valparaíso, Valparaíso 2360102, Chile; (M.M.); (P.R.M.); (J.M.-K.)
| | - Pablo R. Moya
- Center for Translational Studies in Stress and Mental Health (C-ESTRES), Faculty of Sciences, Universidad de Valparaíso, Valparaíso 2360102, Chile; (M.M.); (P.R.M.); (J.M.-K.)
- Institute of Physiology, Faculty of Sciences, Universidad de Valparaíso, Valparaíso 2360102, Chile
| | - Javier Moran-Kneer
- Center for Translational Studies in Stress and Mental Health (C-ESTRES), Faculty of Sciences, Universidad de Valparaíso, Valparaíso 2360102, Chile; (M.M.); (P.R.M.); (J.M.-K.)
- Department of Clinical Psychology, School of Psychology, Faculty of Social Sciences, Universidad de Valparaíso, Valparaíso 2341369, Chile
| | - M. Leonor Bustamante
- Center for Translational Studies in Stress and Mental Health (C-ESTRES), Faculty of Sciences, Universidad de Valparaíso, Valparaíso 2360102, Chile; (M.M.); (P.R.M.); (J.M.-K.)
- Program of Human Genetics, Biomedical Science Institute, Universidad de Chile, Independencia 8380453, Chile
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Yang TC, Tsai JP, Hsu H, Chen YC, Liaw YC, Hsu SY, Yang HJ, Liaw YP. Delving Into the Interaction Between Exercise and Diabetes on Methylation of the FKBP5 Gene. J Diabetes Res 2025; 2025:1162708. [PMID: 40017583 PMCID: PMC11865466 DOI: 10.1155/jdr/1162708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 01/23/2025] [Indexed: 03/01/2025] Open
Abstract
Objective: FKBP5 is a critical gene involved in regulating the hypothalamic-pituitary-adrenal (HPA) axis and stress response. Aberrant DNA methylation at FKBP5 cytosine-phosphate-guanine (CpG) sites, such as cg22363520 and cg00862770, has been implicated in mental health disorders and metabolic diseases, including Type 2 diabetes. Exercise is a modulator of DNA methylation and metabolic health. This study investigates the interaction between exercise, diabetes, and FKBP5 methylation at cg22363520 and cg00862770 and explores their implications for mental health and disease development. Materials and Methods: FKBP5 methylation levels at cg22363520 and cg00862770 were analyzed in a cohort stratified by diabetes and exercise. Multiple linear regression models assessed the main effects and interactions of exercise and diabetes on FKBP5 methylation, with further stratified analyses for site-specific effects. Results: Exercise and diabetes showed significant and site-specific effects on FKBP5 methylation at cg22363520 and cg00862770. At cg22363520, exercise significantly reduced methylation levels in nondiabetic participants (β = -0.00195, p = 0.0157), while no significant effect was observed in diabetic individuals. Conversely, at cg00862770, exercise significantly decreased methylation levels in diabetic participants (β = -0.00611, p = 0.0081), with no significant effect in the nondiabetic group. Diabetes itself was associated with increased FKBP5 methylation at both sites, particularly in individuals without regular exercise. Additionally, significant interaction effects between exercise and diabetes were identified for both cg22363520 (p = 0.0336) and cg00862770 (p = 0.0021), highlighting the interplay between metabolic status and physical activity in regulating FKBP5 methylation. Conclusion: This study demonstrates that the effects of exercise on FKBP5 methylation are site-specific and influenced by diabetes status. Exercise reduces methylation at cg22363520 in nondiabetics and at cg00862770 in diabetics, indicating its role in modulating epigenetic regulation of stress and metabolic pathways. These findings underscore the interplay between exercise, diabetes, and FKBP5 methylation, with potential implications for improving mental health and metabolic outcomes.
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Affiliation(s)
- Teng-Chi Yang
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
- Department of Medical Affairs, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi County, Taiwan
| | - Jen Pi Tsai
- Division of Nephrology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi County, Taiwan
- School of Medicine, Tzu Chi University, Buddhist Tzu Chi School Foundation, Hualien County, Taiwan
| | - Honda Hsu
- School of Medicine, Tzu Chi University, Buddhist Tzu Chi School Foundation, Hualien County, Taiwan
- Division of Plastic Surgery, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi County, Taiwan
| | - Yen-Chung Chen
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
- Department of Neurology, Changhua Christian Hospital, Changhua City, Taiwan
| | - Yi-Chia Liaw
- Neurological Institute, Taipei Veterans General Hospital, Taipei City, Taiwan
| | - Shu Yi Hsu
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
| | - Hao Jan Yang
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
| | - Yung-Po Liaw
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
- Institute of Medicine, Chug Shan Medical University, Taichung City, Taiwan
- Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, Taiwan
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Barthel MC, Fricke K, Muehlhan M, Vogel S, Alexander N. Habituation of the biological response to repeated psychosocial stress: a systematic review and meta-analysis. Neurosci Biobehav Rev 2025; 169:105996. [PMID: 39755292 DOI: 10.1016/j.neubiorev.2024.105996] [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: 11/27/2024] [Revised: 12/17/2024] [Accepted: 12/29/2024] [Indexed: 01/06/2025]
Abstract
Recurrent psychosocial stress poses a significant health challenge, prompting research into mechanisms of successful adaptation. Physiological habituation, defined as decreased reactivity to repeated stressors, is pivotal in protecting the organism from allostatic load. Here, we systematically review and meta-analyze data from studies investigating the capacity of central stress systems to habituate when repeatedly exposed to a standardized psychosocial stressor, the Trier Social Stress Test (k = 47). For a comprehensive overview of biological stress systems, we examine multiple markers of the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous system (ANS), and the immune system. Our findings indicate that habituation patterns vary substantially between different stress systems. While most studies provide robust evidence for rapid and substantial HPA-axis habituation, ANS and immune marker responses to repeated stress are less uniform. We further integrate existing knowledge on personal and environmental influences contributing to individual differences in habituation capacity. Additionally, we discuss the implications of stress habituation patterns for health outcomes and the design of longitudinal stress studies and highlight potential avenues for future research.
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Affiliation(s)
- Marie-Christin Barthel
- Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg - University of Applied Sciences and Medical University, Am Kaiserkai 1, Hamburg 20457, Germany; ICAN Institute for Cognitive and Affective Neuroscience, MSH Medical School Hamburg - University of Applied Sciences and Medical University, Am Kaiserkai 1, Hamburg 20457, Germany.
| | - Kim Fricke
- Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg - University of Applied Sciences and Medical University, Am Kaiserkai 1, Hamburg 20457, Germany; ICAN Institute for Cognitive and Affective Neuroscience, MSH Medical School Hamburg - University of Applied Sciences and Medical University, Am Kaiserkai 1, Hamburg 20457, Germany
| | - Markus Muehlhan
- Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg - University of Applied Sciences and Medical University, Am Kaiserkai 1, Hamburg 20457, Germany; ICAN Institute for Cognitive and Affective Neuroscience, MSH Medical School Hamburg - University of Applied Sciences and Medical University, Am Kaiserkai 1, Hamburg 20457, Germany
| | - Susanne Vogel
- Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg - University of Applied Sciences and Medical University, Am Kaiserkai 1, Hamburg 20457, Germany; ICAN Institute for Cognitive and Affective Neuroscience, MSH Medical School Hamburg - University of Applied Sciences and Medical University, Am Kaiserkai 1, Hamburg 20457, Germany
| | - Nina Alexander
- Department of Psychiatry and Psychotherapy, Philipps University Marburg, Rudolf-Bultmann-Str. 8, Marburg 35039, Germany; Center for Mind, Brain and Behaviour, Philipps University Marburg, Hans-Meerwein-Str. 6, Marburg 35032, Germany.
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Zhu BL, Tang JY, Chen WJ, Qian JJ, Zhang F, Zhang XL, Chen TT, Jiang B, Zhao HY. Fluoxetine treatment reverses chronic stress-induced promotion on Fk506-binding protein 5 expression and multiple effects on glucocorticoid receptor phosphorylation in the paraventricular nucleus of mice. Pharmacol Biochem Behav 2025; 246:173916. [PMID: 39615557 DOI: 10.1016/j.pbb.2024.173916] [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: 08/06/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND Fluoxetine is widely used as a first-line antidepressant. However, the molecular mechanisms for its antidepressant effects are still not fully understood. Hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is a core pathogenic mechanism contributing to depression, and fluoxetine treatment prevents this dysfunction. The glucocorticoid receptor (GR) is a major negative feedback regulator of the HPA axis, while Fk506-binding protein 5 (Fkbp5) is a negative regulator of the GR signaling. Therefore, we examined the effects of fluoxetine on Fkbp5 and the GR signaling in the hypothalamic paraventricular nucleus (PVN) of depressed mice. METHODS Mice were exposed to chronic social defeat stress (CSDS), chronic unpredictable mild stress (CUMS), or chronic restraint stress (CRS) with or without fluoxetine treatment (intraperitoneally injected, 20 mg/kg) and examined for changes in depression-like behaviors and HPA axis activity as well as Fkbp5 expression and GR phosphorylation in the PVN. We then examined if adeno-associated virus (AAV)-mediated Fkbp5 overexpression in the PVN affected the antidepressant actions of fluoxetine in mice. RESULTS Fluoxetine treatment significantly mitigated CSDS-, CUMS-, and CRS-induced depression-like behaviors and HPA axis hyperactivity in mice. Subsequent western blotting analyses showed that fluoxetine treatment fully reversed not only chronic stress-induced upregulation of Fkbp5 and CRH but also chronic stress-induced increase in Ser203 phosphorylation and decrease in Ser211 and Ser234 phosphorylation in GR in the PVN. Moreover, quantitative real-time reverse transcription PCR (qRT-PCR) analyses revealed that the enhanced mRNA levels of Fkbp5 and CRH in PVN neurons of mice subjected to CSDS/CUMS/CRS were also notably reversed by fluoxetine administration. Conversely, Fkbp5 overexpression in the PVN significantly eliminated the antidepressant effects of fluoxetine in mice without affecting their locomotor activity. CONCLUSION These results together suggest that fluoxetine treatment reverses chronic stress-induced promotion on Fkbp5 expression and multiple effects on GR phosphorylation in the PVN of mice. SIGNIFICANCE STATEMENT The selective serotonin reuptake inhibitor fluoxetine (sold as Prozac) is a widely used treatment for depression, but the full spectrum of therapeutic mechanisms is still debated. Recent evidence suggests that these therapeutic mechanisms include suppression of chronic stress-activated hypothalamus-pituitary-adrenal (HPA) axis. The current study presents the first in vivo evidence showing that suppression of HPA axis hyperactivity by fluoxetine treatment involves reversal of glucocorticoid receptor (GR) phosphorylation via modulation of the GR negative regulator Fk506-binding protein 5 (Fkbp5) in the hypothalamic paraventricular nucleus (PVN). Fluoxetine treatment not only inhibited chronic stress-induced depression-like behaviors and HPA axis hyperactivity but also reversed Fkbp5 upregulation and GR phosphorylation changes in the PVN, while adeno-associated virus (AAV)-based Fkbp5 overexpression in the PVN eliminated the antidepressant effects of fluoxetine. These findings may expand our understanding of the pharmacological effects of fluoxetine, and further identify Fkbp5 as a possible target for novel antidepressants.
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Affiliation(s)
- Bao-Lun Zhu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Department of Clinical Nursing, School of Nursing and Rehabilitation, Nantong University, Nantong 226001, Jiangsu, China
| | - Jin-Yan Tang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Department of Pharmacy, Rugao People's Hospital, Rugao 226500, Jiangsu, China
| | - Wei-Jia Chen
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Jun-Jie Qian
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Feng Zhang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Xiao-Ling Zhang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Ting-Ting Chen
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Bo Jiang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China.
| | - He-Yan Zhao
- Department of Clinical Nursing, School of Nursing and Rehabilitation, Nantong University, Nantong 226001, Jiangsu, China.
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Grillo AR. Polygene by environment interactions predicting depressive outcomes. Am J Med Genet B Neuropsychiatr Genet 2025; 198:e33000. [PMID: 39012198 DOI: 10.1002/ajmg.b.33000] [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: 05/01/2023] [Revised: 06/13/2024] [Accepted: 06/17/2024] [Indexed: 07/17/2024]
Abstract
Depression is a major public health problem with a continued need to uncover its etiology. Current models of depression contend that gene-by-environment (G × E) interactions influence depression risk, and further, that depression is polygenic. Thus, recent models have emphasized two polygenic approaches: a hypothesis-driven multilocus genetic profile score (MGPS; "MGPS × E") and a polygenic risk score (PRS; "PRS × E") derived from genome-wide association studies (GWAS). This review for the first time synthesizes current knowledge on polygene by environment "P × E" interaction research predicting primarily depression-related outcomes, and in brief, neurobiological outcomes. The "environment" of focus in this project is stressful life events. It further discusses findings in the context of differential susceptibility and diathesis-stress theories-two major theories guiding G × E work. This synthesis indicates that, within the MGPS literature, polygenic scores based on the serotonin system, the HPA axis, or across multiple systems, interact with environmental stress exposure to predict outcomes at multiple levels of analyses and most consistently align with differential susceptibility theory. Depressive outcomes are the most studied, but neuroendocrine, and neuroimaging findings are observed as well. By contrast, vast methodological differences between GWAS-based PRS studies contribute to mixed findings that yield inconclusive results.
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Affiliation(s)
- Alessandra R Grillo
- Department of Psychology, University of North Carolina, Greensboro, North Carolina, USA
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LaFond M, DeAngelis B, al'Absi M. Hypothalamic pituitary adrenal and autonomic nervous system biomarkers of stress and tobacco relapse: Review of the research. Biol Psychol 2024; 192:108854. [PMID: 39151748 DOI: 10.1016/j.biopsycho.2024.108854] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 08/01/2024] [Accepted: 08/07/2024] [Indexed: 08/19/2024]
Abstract
Tobacco smoking is a risk factor for countless diseases, and smoking relapse remains a major public health concern. Subjective reports of stress by smokers are a common theme for relapse, however, the role of objective stress-related biomarkers in predicting tobacco relapse risk has been less studied. The aim of this manuscript was to review existing literature on the connection between biomarkers of stress and smoking relapse. Overall, trends indicate that blunted hypothalamic-pituitary-adrenal (HPA) responses to acute stress, larger reductions in HPA biomarkers during the initial days of abstinence during cessation (compared to pre-cessation levels), and exaggerated autonomic responses to stress predict increased risk of relapse. In addition, successful cessation is followed by changes in stress biomarkers (e.g., reductions in cortisol and heart rate, HR). This review also identifies potential modifiers, such as methodological differences, biological sex, and chronic stress, to account for heterogeneity of findings within and across studies. In addition, we identify gaps in the literature and suggest future research directions focusing on the roles of genetics and gene expression as well as the influence of neurobiological mechanisms on stress and relapse risk. Future clinical implications of this research include identifying reliable indicators of relapse risk and the potential of pharmacotherapeutic treatments to target stress response systems to correct dysregulation and potentially reduce stress-related risk of relapse.
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Affiliation(s)
- Madeleine LaFond
- Family Medicine and Biobehavioral Health, University of Minnesota Medical School, Duluth, MN 55812, USA
| | - Briana DeAngelis
- Family Medicine and Biobehavioral Health, University of Minnesota Medical School, Duluth, MN 55812, USA
| | - Mustafa al'Absi
- Family Medicine and Biobehavioral Health, University of Minnesota Medical School, Duluth, MN 55812, USA.
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Lafta MS, Sokolov AV, Landtblom AM, Ericson H, Schiöth HB, Abu Hamdeh S. Exploring biomarkers in trigeminal neuralgia patients operated with microvascular decompression: A comparison with multiple sclerosis patients and non-neurological controls. Eur J Pain 2024; 28:929-942. [PMID: 38158702 DOI: 10.1002/ejp.2231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 12/07/2023] [Accepted: 12/18/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Trigeminal neuralgia (TN) is a severe facial pain condition often associated with a neurovascular conflict. However, neuroinflammation has also been implicated in TN, as it frequently co-occurs with multiple sclerosis (MS). METHODS We analysed protein expression levels of TN patients compared to MS patients and controls. Proximity Extension Assay technology was used to analyse the levels of 92 proteins with the Multiplex Neuro-Exploratory panel provided by SciLifeLab, Uppsala, Sweden. Serum and CSF samples were collected from TN patients before (n = 33 and n = 27, respectively) and after (n = 28 and n = 8, respectively) microvascular decompression surgery. Additionally, we included samples from MS patients (n = 20) and controls (n = 20) for comparison. RESULTS In both serum and CSF, several proteins were found increased in TN patients compared to either MS patients, controls, or both, including EIF4B, PTPN1, EREG, TBCB, PMVK, FKBP5, CD63, CRADD, BST2, CD302, CRIP2, CCL27, PPP3R1, WWP2, KLB, PLA2G10, TDGF1, SMOC1, RBKS, LTBP3, CLSTN1, NXPH1, SFRP1, HMOX2, and GGT5. The overall expression of the 92 proteins in postoperative TN samples seems to shift towards the levels of MS patients and controls in both serum and CSF, as compared to preoperative samples. Interestingly, there was no difference in protein levels between MS patients and controls. CONCLUSIONS We conclude that TN patients showed increased serum and CSF levels of specific proteins and that successful surgery normalizes these protein levels, highlighting its potential as an effective treatment. However, the similarity between MS and controls challenges the idea of shared pathophysiology with TN, suggesting distinct underlying mechanisms in these conditions. SIGNIFICANCE This study advances our understanding of trigeminal neuralgia (TN) and its association with multiple sclerosis (MS). By analysing 92 protein biomarkers, we identified distinctive molecular profiles in TN patients, shedding light on potential pathophysiological mechanisms. The observation that successful surgery normalizes many protein levels suggests a promising avenue for TN treatment. Furthermore, the contrasting protein patterns between TN and MS challenge prevailing assumptions of similarity between the two conditions and point to distinct pathophysiological mechanisms.
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Affiliation(s)
- Muataz S Lafta
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Aleksandr V Sokolov
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Anne-Marie Landtblom
- Department of Medical Sciences, Neurology, Uppsala University, Uppsala, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Hans Ericson
- Department of Medical Sciences, Section of Neurosurgery, Uppsala University, Uppsala, Sweden
| | - Helgi B Schiöth
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Sami Abu Hamdeh
- Department of Medical Sciences, Section of Neurosurgery, Uppsala University, Uppsala, Sweden
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Zhang Y, Randesi M, Blendy JA, Kreek MJ, Butelman ER. Impact of OPRM1 (Mu-opioid Receptor Gene) A112G Polymorphism on Dual Oxycodone and Cocaine Self-administration Behavior in a Mouse Model. Neuroscience 2024; 539:76-85. [PMID: 38211933 DOI: 10.1016/j.neuroscience.2024.01.002] [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: 03/31/2023] [Revised: 12/28/2023] [Accepted: 01/05/2024] [Indexed: 01/13/2024]
Abstract
The use of mu-opioid receptor (MOP-r) agonists such as oxycodone together with cocaine is prevalent, and deaths attributed to using these combinations have increased. RATIONALE It is unknown if functional single nucleotide polymorphisms (SNPs), such as the OPRM1 (MOP-r gene) SNP A118G, can predispose individuals to more dual opioid and psychostimulant intake. The dual self-administration (SA) of MOP-r agonists and cocaine has not been thoroughly examined, especially with regard to neurobiological changes. OBJECTIVES We examined oxycodone SA and subsequent dual oxycodone and cocaine SA in male and female A112G (A/G and G/G, heterozygote and homozygote, respectively) mice, models of human A118G carriers, versus wild-type (A/A) mice. METHODS Adult male and female A/G, G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, 4hr/session, FR 1.) for 10 consecutive days (sessions 1-10). Mice then self-administered cocaine (2 hr) following oxycodone SA (4 hr, as above) in each session for a further 10 consecutive days (sessions 11-20). Message RNA transcripts of 24 reward-related genes were examined in the dorsal striatum. RESULTS Male and female A/G and G/G mice had greater oxycodone SA than A/A mice did in the initial 10 days and in the last 10 sessions. Further, A/G and G/G mice showed greater cocaine intake than A/A mice. Dorsal striatal mRNA levels of Pdyn, Fkbp5, Oprk1, and Oprm1 were altered following oxycodone and cocaine SA. CONCLUSIONS These studies demonstrated that this functional genetic variation in Oprm1 affected dual opioid and cocaine SA and altered specific gene expression in the striatum.
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Affiliation(s)
- Yong Zhang
- Laboratory of the Biology of Addictive Diseases, the Rockefeller University, New York, NY 10065, United States.
| | - Matthew Randesi
- Laboratory of the Biology of Addictive Diseases, the Rockefeller University, New York, NY 10065, United States
| | - Julie A Blendy
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Mary Jeanne Kreek
- Laboratory of the Biology of Addictive Diseases, the Rockefeller University, New York, NY 10065, United States
| | - Eduardo R Butelman
- Laboratory of the Biology of Addictive Diseases, the Rockefeller University, New York, NY 10065, United States; Neuropsychoimaging of Addictions and Related Conditions Research Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
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Williams KE, Zou Y, Qiu B, Kono T, Guo C, Garcia D, Chen H, Graves T, Lai Z, Evans-Molina C, Ma YY, Liangpunsakul S, Yong W, Liang T. Sex-Specific Impact of Fkbp5 on Hippocampal Response to Acute Alcohol Injection: Involvement in Alterations of Metabolism-Related Pathways. Cells 2023; 13:89. [PMID: 38201293 PMCID: PMC10778370 DOI: 10.3390/cells13010089] [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: 10/30/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
High levels of alcohol intake alter brain gene expression and can produce long-lasting effects. FK506-binding protein 51 (FKBP51) encoded by Fkbp5 is a physical and cellular stress response gene and has been associated with alcohol consumption and withdrawal severity. Fkbp5 has been previously linked to neurite outgrowth and hippocampal morphology, sex differences in stress response, and epigenetic modification. Presently, primary cultured Fkbp5 KO and WT mouse neurons were examined for neurite outgrowth and mitochondrial signal with and without alcohol. We found neurite specification differences between KO and WT; particularly, mesh-like morphology was observed after alcohol treatment and confirmed higher MitoTracker signal in cultured neurons of Fkbp5 KO compared to WT at both naive and alcohol-treated conditions. Brain regions that express FKBP51 protein were identified, and hippocampus was confirmed to possess a high level of expression. RNA-seq profiling was performed using the hippocampus of naïve or alcohol-injected (2 mg EtOH/Kg) male and female Fkbp5 KO and WT mice. Differentially expressed genes (DEGs) were identified between Fkbp5 KO and WT at baseline and following alcohol treatment, with female comparisons possessing a higher number of DEGs than male comparisons. Pathway analysis suggested that genes affecting calcium signaling, lipid metabolism, and axon guidance were differentially expressed at naïve condition between KO and WT. Alcohol treatment significantly affected pathways and enzymes involved in biosynthesis (Keto, serine, and glycine) and signaling (dopamine and insulin receptor), and neuroprotective role. Functions related to cell morphology, cell-to-cell signaling, lipid metabolism, injury response, and post-translational modification were significantly altered due to alcohol. In summary, Fkbp5 plays a critical role in the response to acute alcohol treatment by altering metabolism and signaling-related genes.
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Affiliation(s)
- Kent E. Williams
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USA; (K.E.W.); (T.G.); (S.L.)
| | - Yi Zou
- Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (Y.Z.); (D.G.); (Z.L.)
| | - Bin Qiu
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA;
| | - Tatsuyoshi Kono
- Diabetes Research Center, Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.K.); (C.E.-M.)
| | - Changyong Guo
- Department Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (C.G.); (Y.-Y.M.)
| | - Dawn Garcia
- Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (Y.Z.); (D.G.); (Z.L.)
| | - Hanying Chen
- Department Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Tamara Graves
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USA; (K.E.W.); (T.G.); (S.L.)
| | - Zhao Lai
- Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (Y.Z.); (D.G.); (Z.L.)
| | - Carmella Evans-Molina
- Diabetes Research Center, Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.K.); (C.E.-M.)
| | - Yao-Ying Ma
- Department Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (C.G.); (Y.-Y.M.)
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USA; (K.E.W.); (T.G.); (S.L.)
- Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Weidong Yong
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Tiebing Liang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USA; (K.E.W.); (T.G.); (S.L.)
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11
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Palamarchuk IS, Slavich GM, Vaillancourt T, Rajji TK. Stress-related cellular pathophysiology as a crosstalk risk factor for neurocognitive and psychiatric disorders. BMC Neurosci 2023; 24:65. [PMID: 38087196 PMCID: PMC10714507 DOI: 10.1186/s12868-023-00831-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/24/2023] [Indexed: 12/18/2023] Open
Abstract
In this narrative review, we examine biological processes linking psychological stress and cognition, with a focus on how psychological stress can activate multiple neurobiological mechanisms that drive cognitive decline and behavioral change. First, we describe the general neurobiology of the stress response to define neurocognitive stress reactivity. Second, we review aspects of epigenetic regulation, synaptic transmission, sex hormones, photoperiodic plasticity, and psychoneuroimmunological processes that can contribute to cognitive decline and neuropsychiatric conditions. Third, we explain mechanistic processes linking the stress response and neuropathology. Fourth, we discuss molecular nuances such as an interplay between kinases and proteins, as well as differential role of sex hormones, that can increase vulnerability to cognitive and emotional dysregulation following stress. Finally, we explicate several testable hypotheses for stress, neurocognitive, and neuropsychiatric research. Together, this work highlights how stress processes alter neurophysiology on multiple levels to increase individuals' risk for neurocognitive and psychiatric disorders, and points toward novel therapeutic targets for mitigating these effects. The resulting models can thus advance dementia and mental health research, and translational neuroscience, with an eye toward clinical application in cognitive and behavioral neurology, and psychiatry.
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Affiliation(s)
- Iryna S Palamarchuk
- Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, M6J1H4, Canada.
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Sunnybrook Health Sciences Centre, Division of Neurology, Toronto, ON, Canada.
- Temerty Faculty of Medicine, Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada.
| | - George M Slavich
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA
| | - Tracy Vaillancourt
- Counselling Psychology, Faculty of Education, University of Ottawa, Ottawa, ON, Canada
- School of Psychology, Faculty of Social Sciences, University of Ottawa, Ottawa, ON, Canada
| | - Tarek K Rajji
- Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, M6J1H4, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Temerty Faculty of Medicine, Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada
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12
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Kühnel A, Hagenberg J, Knauer-Arloth J, Ködel M, Czisch M, Sämann PG, Binder EB, Kroemer NB. Stress-induced brain responses are associated with BMI in women. Commun Biol 2023; 6:1031. [PMID: 37821711 PMCID: PMC10567923 DOI: 10.1038/s42003-023-05396-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 09/27/2023] [Indexed: 10/13/2023] Open
Abstract
Overweight and obesity are associated with altered stress reactivity and increased inflammation. However, it is not known whether stress-induced changes in brain function scale with BMI and if such associations are driven by peripheral cytokines. Here, we investigate multimodal stress responses in a large transdiagnostic sample using predictive modeling based on spatio-temporal profiles of stress-induced changes in activation and functional connectivity. BMI is associated with increased brain responses as well as greater negative affect after stress and individual response profiles are associated with BMI in females (pperm < 0.001), but not males. Although stress-induced changes reflecting BMI are associated with baseline cortisol, there is no robust association with peripheral cytokines. To conclude, alterations in body weight and energy metabolism might scale acute brain responses to stress more strongly in females compared to males, echoing observational studies. Our findings highlight sex-dependent associations of stress with differences in endocrine markers, largely independent of peripheral inflammation.
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Affiliation(s)
- Anne Kühnel
- Section of Medical Psychology, Department of Psychiatry and Psychotherapy, Faculty of Medicine, University of Bonn, Bonn, Germany.
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany.
| | - Jonas Hagenberg
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany
- Institute of Computational Biology, Helmholtz Zentrum Munich, Neuherberg, Germany
| | - Janine Knauer-Arloth
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
- Institute of Computational Biology, Helmholtz Zentrum Munich, Neuherberg, Germany
| | - Maik Ködel
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
| | | | | | - Elisabeth B Binder
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
- German Center for Mental Health, Tübingen, Germany.
| | - Nils B Kroemer
- Section of Medical Psychology, Department of Psychiatry and Psychotherapy, Faculty of Medicine, University of Bonn, Bonn, Germany
- German Center for Mental Health, Tübingen, Germany
- Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health (TüCMH), University of Tübingen, Tübingen, Germany
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13
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Li A, Bao J, Gao S, He Y, Nie X, Hosyanto FF, He X, Li T, Xu L. MicroRNA hsa-miR-320a-3p and Its Targeted mRNA FKBP5 Were Differentially Expressed in Patients with HIV/TB Co-Infection. ACS Infect Dis 2023; 9:1742-1753. [PMID: 37624586 DOI: 10.1021/acsinfecdis.3c00211] [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: 08/26/2023]
Abstract
Among the PLWH (people living with HIV) population, the risk of developing active tuberculosis (TB) is increasing. Active TB also accelerates the deterioration of PLWH's immune function and is one of the leading causes of death in the PLWH population. So far, accurate diagnosis of active TB in the PLWH population remains challenging. Through data analysis of HIV/TB co-infection in the GEO database, the differentially expressed genes as well as their related microRNA (miRNA) were acquired and were further verified through clinical blood samples. Dual-luciferase assay was used to verify the mechanism of miRNA on mRNA. The enrichment of immune cells in database patient samples was analyzed by bioinformatics and finally verified by blood routine data. Our study found that FKBP5 (FK506 binding protein 5) was highly expressed in the HIV/TB co-infection group; hsa-miR-320a-3p was highly expressed in the HIV infection group but decreased in the HIV/TB co-infection group. Dual-luciferase assay results showed that hsa-miR-320a-3p mimics significantly reduced the relative luciferase activity of the WT-FKBP5 group; however, this phenomenon was not observed in the MUT-FKBP5 group. At the same time, as a key molecule of the immune-related pathway, FKBP5 is highly correlated with the amount of neutrophils, which provides a new suggestion for the treatment of the HIV/TB co-infection population. Our study found that hsa-miR-320a-3p can decrease FKBP5 expression, suggesting a potential regulatory role for FKBP5. The involvement of FKBP5 and its related molecule hsa-miR-320a-3p in HIV/TB co-infection proposes them as potential biomarkers for the diagnosis of active TB in the PLWH population.
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Affiliation(s)
- Anlong Li
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Jiajia Bao
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
- Hospital-Acquired Infection Control Department, First People's Hospital of Jintang County, Chengdu 610400, China
| | - Sijia Gao
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Ying He
- Central Laboratory, Chongqing Public Health Medical Center, Southwest University Public Health Hospital, Chongqing 400036, China
| | - Xiaoping Nie
- Central Laboratory, Chongqing Public Health Medical Center, Southwest University Public Health Hospital, Chongqing 400036, China
| | | | - Xintong He
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Tongxin Li
- Central Laboratory, Chongqing Public Health Medical Center, Southwest University Public Health Hospital, Chongqing 400036, China
| | - Lei Xu
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
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14
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Malekpour M, Shekouh D, Safavinia ME, Shiralipour S, Jalouli M, Mortezanejad S, Azarpira N, Ebrahimi ND. Role of FKBP5 and its genetic mutations in stress-induced psychiatric disorders: an opportunity for drug discovery. Front Psychiatry 2023; 14:1182345. [PMID: 37398599 PMCID: PMC10313426 DOI: 10.3389/fpsyt.2023.1182345] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 05/24/2023] [Indexed: 07/04/2023] Open
Abstract
Stress-induced mental health disorders are affecting many people around the world. However, effective drug therapy for curing psychiatric diseases does not occur sufficiently. Many neurotransmitters, hormones, and mechanisms are essential in regulating the body's stress response. One of the most critical components of the stress response system is the hypothalamus-pituitary-adrenal (HPA) axis. The FKBP prolyl isomerase 51 (FKBP51) protein is one of the main negative regulators of the HPA axis. FKBP51 negatively regulates the cortisol effects (the end product of the HPA axis) by inhibiting the interaction between glucocorticoid receptors (GRs) and cortisol, causing reduced transcription of downstream cortisol molecules. By regulating cortisol effects, the FKBP51 protein can indirectly regulate the sensitivity of the HPA axis to stressors. Previous studies have indicated the influence of FKBP5 gene mutations and epigenetic changes in different psychiatric diseases and drug responses and recommended the FKBP51 protein as a drug target and a biomarker for psychological disorders. In this review, we attempted to discuss the effects of the FKBP5 gene, its mutations on different psychiatric diseases, and drugs affecting the FKBP5 gene.
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Affiliation(s)
- Mahdi Malekpour
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Dorsa Shekouh
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Shadi Shiralipour
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Jalouli
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sahar Mortezanejad
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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15
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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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16
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Bales KL, Hang S, Paulus JP, Jahanfard E, Manca C, Jost G, Boyer C, Bern R, Yerumyan D, Rogers S, Mederos SL. Individual differences in social homeostasis. Front Behav Neurosci 2023; 17:1068609. [PMID: 36969803 PMCID: PMC10036751 DOI: 10.3389/fnbeh.2023.1068609] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 02/15/2023] [Indexed: 03/12/2023] Open
Abstract
The concept of “social homeostasis”, introduced by Matthews and Tye in 2019, has provided a framework with which to consider our changing individual needs for social interaction, and the neurobiology underlying this system. This model was conceived as including detector systems, a control center with a setpoint, and effectors which allow us to seek out or avoid additional social contact. In this article, we review and theorize about the many different factors that might contribute to the setpoint of a person or animal, including individual, social, cultural, and other environmental factors. We conclude with a consideration of the empirical challenges of this exciting new model.
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Affiliation(s)
- Karen L. Bales
- Department of Psychology, University of California, Davis, >Davis, CA, United States
- *Correspondence: Karen L. Bales
| | - Sally Hang
- Graduate Group in Psychology, University of California, Davis, Davis, CA, United States
| | - John P. Paulus
- Graduate Group in Neuroscience, University of California, Davis, Davis, CA, United States
| | - Elaina Jahanfard
- Graduate Group in Psychology, University of California, Davis, Davis, CA, United States
| | - Claudia Manca
- Graduate Group in Psychology, University of California, Davis, Davis, CA, United States
| | - Geneva Jost
- Graduate Group in Psychology, University of California, Davis, Davis, CA, United States
| | - Chase Boyer
- Graduate Group in Human Development, University of California, Davis, Davis, CA, United States
| | - Rose Bern
- Graduate Group in Psychology, University of California, Davis, Davis, CA, United States
| | - Daniella Yerumyan
- Graduate Group in Psychology, University of California, Davis, Davis, CA, United States
| | - Sophia Rogers
- Graduate Group in Psychology, University of California, Davis, Davis, CA, United States
| | - Sabrina L. Mederos
- Graduate Group in Animal Behavior, University of California, Davis, Davis, CA, United States
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17
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Raza Z, Hussain SF, Foster VS, Wall J, Coffey PJ, Martin JF, Gomes RSM. Exposure to war and conflict: The individual and inherited epigenetic effects on health, with a focus on post-traumatic stress disorder. FRONTIERS IN EPIDEMIOLOGY 2023; 3:1066158. [PMID: 38455905 PMCID: PMC10910933 DOI: 10.3389/fepid.2023.1066158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/03/2023] [Indexed: 03/09/2024]
Abstract
War and conflict are global phenomena, identified as stress-inducing triggers for epigenetic modifications. In this state-of-the-science narrative review based on systematic principles, we summarise existing data to explore the outcomes of these exposures especially in veterans and show that they may result in an increased likelihood of developing gastrointestinal, auditory, metabolic and circadian issues, as well as post-traumatic stress disorder (PTSD). We also note that, despite a potential "healthy soldier effect", both veterans and civilians with PTSD exhibit the altered DNA methylation status in hypothalamic-pituitary-adrenal (HPA) axis regulatory genes such as NR3C1. Genes associated with sleep (PAX8; LHX1) are seen to be differentially methylated in veterans. A limited number of studies also revealed hereditary effects of war exposure across groups: decreased cortisol levels and a heightened (sex-linked) mortality risk in offspring. Future large-scale studies further identifying the heritable risks of war, as well as any potential differences between military and civilian populations, would be valuable to inform future healthcare directives.
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Affiliation(s)
- Zara Raza
- Research & Innovation, Blind Veterans UK, London, United Kingdom
- BRAVO VICTOR, Research & Innovation, London, United Kingdom
- Hull York Medical School, University of York, York, United Kingdom
| | - Syeda F Hussain
- Research & Innovation, Blind Veterans UK, London, United Kingdom
- BRAVO VICTOR, Research & Innovation, London, United Kingdom
| | - Victoria S Foster
- Research & Innovation, Blind Veterans UK, London, United Kingdom
- BRAVO VICTOR, Research & Innovation, London, United Kingdom
- St George's Hospital Medical School, London, United Kingdom
| | - Joseph Wall
- Hull York Medical School, University of York, York, United Kingdom
- Haxby Group Hull, General Practice Surgery, Hull, United Kingdom
| | - Peter J Coffey
- Development, Ageing and Disease, UCL Institute of Ophthalmology, University College London, London, United Kingdom
| | - John F Martin
- Centre for Cardiovascular Biology and Medicine, University College London, London, United Kingdom
| | - Renata S M Gomes
- Research & Innovation, Blind Veterans UK, London, United Kingdom
- BRAVO VICTOR, Research & Innovation, London, United Kingdom
- Northern Hub for Veterans and Military Families Research, Department of Nursing, Midwifery and Health, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom
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18
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Laricchiuta D, Panuccio A, Picerni E, Biondo D, Genovesi B, Petrosini L. The body keeps the score: The neurobiological profile of traumatized adolescents. Neurosci Biobehav Rev 2023; 145:105033. [PMID: 36610696 DOI: 10.1016/j.neubiorev.2023.105033] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 12/13/2022] [Accepted: 01/02/2023] [Indexed: 01/05/2023]
Abstract
Trauma-related disorders are debilitating psychiatric conditions that affect people who have directly or indirectly witnessed adversities. Experiencing multiple types of traumas appears to be common during childhood, and even more so during adolescence. Dramatic brain/body transformations occurring during adolescence may provide a highly responsive substrate to external stimuli and lead to trauma-related vulnerability conditions, such as internalizing (anxiety, depression, anhedonia, withdrawal) and externalizing (aggression, delinquency, conduct disorders) problems. Analyzing relations among neuronal, endocrine, immune, and biochemical signatures of trauma and internalizing and externalizing behaviors, including the role of personality traits in shaping these conducts, this review highlights that the marked effects of traumatic experience on the brain/body involve changes at nearly every level of analysis, from brain structure, function and connectivity to endocrine and immune systems, from gene expression (including in the gut) to the development of personality.
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Affiliation(s)
- Daniela Laricchiuta
- Department of Philosophy, Social Sciences & Education, University of Perugia, Perugia, Italy.
| | - Anna Panuccio
- Laboratory of Experimental and Behavioral Neurophysiology, IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Psychology, University Sapienza of Rome, Rome, Italy
| | - Eleonora Picerni
- Laboratory of Experimental and Behavioral Neurophysiology, IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Neuroscience Imaging and Clinical Sciences, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy
| | | | | | - Laura Petrosini
- Laboratory of Experimental and Behavioral Neurophysiology, IRCCS Fondazione Santa Lucia, Rome, Italy
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19
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Fang T, Liu MN, Tian XY, Lu GY, Li F, Zhang X, Liu F, Hao W, Wu N, Li H, Li J. The association of FKBP5 polymorphisms with the severity of depressive disorder in patients with methamphetamine use disorders. Front Psychiatry 2023; 14:1147060. [PMID: 37051166 PMCID: PMC10083280 DOI: 10.3389/fpsyt.2023.1147060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 02/28/2023] [Indexed: 04/14/2023] Open
Abstract
Background Co-occurring depressive disorder (DD) in patients of methamphetamine use disorder (MAUD) impacts the diagnosis, treatment, and prognosis of the disease. Although FKBP5 has been associated with a variety of psychiatric disorders, whether FKBP5 influences depression susceptibility in MAUD is unknown so far. Methods Here, we sequenced six FKBP5 single-nucleotide polymorphism (SNP) sites (rs4713916, rs6926133, rs9470080, rs737054, rs4713902, and rs9470079) in 282 methamphetamine users. MAUD and DD were evaluated by clinical questionnaires. SPSS was used to analyze the relationship between FKBP5 SNPs and DD in individuals with MAUD. Results Of the 282 methamphetamine users, 161 individuals met the MAUD criteria, and among them, 50 patients (31.1%) had DD co-occurring. Importantly, the incidence of DD in individuals with MAUD was 3.314 times greater than that of the methamphetamine users who did not meet the MAUD criteria (p < 0.001). Although none of the six SNPs of FKBP5 were correlated with the co-occurrence of DD in the population with MAUD, two FKBP5 alleles (rs4713916A and rs6926133A) were substantially associated with the higher DD scores in patients with MAUD (p < 0.05). Moreover, those with the two risk alleles do not have much higher scores than those with a single risk allele, and the strong linkage disequilibrium of the two SNPs may be the underlying cause of this result. Despite having weak linkage disequilibrium with either rs4713916 or rs6926133, FKBP5 rs9470079 became risky when paired with either. Conclusion The results of this study revealed that the FKBP5 risk alleles (rs4713916A and rs6926133A) were associated with a greater probability of severe DD in patients with MAUD. These findings here would help with the development of biological early warning markers and the creation of personalized treatment strategies for MAUD.
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Affiliation(s)
- Ting Fang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Meng-Nan Liu
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Xiao-Yu Tian
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Guan-Yi Lu
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Fei Li
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Xiaojie Zhang
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Feng Liu
- Compulsory Detoxification Center of Changsha Public Security Bureau, Changsha, Hunan, China
| | - Wei Hao
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ning Wu
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Hong Li
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China
- Hong Li
| | - Jin Li
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China
- *Correspondence: Jin Li
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20
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Womersley JS, Roeh S, Martin L, Ahmed-Leitao F, Sauer S, Rex-Haffner M, Hemmings SMJ, Binder EB, Seedat S. FKBP5 intron 7 methylation is associated with higher anxiety proneness and smaller right thalamus volume in adolescents. Brain Struct Funct 2022; 227:2809-2820. [PMID: 36197505 DOI: 10.1007/s00429-022-02577-9] [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: 05/19/2022] [Accepted: 09/23/2022] [Indexed: 11/28/2022]
Abstract
Dysregulation of stress response systems may mediate the detrimental effects of childhood trauma (CT) on mental health. FKBP5 regulates glucocorticoid receptor sensitivity and exerts pleiotropic effects on intracellular signaling, neurobiology and behavior. We investigated whether CT, alone and in combination with rs1360780 genotype, is associated with altered FKBP5 methylation and whether CT-associated methylation profiles are associated with anxiety proneness (AP) and structural brain volumes. Ninety-four adolescents completed the Childhood Trauma Questionnaire, and a composite AP score was generated from the Childhood Anxiety Sensitivity Index and the State-Trait Anxiety Inventory-Trait measure. Mean methylation values for 12 regulatory regions and 25 individual CpG sites were determined using high-accuracy measurement via targeted bisulfite sequencing. FKBP5 rs1360780 genotype and structural MRI data were available for a subset of participants (n = 71 and n = 75, respectively). Regression models revealed an inverse association between methylation of three intron 7 CpG sites (35558438, 35558566 and 35558710) and right thalamus volume. CpG35558438 methylation was positively associated with AP scores. Our data indicate that an intron 7 methylation profile, consistent with lower FKBP5 expression and elevated high sensitivity glucocorticoid receptor levels, is associated with higher AP and smaller right thalamus volume. Research into the mechanisms underlying the intron 7 methylation-thalamus volume relationship, and whether it confers increased risk for long-term psychopathology by altering the regulatory threshold of stress responding, is required.
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Affiliation(s)
- Jacqueline S Womersley
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. .,South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. .,Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
| | - Simone Roeh
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
| | - Lindi Martin
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Fatima Ahmed-Leitao
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Susann Sauer
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
| | - Monika Rex-Haffner
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
| | - Sian M J Hemmings
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.,South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Elisabeth B Binder
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.,Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Soraya Seedat
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.,South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.,South African Research Chairs Initiative (SARChI) in PTSD, Department of Psychiatry, Stellenbosch University, Cape Town, South Africa
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21
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Eskandari F, Salimi M, Binayi F, Abdollahifar MA, Eftekhary M, Hedayati M, Ghanbarian H, Zardooz H. Investigating the Effects of Maternal Separation on Hypothalamic-Pituitary-Adrenal Axis and Glucose Homeostasis under Chronic Social Defeat Stress in Young Adult Male Rat Offspring. Neuroendocrinology 2022; 113:361-380. [PMID: 36088912 DOI: 10.1159/000526989] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 09/05/2022] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Given the suggested metabolic regulatory effects of stress-responsive genes and based on the impacts of early-life stress on HPA axis development, this study aimed to characterize the maternal separation (MS) impact on the communication between glucose metabolism and HPA axis dysregulations under chronic social defeat stress (CSDS). METHODS During the first 2 weeks of life, male Wistar rats were either exposed to MS or left undisturbed with their mothers (Std). Starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for 3 weeks. There were four groups (n = 10/group): Std-Con, MS-Con, Std-CSDS, and MS-CSDS. RESULTS Early and/or adult life adversity reduced β-cell number, muscular FK506-binding protein 51 (FKBP51) content, and BMI in adulthood. The reduction of β-cell number and BMI in the MS-CSDS rats were more profound than MS-Con group. CSDS either alone or in combination with MS reduced locomotor activity and increased and decreased corticotropin-releasing factor type 1 receptor (CRFR1) content, respectively, in hypothalamus and pancreas. Although, under CSDS, MS intensified HPA axis overactivity and reduced isolated islets' insulin secretion, it could promote resilience to depression symptoms. No differences were observed in hypothalamic Fkbp5 gene DNA methylation and glucose tolerance among groups. CONCLUSION MS exacerbated HPA axis overactivity and the endocrine pancreas dysfunctions under CSDS. The intensified corticosterone secretion and the diminished content of pancreatic CRFR1 protein could be involved in the reduced β-cell number and islets' insulin secretion under CSDS. The decreased muscular FKBP51 content might be a homeostatic response to slow down insulin resistance development under chronic stress.
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Affiliation(s)
- Farzaneh Eskandari
- Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mina Salimi
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fateme Binayi
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad-Amin Abdollahifar
- Department of Biology and Anatomical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohamad Eftekhary
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Hedayati
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Ghanbarian
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Homeira Zardooz
- Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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22
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A pilot investigation of genetic and epigenetic variation of FKBP5 and response to exercise intervention in African women with obesity. Sci Rep 2022; 12:11771. [PMID: 35817784 PMCID: PMC9273786 DOI: 10.1038/s41598-022-15678-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 06/28/2022] [Indexed: 11/23/2022] Open
Abstract
We investigated gluteal (GSAT) and abdominal subcutaneous adipose tissue (ASAT) DNA methylation of FKBP5 in response to a 12-week intervention in African women with obesity, as well as the effect of the rs1360780 single nucleotide polymorphism (SNP) on FKBP5 methylation, gene expression and post-exercise training adaptations in obesity and metabolic related parameters. Exercise (n = 19) participants underwent 12-weeks of supervised aerobic and resistance training while controls (n = 12) continued their usual behaviours. FKBP5 methylation was measured in GSAT and ASAT using pyrosequencing. SNP and gene expression analyses were conducted using quantitative real-time PCR. Exercise training induced FKBP5 hypermethylation at two CpG dinucleotides within intron 7. When stratified based on the rs1360780 SNP, participants with the CT genotype displayed FKBP5 hypermethylation in GSAT (p < 0.05), and ASAT displayed in both CC and CT carriers. CC allele carriers displayed improved cardiorespiratory fitness, insulin sensitivity, gynoid fat mass, and waist circumference (p < 0.05) in response to exercise training, and these parameters were attenuated in women with the CT genotype. These findings provide a basis for future studies in larger cohorts, which should assess whether FKBP5 methylation and/or genetic variants such as the rs1360780 SNP could have a significant impact on responsiveness to exercise interventions.
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23
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Moisan MP. Fkbp5-humanized mice shed light on female higher vulnerability to stress. Lab Anim (NY) 2022; 51:188-189. [DOI: 10.1038/s41684-022-00999-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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24
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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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25
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Marcolongo F, Scarlata S, Tomino C, De Dominicis C, Giacconi R, Malavolta M, Bonassi S, Russo P, Prinzi G. Psycho-cognitive assessment and quality of life in older adults with chronic obstructive pulmonary disease-carrying the rs4713916 gene polymorphism (G/A) of gene FKBP5 and response to pulmonary rehabilitation: a proof of concept study. Psychiatr Genet 2022; 32:116-124. [PMID: 35102127 DOI: 10.1097/ypg.0000000000000308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary and extra-pulmonary multi-morbidity including depression, anxiety and cognitive disorders. Several studies investigated the association of the FKBP5 gene polymorphisms with susceptibility to anxiety, depression, and behavioral disorders. The FKBP5 gene codifies the FKBP51 protein which modulates the glucocorticoid receptor in the adaptive stress response. Genetic variants of the FKBP5 gene have been associated to a higher risk of developing mental disorders. We analyzed the association of genetic variants and stress exposure investigating the susceptibility to psychological distress and the impact on cognitive balance and quality of life (QoL) of COPD patients carrying the rs4713916 polymorphism (G/A) and we examined its association, with COPD rehabilitative outcomes. MATERIALS AND METHODS A pilot study evaluated cognitive, psychological, clinical alterations/disorders, QoL, and coping strategies in 70 older adults with COPD, undergoing pulmonary rehabilitation, stratified according to the FKBP5 rs4713916 genotype (GG or GA). RESULTS Carriers of rs4713916 polymorphisms (G/A) show better cognitive performances, a higher degree of independence in the daily living activities, better QoL, no presence of depressive mood and anxiety symptoms, no family history of psychiatric disorders, more ability to cope with stressors by avoiding emotions but demanding emotional support, and lesser use of anti-anxiety, anti-depressant, anti-psychotic, hypnotic-sedative drugs. No difference was found in the number of comorbidities. CONCLUSION These results offer valuable insights into the role of FKBP5 in the complex network of mechanisms associated to clinical, psychological and behavioral features of COPD patients.
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Affiliation(s)
- Federica Marcolongo
- Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Roma, Via di Val Cannuta
| | - Simone Scarlata
- Unit of Geriatrics, Campus Bio-Medico di Roma, University, Via Alvaro del Portillo
| | - Carlo Tomino
- Scientific Direction, IRCCS San Raffaele Roma, Via di Val Cannuta
| | - Chiara De Dominicis
- Molecular and Cellular Neurobiology, IRCCS San Raffaele Roma, Via di Val Cannuta, Rome
| | - Robertina Giacconi
- Technology Center for Aging Research, Scientific Technological Area, IRCCS-INRCA, Via Giuseppe Birarelli, Ancona
| | - Marco Malavolta
- Technology Center for Aging Research, Scientific Technological Area, IRCCS-INRCA, Via Giuseppe Birarelli, Ancona
| | - Stefano Bonassi
- Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Roma, Via di Val Cannuta
- Department of Human Sciences and Quality of Life Promotion, San Raffaele University, Via di Val Cannuta, Rome, Italy
| | - Patrizia Russo
- Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Roma, Via di Val Cannuta
- Department of Human Sciences and Quality of Life Promotion, San Raffaele University, Via di Val Cannuta, Rome, Italy
| | - Giulia Prinzi
- Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Roma, Via di Val Cannuta
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26
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Effects of stress on endophenotypes of suicide across species: A role for ketamine in risk mitigation. Neurobiol Stress 2022; 18:100450. [PMID: 35685678 PMCID: PMC9170747 DOI: 10.1016/j.ynstr.2022.100450] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/05/2022] [Accepted: 04/15/2022] [Indexed: 12/28/2022] Open
Abstract
Suicide is a leading cause of death and morbidity worldwide, yet few interventions are available to mitigate its risk. Barriers to effective treatments involve a limited understanding of factors that predict the onset of suicidal thoughts and behaviors. In the context of suicide risk, stress is a precipitating factor that is largely overlooked in the literature. Indeed, the pathophysiology of stress and suicide are heavily interconnected, underscoring the need to target the stress system in suicide prevention. In this review, we integrate findings from the preclinical and clinical literature that links stress and suicide. We focus specifically on the effects of stress on underlying biological functions and processes associated with suicide, allowing for the review of research using animal models. Owing to the rapid anti-suicidal effects of (R,S)-ketamine, we discuss its ability to modulate various stress-related endophenotypes of suicide, as well as its potential role in preventing suicide in those with a history of chronic life stress (e.g., early life adversity). We highlight future research directions that could advance our understanding of stress-related effects on suicide risk, advocating a dimensional, endophenotype approach to suicide research.
Suicide and chronic stress pathophysiology are interconnected. Chronic stress has profound impacts on several endophenotypes of suicide. Animal and human research points to stress as a precipitating factor in suicide. Ketamine modulates specific biological processes associated with stress and suicide. Suicide research into endophenotypes can help inform risk-mitigation strategies.
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27
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Budziñski ML, Sokn C, Gobbini R, Ugo B, Antunica-Noguerol M, Senin S, Bajaj T, Gassen NC, Rein T, Schmidt MV, Binder EB, Arzt E, Liberman AC. Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity. Mol Psychiatry 2022; 27:2533-2545. [PMID: 35256747 DOI: 10.1038/s41380-022-01491-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 02/02/2022] [Accepted: 02/14/2022] [Indexed: 12/11/2022]
Abstract
FKBP51 is an important inhibitor of the glucocorticoid receptor (GR) signaling. High FKBP51 levels are associated to stress-related disorders, which are linked to GR resistance. SUMO conjugation to FKBP51 is necessary for FKBP51's inhibitory action on GR. The GR/FKBP51 pathway is target of antidepressant action. Thus we investigated if these drugs could inhibit FKBP51 SUMOylation and therefore restore GR activity. Screening cells using Ni2+ affinity and in vitro SUMOylation assays revealed that tricyclic antidepressants- particularly clomipramine- inhibited FKBP51 SUMOylation. Our data show that clomipramine binds to FKBP51 inhibiting its interaction with PIAS4 and therefore hindering its SUMOylation. The inhibition of FKBP51 SUMOylation decreased its binding to Hsp90 and GR facilitating FKBP52 recruitment, and enhancing GR activity. Reduction of PIAS4 expression in rat primary astrocytes impaired FKBP51 interaction with GR, while clomipramine could no longer exert its inhibitory action. This mechanism was verified in vivo in mice treated with clomipramine. These results describe the action of antidepressants as repressors of FKBP51 SUMOylation as a molecular switch for restoring GR sensitivity, thereby providing new potential routes of antidepressant intervention.
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Affiliation(s)
- Maia L Budziñski
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina
| | - Clara Sokn
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina
| | - Romina Gobbini
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina
| | - Belén Ugo
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina
| | - María Antunica-Noguerol
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina
| | - Sergio Senin
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina
| | - Thomas Bajaj
- Neurohomeostasis Research Group, Department of Psychiatry, Bonn Clinical Center, University of Bonn, 53127, Bonn, Germany
| | - Nils C Gassen
- Neurohomeostasis Research Group, Department of Psychiatry, Bonn Clinical Center, University of Bonn, 53127, Bonn, Germany.,Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, D-80804, Munich, Germany
| | - Theo Rein
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, D-80804, Munich, Germany
| | - Mathias V Schmidt
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, D-80804, Munich, Germany
| | - Elisabeth B Binder
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, D-80804, Munich, Germany
| | - Eduardo Arzt
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina. .,Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428EGA, Argentina.
| | - Ana C Liberman
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina.
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28
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Impact of Fkbp5 × early life adversity × sex in humanised mice on multidimensional stress responses and circadian rhythmicity. Mol Psychiatry 2022; 27:3544-3555. [PMID: 35449298 PMCID: PMC9708571 DOI: 10.1038/s41380-022-01549-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 03/04/2022] [Accepted: 03/23/2022] [Indexed: 12/19/2022]
Abstract
The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes the prevalence of psychiatric disorders. Single nucleotide polymorphisms (SNPs) in the human FKBP5 gene were shown to modulate disease risk. To enable investigation of disease-related SNPs in behaviourally relevant context, we generated humanised mouse lines carrying either the risk (AT) or the resiliency (CG) allele of the rs1360780 locus and exposed litters of these mice to maternal separation. Behavioural and physiological aspects of their adult stress responsiveness displayed interactions of genotype, early life condition, and sex. In humanised females carrying the CG- but not the AT-allele, ELA led to altered HPA axis functioning, exploratory behaviour, and sociability. These changes correlated with differential expression of genes in the hypothalamus, where synaptic transmission, metabolism, and circadian entrainment pathways were deregulated. Our data suggest an integrative role of FKBP5 in shaping the sex-specific outcome of ELA in adulthood.
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29
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Interaction Between Glucocorticoid Receptors and FKBP5 in Regulating Neurotransmission of the Hippocampus. Neuroscience 2021; 483:95-103. [PMID: 34923037 DOI: 10.1016/j.neuroscience.2021.12.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 11/19/2021] [Accepted: 12/13/2021] [Indexed: 11/20/2022]
Abstract
FK501 binding protein 51 (FKBP5) is a stress response prolyl isomerase that inhibits the translocation of the glucocorticoid receptor (GR) heterocomplex to the nucleus. Previous studies have shown that the expression levels of FKBP5 are positively correlated with psychiatric disorders, including depression and post-traumatic stress disorder. In rodents, FKBP5 deletion in the brain leads to be resilient to stress-induced depression. The hippocampus is known to be one of the primary locations mediating stress responses in the brain by providing negative feedback signals to the hypothalamus-pituitaryadrenal gland axis. Therefore, we aimed to investigate the role of FKBP5 and its interaction with GRs in the hippocampus. We observed that FKBP5 deletion in the hippocampus resulted in a minimal change in synaptic transmission. In the hippocampus, GR activation alters the release probability in inhibitory synapses as well as the postsynaptic contribution of glutamate receptors in excitatory synapses; however, no such alterations were induced in the absence of FKBP5. FKBP5 deficiency causes insensitivity to activated GRs in the hippocampus suggesting that FKBP5 mediates synaptic changes caused by GR activation. Our study provides electrophysiological evidence of stress resilience observed in FKBP5-deficient mice.
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30
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FKBP51 in the Oval Bed Nucleus of the Stria Terminalis Regulates Anxiety-Like Behavior. eNeuro 2021; 8:ENEURO.0425-21.2021. [PMID: 34872938 PMCID: PMC8687485 DOI: 10.1523/eneuro.0425-21.2021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/11/2021] [Accepted: 11/15/2021] [Indexed: 12/22/2022] Open
Abstract
The cochaperone FKBP51, encoded by the Fkbp5 gene, has been identified as central risk factor for anxiety-related disorders and stress system dysregulation. In the brain, the oval bed nucleus of the stria terminalis (ovBNST) has been implicated in stress-induced anxiety. However, the role of Fkbp5 in the ovBNST and its impact on anxiety-like behavior have remained unknown. Here, we show in mice that Fkbp5 in the ovBNST is reactive to acute stress and coexpressed with the stress-regulated neuropeptides Tac2 and Crh Subsequently, results obtained from viral-mediated manipulation indicate that Fkbp5 overexpression (OE) in the ovBNST results in an anxiolytic-like tendency regarding behavior and endocrinology, whereas a Fkbp5 knock-out (KO) exposed a clear anxiogenic phenotype, indicating that native ovBNST expression and regulation is necessary for normal anxiety-related behavior. Notably, our data suggests that a stress-induced increase of Fkbp5 in the ovBNST may in fact have a protective role, leading to a transient decrease in anxiety and suppression of a future stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation. Together, our findings provide a first insight into the previously unknown relationship and effects of Fkbp5 and the ovBNST on anxiety-like behavior and HPA axis functioning.
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31
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Kanagaraj S, Devishrree S, Swetha J, Priya BK, Sankar S, Cherian J, Gopal CR, Karthikeyan S. Autism and Emotion: A Narrative Review. JOURNAL OF HEALTH AND ALLIED SCIENCES NU 2021. [DOI: 10.1055/s-0041-1736277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
AbstractAutism spectrum disorder (ASD) includes a variety of childhood-onset and lifelong neurodevelopmental condition with an enduring impact on multiple domains of functioning characterized by persistent deficits in social communication, restricted and repetitive behavior interest, and activities. They often find it hard to recognize and control emotions but their emotional expression can be improved by various intervention techniques that in turn can help them understand and respond more appropriately to other people. Problems in the area on emotional reciprocity among individual with ASD involve recognizing, understanding, expressing, and regulating emotions. Their ability in emotional reciprocity is often improved with a comprehensive treatment approach, especially by focused emotional enhancement intervention. In this review, we followed the standard IMRAD (Introduction, Methods, Results, and Discussion) structure to critically examine the condition of autism and its relation with genetic mechanism, and how theories of emotion and theory of mind associated with persons with ASD, some of the widely used assessment tools and future research direction in the emotional development of individuals diagnosed with ASD by using the narrative review method. Records collected through research databases such as Scopus, PubMed, Web of Science, Medline, EBSCO and published books with ISBN (International Standard Book Number), and published test manuals were evaluated in-depth and summarized based on the subtopic of the proposed title. A critical theoretical analysis of the genetic mechanism of emotions, theories of emotions, and theory of mind was explained in connection with ASD.
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Affiliation(s)
- Sagayaraj Kanagaraj
- Department of Counseling Psychology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Chennai, Tamil Nadu, India
| | - S. Devishrree
- Department of Clinical Psychology, National Institute for Empowerment of Persons with Multiple Disabilities (Divyangjan), East Coast Road, Chennai, Tamil Nadu, India
| | - J. Swetha
- Department of Rehabilitation Psychology, National Institute for Empowerment of Persons with Intellectual Disabilities (Divyangjan), Manovikas Nagar, Secunderabad, Telangana, India
| | - B. Krishna Priya
- Department of Counseling Psychology, University of Madras, Chennai, Tamil Nadu, India
| | - Srivarshini Sankar
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Jincy Cherian
- Department of Psychology, Dayalbagh Educational Institute, Agra, Uttar Pradesh, India
| | - C.N. Ram Gopal
- Department of Counseling Psychology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Chennai, Tamil Nadu, India
| | - S. Karthikeyan
- Department of Clinical Psychology, National Institute for Empowerment of Persons with Multiple Disabilities (Divyangjan), East Coast Road, Chennai, Tamil Nadu, India
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Kusumanchi P, Liang T, Zhang T, Ross RA, Han S, Chandler K, Oshodi A, Jiang Y, Dent AL, Skill NJ, Huda N, Ma J, Yang Z, Liangpunsakul S. Stress-Responsive Gene FK506-Binding Protein 51 Mediates Alcohol-Induced Liver Injury Through the Hippo Pathway and Chemokine (C-X-C Motif) Ligand 1 Signaling. Hepatology 2021; 74:1234-1250. [PMID: 33710653 PMCID: PMC8435051 DOI: 10.1002/hep.31800] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 02/05/2021] [Accepted: 02/08/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Chronic alcohol drinking is a major risk factor for alcohol-associated liver disease (ALD). FK506-binding protein 51 (FKBP5), a cochaperone protein, is involved in many key regulatory pathways. It is known to be involved in stress-related disorders, but there are no reports regarding its role in ALD. This present study aimed to examine the molecular mechanism of FKBP5 in ALD. APPROACH AND RESULTS We found a significant increase in hepatic FKBP5 transcripts and protein expression in patients with ALD and mice fed with chronic-plus-single binge ethanol. Loss of Fkbp5 in mice protected against alcohol-induced hepatic steatosis and inflammation. Transcriptomic analysis revealed a significant reduction of Transcriptional enhancer factor TEF-1 (TEA) domain transcription factor 1 (Tead1) and chemokine (C-X-C motif) ligand 1 (Cxcl1) mRNA in ethanol-fed Fkbp5-/- mice. Ethanol-induced Fkbp5 expression was secondary to down-regulation of methylation level at its 5' untranslated promoter region. The increase in Fkbp5 expression led to induction in transcription factor TEAD1 through Hippo signaling pathway. Fkbp5 can interact with yes-associated protein (YAP) upstream kinase, mammalian Ste20-like kinase 1 (MST1), affecting its ability to phosphorylate YAP and the inhibitory effect of hepatic YAP phosphorylation by ethanol leading to YAP nuclear translocation and TEAD1 activation. Activation of TEAD1 led to increased expression of its target, CXCL1, a chemokine-mediated neutrophil recruitment, causing hepatic inflammation and neutrophil infiltration in our mouse model. CONCLUSIONS We identified an FKBP5-YAP-TEAD1-CXCL1 axis in the pathogenesis of ALD. Loss of FKBP5 ameliorates alcohol-induced liver injury through the Hippo pathway and CXCL1 signaling, suggesting its potential role as a target for the treatment of ALD.
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Affiliation(s)
- Praveen Kusumanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Tiebing Liang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Ting Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Ruth Ann Ross
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Sen Han
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Kristina Chandler
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Adepeju Oshodi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Yanchao Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Alexander L Dent
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN
| | - Nicholas J Skill
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Nazmul Huda
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Jing Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
- Roudebush Veterans Administration Medical Center, Indianapolis, IN
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33
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Häusl AS, Brix LM, Hartmann J, Pöhlmann ML, Lopez JP, Menegaz D, Brivio E, Engelhardt C, Roeh S, Bajaj T, Rudolph L, Stoffel R, Hafner K, Goss HM, Reul JMHM, Deussing JM, Eder M, Ressler KJ, Gassen NC, Chen A, Schmidt MV. The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice. Mol Psychiatry 2021; 26:3060-3076. [PMID: 33649453 PMCID: PMC8505251 DOI: 10.1038/s41380-021-01044-x] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/19/2021] [Accepted: 02/02/2021] [Indexed: 01/31/2023]
Abstract
Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1+ neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh+ neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response.
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Affiliation(s)
- Alexander S Häusl
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany
| | - Lea M Brix
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany
| | - Jakob Hartmann
- Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA
| | - Max L Pöhlmann
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany
| | - Juan-Pablo Lopez
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Danusa Menegaz
- Electrophysiology Core Unit, Max Planck Institute of Psychiatry, Munich, Germany
| | - Elena Brivio
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Clara Engelhardt
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany
| | - Simone Roeh
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
| | - Thomas Bajaj
- Department of Psychiatry and Psychotherapy, Bonn Clinical Center, University of Bonn, Bonn, Germany
| | - Lisa Rudolph
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Rainer Stoffel
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Kathrin Hafner
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
| | - Hannah M Goss
- Neuro-Epigenetics Research Group, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Johannes M H M Reul
- Neuro-Epigenetics Research Group, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Jan M Deussing
- Research Group Molecular Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Matthias Eder
- Electrophysiology Core Unit, Max Planck Institute of Psychiatry, Munich, Germany
| | - Kerry J Ressler
- Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA
| | - Nils C Gassen
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
- Department of Psychiatry and Psychotherapy, Bonn Clinical Center, University of Bonn, Bonn, Germany
| | - Alon Chen
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
- Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
| | - Mathias V Schmidt
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany.
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34
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Richter A, Al-Bayati M, Paraskevopoulou F, Krämer B, Pruessner JC, Binder EB, Gruber O. Interaction of FKBP5 variant rs3800373 and city living alters the neural stress response in the anterior cingulate cortex. Stress 2021; 24:421-429. [PMID: 33541187 DOI: 10.1080/10253890.2020.1855420] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Psychosocial stress effects of urban living are associated with substantially increased risk for schizophrenia, mood and anxiety disorders, by altering stress-induced activity in the amygdala and pregenual anterior cingulate cortex (ACC). Genetic factors are likely to modulate the impact of city living on stress processing. Growing evidence suggests a key role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of stress-related disorders. Here we investigated the interaction of city living and genetic variation in FKBP5 (rs3800373) on neural activity in stress-sensitive brain systems. Functional magnetic resonance imaging was performed in 31 healthy young adults using the Montreal Imaging Stress Task. Subjects were divided into groups depending on the number of inhabitants of their current residency. There was a significant main effect of city living on neural activity in the amygdala-hippocampus complex, replicating prior findings. Moreover, we found an interaction between rs3800373 and city living modulating responses in the bilateral subgenual ACC and right pregenual ACC. Specifically, only city dwellers carrying the FKBP5 minor risk allele showed increased stress responses in the subgenual and pregenual ACC when compared to those living in small towns. A significant gene-environment interaction on neural stress responses in the amygdala or hippocampus was only found in FKBP5 major allele carriers. These results point to a potential role of the FKBP5 rs3800373 minor risk allele in predisposing those who live in bigger cities to changes of functional responsivity in the pre- and subgenual ACC, thereby increasing the risk for developing stress-related mental disorders.
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Affiliation(s)
- Anja Richter
- Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Mohammad Al-Bayati
- Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
| | - Foteini Paraskevopoulou
- Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
| | - Bernd Krämer
- Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany
| | - Jens C Pruessner
- Department of Psychology, University of Constance, Constance, Germany
| | - Elisabeth B Binder
- Department of Translational Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
| | - Oliver Gruber
- Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany
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35
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Wesarg C, Veer IM, Oei NYL, Daedelow LS, Lett TA, Banaschewski T, Barker GJ, Bokde AL, Quinlan EB, Desrivières S, Flor H, Grigis A, Garavan H, Brühl R, Martinot J, Artiges E, Nees F, Orfanos DP, Poustka L, Hohmann S, Fröhner JH, Smolka MN, Whelan R, Schumann G, Heinz A, Walter H, IMAGEN Consortium. The interaction of child abuse and rs1360780 of the FKBP5 gene is associated with amygdala resting-state functional connectivity in young adults. Hum Brain Mapp 2021; 42:3269-3281. [PMID: 33818852 PMCID: PMC8193540 DOI: 10.1002/hbm.25433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 03/25/2021] [Indexed: 01/15/2023] Open
Abstract
Extensive research has demonstrated that rs1360780, a common single nucleotide polymorphism within the FKBP5 gene, interacts with early-life stress in predicting psychopathology. Previous results suggest that carriers of the TT genotype of rs1360780 who were exposed to child abuse show differences in structure and functional activation of emotion-processing brain areas belonging to the salience network. Extending these findings on intermediate phenotypes of psychopathology, we examined if the interaction between rs1360780 and child abuse predicts resting-state functional connectivity (rsFC) between the amygdala and other areas of the salience network. We analyzed data of young European adults from the general population (N = 774; mean age = 18.76 years) who took part in the IMAGEN study. In the absence of main effects of genotype and abuse, a significant interaction effect was observed for rsFC between the right centromedial amygdala and right posterior insula (p < .025, FWE-corrected), which was driven by stronger rsFC in TT allele carriers with a history of abuse. Our results suggest that the TT genotype of rs1360780 may render individuals with a history of abuse more vulnerable to functional changes in communication between brain areas processing emotions and bodily sensations, which could underlie or increase the risk for psychopathology.
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Affiliation(s)
- Christiane Wesarg
- Department of Developmental Psychology, Addiction Development and Psychopathology (ADAPT)‐LabUniversity of AmsterdamAmsterdamThe Netherlands
- Research Priority Area (RPA) YieldUniversity of AmsterdamAmsterdamThe Netherlands
| | - Ilya M. Veer
- Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlinand Berlin Institute of HealthBerlinGermany
| | - Nicole Y. L. Oei
- Department of Developmental Psychology, Addiction Development and Psychopathology (ADAPT)‐LabUniversity of AmsterdamAmsterdamThe Netherlands
- Research Priority Area (RPA) YieldUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Brain and Cognition (ABC)University of AmsterdamAmsterdamThe Netherlands
| | - Laura S. Daedelow
- Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlinand Berlin Institute of HealthBerlinGermany
| | - Tristram A. Lett
- Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlinand Berlin Institute of HealthBerlinGermany
- Department of Neurology with Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität BerlinHumboldt‐Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
| | - Tobias Banaschewski
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Gareth J. Barker
- Department of NeuroimagingInstitute of Psychiatry, Psychology & Neuroscience, King's College LondonLondonUK
| | - Arun L.W. Bokde
- Discipline of Psychiatry, School of Medicine and Trinity College Institute of NeuroscienceTrinity College DublinDublinIreland
| | - Erin Burke Quinlan
- Centre for Population Neuroscience and Precision Medicine (PONS)Institute of Psychiatry, Psychology & Neuroscience, SGDP Centre, King's College LondonLondonUK
| | - Sylvane Desrivières
- Centre for Population Neuroscience and Precision Medicine (PONS)Institute of Psychiatry, Psychology & Neuroscience, SGDP Centre, King's College LondonLondonUK
| | - Herta Flor
- Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
- Department of Psychology, School of Social SciencesUniversity of MannheimMannheimGermany
| | - Antoine Grigis
- NeuroSpin, CEAUniversité Paris‐SaclayGif‐sur‐YvetteFrance
| | - Hugh Garavan
- Departments of Psychiatry and PsychologyUniversity of VermontBurlingtonVermontUSA
| | - Rüdiger Brühl
- Physikalisch‐Technische Bundesanstalt (PTB)Braunschweig and BerlinBerlinGermany
| | - Jean‐Luc Martinot
- Institut National de la Santé et de la Recherche MédicaleINSERM U A10 “Trajectoires développementales en psychiatrie”; Université Paris‐Saclay, Ecole Normale supérieure Paris‐Saclay, CNRS, Centre BorelliGif‐sur‐YvetteFrance
| | - Eric Artiges
- Institut National de la Santé et de la Recherche MédicaleINSERM U A10 “Trajectoires développementales en psychiatrie”; Université Paris‐Saclay, Ecole Normale supérieure Paris‐Saclay, CNRS, Centre BorelliGif‐sur‐YvetteFrance
- Department of Psychiatry 91G16Orsay HospitalGif‐sur‐YvetteFrance
| | - Frauke Nees
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
- Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
- Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig HolsteinKiel UniversityKielGermany
| | | | - Luise Poustka
- Department of Child and Adolescent Psychiatry and PsychotherapyUniversity Medical Centre GöttingenGöttingenGermany
| | - Sarah Hohmann
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Juliane H. Fröhner
- Department of Psychiatry and Neuroimaging CenterTechnische Universität DresdenDresdenGermany
| | - Michael N. Smolka
- Department of Psychiatry and Neuroimaging CenterTechnische Universität DresdenDresdenGermany
| | - Robert Whelan
- School of Psychology and Global Brain Health InstituteTrinity College DublinDublinIreland
| | - Gunter Schumann
- Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlinand Berlin Institute of HealthBerlinGermany
- Centre for Population Neuroscience and Precision Medicine (PONS)Institute of Psychiatry, Psychology & Neuroscience, SGDP Centre, King's College LondonLondonUK
- Leibniz Institute for NeurobiologyMagdeburgGermany
- Institute for Science and Technology of Brain‐inspired Intelligence (ISTBI)Fudan UniversityShanghaiChina
| | - Andreas Heinz
- Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlinand Berlin Institute of HealthBerlinGermany
| | - Henrik Walter
- Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlinand Berlin Institute of HealthBerlinGermany
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36
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Imagery of negative interpersonal experiences influence the neural mechanisms of social interaction. Neuropsychologia 2021; 160:107923. [PMID: 34175371 DOI: 10.1016/j.neuropsychologia.2021.107923] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/31/2021] [Accepted: 06/21/2021] [Indexed: 11/22/2022]
Abstract
Negative interpersonal experiences are a key contributor to psychiatric disorders. While previous research has shown that negative interpersonal experiences influence social cognition, less is known about the effects on participation in social interactions and the underlying neurobiology. To address this, we developed a new naturalistic version of a gaze-contingent paradigm using real video sequences of gaze behaviour that respond to the participants' gaze in real-time in order to create a believable and continuous interactive social situation. Additionally, participants listened to two autobiographical audio-scripts that guided them to imagine a recent stressful and a relaxing situation and performed the gaze-based social interaction task before and after the presentation of either the stressful or the relaxing audio-script. Our results demonstrate that the social interaction task robustly recruits brain areas with known involvement in social cognition, namely the medial prefrontal cortex, bilateral temporoparietal junction, superior temporal sulcus as well as the precuneus. Imagery of negative interpersonal experiences compared to relaxing imagery led to a prolonged change in affective state and to increased brain responses during the subsequent social interaction paradigm in the temporoparietal junction, medial prefrontal cortex, anterior cingulate cortex, precuneus and inferior frontal gyrus. Taken together this study presents a new naturalistic social interaction paradigm suitable to study the neural mechanisms of social interaction and the results demonstrate that the imagery of negative interpersonal experiences affects social interaction on neural levels.
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37
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Milligan Armstrong A, Porter T, Quek H, White A, Haynes J, Jackaman C, Villemagne V, Munyard K, Laws SM, Verdile G, Groth D. Chronic stress and Alzheimer's disease: the interplay between the hypothalamic-pituitary-adrenal axis, genetics and microglia. Biol Rev Camb Philos Soc 2021; 96:2209-2228. [PMID: 34159699 DOI: 10.1111/brv.12750] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 05/12/2021] [Accepted: 05/14/2021] [Indexed: 12/21/2022]
Abstract
Chronic psychosocial stress is increasingly being recognised as a risk factor for sporadic Alzheimer's disease (AD). The hypothalamic-pituitary-adrenal axis (HPA axis) is the major stress response pathway in the body and tightly regulates the production of cortisol, a glucocorticoid hormone. Dysregulation of the HPA axis and increased levels of cortisol are commonly found in AD patients and make a major contribution to the disease process. The underlying mechanisms remain poorly understood. In addition, within the general population there are interindividual differences in sensitivities to glucocorticoid and stress responses, which are thought to be due to a combination of genetic and environmental factors. These differences could ultimately impact an individuals' risk of AD. The purpose of this review is first to summarise the literature describing environmental and genetic factors that can impact an individual's HPA axis reactivity and function and ultimately AD risk. Secondly, we propose a mechanism by which genetic factors that influence HPA axis reactivity may also impact inflammation, a key driver of neurodegeneration. We hypothesize that these factors can mediate glucocorticoid priming of the immune cells of the brain, microglia, to become pro-inflammatory and promote a neurotoxic environment resulting in neurodegeneration. Understanding the underlying molecular mechanisms and identifying these genetic factors has implications for evaluating stress-related risk/progression to neurodegeneration, informing the success of interventions based on stress management and potential risks associated with the common use of glucocorticoids.
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Affiliation(s)
- Ayeisha Milligan Armstrong
- Curtin Health Innovation Research Institute, Curtin University, Kent St, Bentley, WA, 6102, Australia.,Curtin Medical School, Curtin University, Kent St, Bentley, WA, 6102, Australia
| | - Tenielle Porter
- Curtin Medical School, Curtin University, Kent St, Bentley, WA, 6102, Australia.,Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA, 6027, Australia
| | - Hazel Quek
- QIMR Berghofer Medical Institute, 300 Herston Rd, Herston, QLD, Australia
| | - Anthony White
- QIMR Berghofer Medical Institute, 300 Herston Rd, Herston, QLD, Australia
| | - John Haynes
- Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia
| | - Connie Jackaman
- Curtin Health Innovation Research Institute, Curtin University, Kent St, Bentley, WA, 6102, Australia.,Curtin Medical School, Curtin University, Kent St, Bentley, WA, 6102, Australia
| | - Victor Villemagne
- School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA, 6027, Australia.,The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia
| | - Kylie Munyard
- Curtin Health Innovation Research Institute, Curtin University, Kent St, Bentley, WA, 6102, Australia.,Curtin Medical School, Curtin University, Kent St, Bentley, WA, 6102, Australia
| | - Simon M Laws
- Curtin Medical School, Curtin University, Kent St, Bentley, WA, 6102, Australia.,Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA, 6027, Australia
| | - Giuseppe Verdile
- Curtin Health Innovation Research Institute, Curtin University, Kent St, Bentley, WA, 6102, Australia.,Curtin Medical School, Curtin University, Kent St, Bentley, WA, 6102, Australia.,School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA, 6027, Australia
| | - David Groth
- Curtin Health Innovation Research Institute, Curtin University, Kent St, Bentley, WA, 6102, Australia.,Curtin Medical School, Curtin University, Kent St, Bentley, WA, 6102, Australia
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38
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Hartmann J, Bajaj T, Klengel C, Chatzinakos C, Ebert T, Dedic N, McCullough KM, Lardenoije R, Joëls M, Meijer OC, McCann KE, Dudek SM, Sarabdjitsingh RA, Daskalakis NP, Klengel T, Gassen NC, Schmidt MV, Ressler KJ. Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5. Cell Rep 2021; 35:109185. [PMID: 34077736 PMCID: PMC8244946 DOI: 10.1016/j.celrep.2021.109185] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 03/04/2021] [Accepted: 05/05/2021] [Indexed: 01/23/2023] Open
Abstract
Responding to different dynamic levels of stress is critical for mammalian survival. Disruption of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) signaling is proposed to underlie hypothalamic-pituitary-adrenal (HPA) axis dysregulation observed in stress-related psychiatric disorders. In this study, we show that FK506-binding protein 51 (FKBP5) plays a critical role in fine-tuning MR:GR balance in the hippocampus. Biotinylated-oligonucleotide immunoprecipitation in primary hippocampal neurons reveals that MR binding, rather than GR binding, to the Fkbp5 gene regulates FKBP5 expression during baseline activity of glucocorticoids. Notably, FKBP5 and MR exhibit similar hippocampal expression patterns in mice and humans, which are distinct from that of the GR. Pharmacological inhibition and region- and cell type-specific receptor deletion in mice further demonstrate that lack of MR decreases hippocampal Fkbp5 levels and dampens the stress-induced increase in glucocorticoid levels. Overall, our findings demonstrate that MR-dependent changes in baseline Fkbp5 expression modify GR sensitivity to glucocorticoids, providing insight into mechanisms of stress homeostasis.
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MESH Headings
- Animals
- Cells, Cultured
- Gene Deletion
- Gene Expression Regulation
- Hippocampus/metabolism
- Humans
- Male
- Mice, Inbred C57BL
- Models, Biological
- Neurons/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Glucocorticoid/genetics
- Receptors, Glucocorticoid/metabolism
- Receptors, Mineralocorticoid/genetics
- Receptors, Mineralocorticoid/metabolism
- Stress, Physiological
- Tacrolimus Binding Proteins/genetics
- Tacrolimus Binding Proteins/metabolism
- Mice
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Affiliation(s)
- Jakob Hartmann
- Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA.
| | - Thomas Bajaj
- Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
| | - Claudia Klengel
- Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA
| | - Chris Chatzinakos
- Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Tim Ebert
- Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
| | - Nina Dedic
- Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA
| | - Kenneth M McCullough
- Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA
| | - Roy Lardenoije
- Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Marian Joëls
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center, Utrecht, 3584 CG Utrecht, the Netherlands
| | - Onno C Meijer
- Department of Medicine, Division of Endocrinology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Katharine E McCann
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Serena M Dudek
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - R Angela Sarabdjitsingh
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center, Utrecht, 3584 CG Utrecht, the Netherlands
| | - Nikolaos P Daskalakis
- Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Torsten Klengel
- Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Nils C Gassen
- Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
| | - Mathias V Schmidt
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
| | - Kerry J Ressler
- Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA.
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39
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Ferrer A, Soria V, Salvat-Pujol N, Martorell L, Armario A, Urretavizcaya M, Gutiérrez-Zotes A, Monreal JA, Crespo JM, Massaneda C, Vilella E, Palao D, Menchón JM, Labad J. The role of childhood trauma, HPA axis reactivity and FKBP5 genotype on cognition in healthy individuals. Psychoneuroendocrinology 2021; 128:105221. [PMID: 33866068 DOI: 10.1016/j.psyneuen.2021.105221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/03/2021] [Accepted: 04/04/2021] [Indexed: 11/24/2022]
Abstract
Cognitive impairment has been associated with both childhood adversity and abnormalities of hypothalamic-pituitary-adrenal (HPA) axis function. An interaction exists between the functional polymorphism rs1360780 in the FKBP5 gene and childhood maltreatment, influencing a variety of clinical outcomes. Our goal was to study the relationship between different types of childhood trauma, HPA axis functionality, rs1360780 genotype and cognitive function in 198 healthy individuals who participated in the study. We obtained clinical data, childhood maltreatment scores and neurocognitive performance by clinical assessment; HPA negative feedback was analysed using the dexamethasone suppression test ratio (DSTR) after administration of 0.25 mg of dexamethasone; and the FKBP5 rs1360780 polymorphism was genotyped in DNA obtained from blood samples. The results showed a significant influence of physical neglect on measures of neurocognition as well as an interaction between the DSTR and physical and emotional neglect. Regarding social cognition, a significant association was found with sexual and physical abuse as well as with rs1360780 risk-allele carrier status. Moreover, an interaction between the rs1360780 genotype and the presence of physical abuse was significantly associated with social cognition results. Our results suggest a specific impact of different kinds of childhood maltreatment on measures of neurocognition and social cognition, which might be influenced by HPA axis reactivity and genetic variants in HPA axis-related genes such as FKBP5. Disentangling the relationship between these elements and their influence on cognitive performance might help identify susceptible individuals with higher stress vulnerability and develop preventive interventions.
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Affiliation(s)
- Alex Ferrer
- Department of Psychiatry, Parc Taulí Hospital Universitari, I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain; Department of Clinical Sciences, School of Medicine, Universitat de Barcelona, Barcelona, Spain.
| | - Virginia Soria
- Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group-Psychiatry and Mental Health, Barcelona, Spain; Department of Clinical Sciences, School of Medicine, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain.
| | - Neus Salvat-Pujol
- Department of Psychiatry, Parc Taulí Hospital Universitari, I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain; Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group-Psychiatry and Mental Health, Barcelona, Spain; Department of Clinical Sciences, School of Medicine, Universitat de Barcelona, Barcelona, Spain.
| | - Lourdes Martorell
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain; Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain.
| | - Antonio Armario
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain; Animal Physiology Unit (Department of Cellular Biology, Physiology and Immunology), Faculty of Biosciences, Universitat Autònoma de Barcelona, Spain; Institut de Neurociències, Spain, Physiology and Immunology), Faculty of Biosciences, Universitat Autònoma de Barcelona, Spain.
| | - Mikel Urretavizcaya
- Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group-Psychiatry and Mental Health, Barcelona, Spain; Department of Clinical Sciences, School of Medicine, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain.
| | - Alfonso Gutiérrez-Zotes
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain; Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain.
| | - José Antonio Monreal
- Department of Mental Health, Hospital Universitari Mútua de Terrassa, Universitat de Barcelona, Terrassa, Spain.
| | - José Manuel Crespo
- Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group-Psychiatry and Mental Health, Barcelona, Spain; Department of Clinical Sciences, School of Medicine, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain.
| | - Clara Massaneda
- Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group-Psychiatry and Mental Health, Barcelona, Spain.
| | - Elisabet Vilella
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain; Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain.
| | - Diego Palao
- Department of Psychiatry, Parc Taulí Hospital Universitari, I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain.
| | - José Manuel Menchón
- Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group-Psychiatry and Mental Health, Barcelona, Spain; Department of Clinical Sciences, School of Medicine, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain.
| | - Javier Labad
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain; Department of Mental Health, Consorci Sanitari del Maresme, Mataró, Spain; Institut de Investigació i Innovació Parc Taulí (I3PT), Barcelona, Spain.
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40
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HPA-axis multilocus genetic profile score moderates the association between maternal prenatal perceived stress and offspring depression in early adulthood. Dev Psychopathol 2021; 33:122-134. [PMID: 31959271 DOI: 10.1017/s0954579419001639] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Maternal stress during pregnancy can cause alterations to the fetal hypothalamus-pituitary-adrenal (HPA) axis, a phenomenon known as fetal programming that may have lasting effects on offspring outcomes, including depression. Evidence suggests that these effects may vary with respect to the offspring's genetic risk. Nonetheless, few studies have examined these effects into adulthood, when risk for depression onset is highest. The present study builds upon the extant literature by examining the interaction of maternal prenatal perceived stress (MPPS) and offspring HPA-axis polygenic risk to predict offspring depression in early adulthood. A total of 381 mother-child dyads participated in a prospective, longitudinal study that spanned from pregnancy until offspring were 20 years of age. Polygenic risk was defined by a multilocus genetic profile score (MGPS) that reflected the additive risk of three HPA-axis candidate genes. The results indicated that the interaction of MPPS and HPA-axis MGPS confers risk for offspring depression at age 20, in line with the differential susceptibility model. This interaction may be specific to prenatal stress, as maternal stress during early childhood did not interact with genetic risk to predict depression. These findings provide the first evidence that genetic variants that are associated with the HPA axis may act in a polygenic, additive fashion to moderate the association between fetal programming and adult depression.
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41
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Abstract
Stress system dysfunction is a typical characteristic of acute depression and other mood disorders. The exact pattern of factors predisposing for stress-related mental disorders is yet to be unraveled. However, corticosteroid receptor function plays an important role for appropriate or dysfunctional neuroendocrine responses to stress exposure and hence in resilience or risk for the development and course of both, depression and anxiety disorders. Solid neuroscience data strongly support that both neuropeptides, corticotropin-releasing hormone (CRH) and vasopressin (AVP), are central in coordinating humoral and behavioral adaptation to stress. Other neuropeptides, including oxytocin, neuropeptide S, neuropeptide Y, and orexin, are also considered important contributors. Attempts to turn neuropeptide biology into treatments for stress-related disorders need to consider that neuropeptide receptors are specific drug targets for certain patient populations rather than universal targets for all patients, like biogenic amine systems. That is why most negative clinical trials testing neuropeptide receptor antagonists have been in fact failed trials by design, because no companion tests were used to identify which patients with depression are most likely to benefit from a specific neuropeptide receptor-targeting drug treatment. Therefore, the most important future research task is discovery and development of appropriate companion tests that will allow the successful transfer of the precious treasure of neuropeptide system-targeting drugs into clinics.
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Affiliation(s)
| | - Marcus Ising
- Max Planck Institute of Psychiatry, Munich, Germany
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42
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Nold V, Richter N, Hengerer B, Kolassa IT, Allers KA. FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells - First insights from novel humanized mice. Eur J Neurosci 2020; 53:402-415. [PMID: 33030232 PMCID: PMC7894319 DOI: 10.1111/ejn.14999] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/22/2020] [Indexed: 12/24/2022]
Abstract
The brain is a central hub for integration of internal and external conditions and, thus, a regulator of the stress response. Glucocorticoids are the essential communicators of this response. Aberrations in glucocorticoid signaling are a common symptom in patients with psychiatric disorders. The gene FKBP5 encodes a chaperone protein that functionally inhibits glucocorticoid signaling and, thus, contributes to the regulation of stress. In the context of childhood trauma, differential expression of FKBP5 has been found in psychiatric patients compared to controls. These variations in expression levels of FKBP5 were reported to be associated with differences in stress responsiveness in human carriers of the single nucleotide polymorphism (SNP) rs1360780. Understanding the mechanisms underlying FKBP5 polymorphism‐associated glucocorticoid responsiveness in the CNS will lead to a better understanding of stress regulation or associated pathology. To study these mechanisms, two novel humanized mouse lines were generated. The lines carried either the risk (A/T) allele or the resilient (C/G) allele of rs1360780. Primary cells from CNS (astrocytes, microglia, and neurons) were analyzed for their basal expression levels of FKBP5 and their responsiveness to glucocorticoids. Differential expression of FKBP5 was found for these cell types and negatively correlated with the cellular glucocorticoid responsiveness. Astrocytes revealed the strongest transcriptional response, followed by microglia and neurons. Furthermore, the risk allele (A/T) was associated with greater induction of FKBP5 than the resilience allele. Novel FKBP5‐humanized mice display differential glucocorticoid responsiveness due to a single intronic SNP. The vulnerability to stress signaling in the shape of glucocorticoids in the brain correlated with FKBP5 expression levels. The strong responsiveness of astrocytes to glucocorticoids implies astrocytes play a prominent role in the stress response, and in FKBP5‐related differences in glucocorticoid signaling. The novel humanized mouse lines will allow for further study of the role that FKBP5 SNPs have in risk and resilience to stress pathology.
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Affiliation(s)
- Verena Nold
- Boehringer Ingelheim Pharma GmbH & Co KG, CNSDR, Ingelheim, Germany.,Institute of Psychology & Education, Clinical & Biological Psychology, Ulm University, Ulm, Germany
| | - Nadine Richter
- Boehringer Ingelheim Pharma GmbH & Co KG, CNSDR, Ingelheim, Germany
| | - Bastian Hengerer
- Boehringer Ingelheim Pharma GmbH & Co KG, CNSDR, Ingelheim, Germany
| | - Iris-Tatjana Kolassa
- Institute of Psychology & Education, Clinical & Biological Psychology, Ulm University, Ulm, Germany
| | - Kelly Ann Allers
- Boehringer Ingelheim Pharma GmbH & Co KG, CNSDR, Ingelheim, Germany
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43
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Genetic risk-factors for anxiety in healthy individuals: polymorphisms in genes important for the HPA axis. BMC MEDICAL GENETICS 2020; 21:184. [PMID: 32957930 PMCID: PMC7507731 DOI: 10.1186/s12881-020-01123-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/14/2020] [Indexed: 01/30/2023]
Abstract
BACKGROUND Two important aspects for the development of anxiety disorders are genetic predisposition and alterations in the hypothalamic-pituitary-adrenal (HPA) axis. In order to identify genetic risk-factors for anxiety, the aim of this exploratory study was to investigate possible relationships between genetic polymorphisms in genes important for the regulation and activity of the HPA axis and self-assessed anxiety in healthy individuals. METHODS DNA from 72 healthy participants, 37 women and 35 men, were included in the analyses. Their DNA was extracted and analysed for the following Single Nucleotide Polymorphisms (SNP)s: rs41423247 in the NR3C1 gene, rs1360780 in the FKBP5 gene, rs53576 in the OXTR gene, 5-HTTLPR in SLC6A4 gene and rs6295 in the HTR1A gene. Self-assessed anxiety was measured by the State and Trait Anxiety Inventory (STAI) questionnaire. RESULTS Self-assessed measure of both STAI-S and STAI-T were significantly higher in female than in male participants (p = 0.030 and p = 0.036, respectively). For SNP rs41423247 in the NR3C1 gene, there was a significant difference in females in the score for STAI-S, where carriers of the G allele had higher scores compared to the females that were homozygous for the C allele (p < 0.01). For the SNP rs53576 in the OXTR gene, there was a significant difference in males, where carriers of the A allele had higher scores in STAI-T compared to the males that were homozygous for the G allele (p < 0.01). CONCLUSION This study shows that SNP rs41423247 in the NR3C1 gene and SNP rs53576 in the OXTR gene are associated with self-assessed anxiety in healthy individuals in a gender-specific manner. This suggests that these SNP candidates are possible genetic risk-factors for anxiety.
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44
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Brandt J, Warnke K, Jörgens S, Arolt V, Beer K, Domschke K, Haverkamp W, Kuhlmann SL, Müller-Nordhorn J, Rieckmann N, Schwarte K, Ströhle A, Tschorn M, Waltenberger J, Grosse L. Association of FKBP5 genotype with depressive symptoms in patients with coronary heart disease: a prospective study. J Neural Transm (Vienna) 2020; 127:1651-1662. [PMID: 32860562 PMCID: PMC7665971 DOI: 10.1007/s00702-020-02243-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 08/10/2020] [Indexed: 12/14/2022]
Abstract
Depression and coronary heart disease (CHD) are prevalent and often co-occurring disorders. Both have been associated with a dysregulated stress system. As a central element of the stress system, the FKBP5 gene has been shown to be associated with depression. In a prospective design, this study aims to investigate the association of FKBP5 with depressive symptoms in CHD patients. N = 268 hospitalized CHD patients were included. Depressive symptoms were measured using the Hospital Anxiety and Depression Scale (HADS-D) at four time points (baseline, and after 1 month, 6 months, and 12 months). The functional FKBP5 single-nucleotide polymorphism (SNP) rs1360780 was selected for genotyping. Linear regression models showed that a higher number of FKBP5 C alleles was associated with more depressive symptoms in CHD patients both at baseline (p = 0.015) and at 12-months follow-up (p = 0.025) after adjustment for confounders. Further analyses revealed that this effect was driven by an interaction of FKBP5 genotype with patients’ prior CHD course. Specifically, only in patients with a prior myocardial infarction or coronary revascularization, more depressive symptoms were associated with a higher number of C alleles (baseline: p = 0.046; 1-month: p = 0.026; 6-months: p = 0.028). Moreover, a higher number of C alleles was significantly related to a greater risk for dyslipidemia (p = .016). Our results point to a relevance of FKBP5 in the association of the two stress-related diseases depression and CHD.
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Affiliation(s)
- Julia Brandt
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Albert-Schweitzer-Campus 1, Geb. A9, 48149, Münster, Germany.
| | - Katharina Warnke
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Albert-Schweitzer-Campus 1, Geb. A9, 48149, Münster, Germany
| | - Silke Jörgens
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Albert-Schweitzer-Campus 1, Geb. A9, 48149, Münster, Germany
| | - Volker Arolt
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Albert-Schweitzer-Campus 1, Geb. A9, 48149, Münster, Germany
| | - Katja Beer
- Charité-Universitätsmedizin Berlin, Corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Department of Psychiatry and Psychotherapy, Berlin, Germany
| | - Katharina Domschke
- Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Wilhelm Haverkamp
- Charité-Universitätsmedizin Berlin, Corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Department of Internal Medicine and Cardiology, Berlin, Germany
| | - Stella L Kuhlmann
- Charité-Universitätsmedizin Berlin, Corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Division of Emergency and Acute Medicine (CVK, CCM), Berlin, Germany
- Charité-Universitätsmedizin Berlin, Corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute of Public Health, Berlin, Germany
| | - Jacqueline Müller-Nordhorn
- Charité-Universitätsmedizin Berlin, Corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute of Public Health, Berlin, Germany
- Bavarian Food and Health Safety Authority, Oberschleißheim, Germany
| | - Nina Rieckmann
- Charité-Universitätsmedizin Berlin, Corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute of Public Health, Berlin, Germany
| | - Kathrin Schwarte
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Albert-Schweitzer-Campus 1, Geb. A9, 48149, Münster, Germany
| | - Andreas Ströhle
- Charité-Universitätsmedizin Berlin, Corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Department of Psychiatry and Psychotherapy, Berlin, Germany
| | - Mira Tschorn
- Charité-Universitätsmedizin Berlin, Corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Department of Psychiatry and Psychotherapy, Berlin, Germany
- Social and Preventive Medicine, University of Potsdam, Potsdam, Germany
| | | | - Laura Grosse
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Albert-Schweitzer-Campus 1, Geb. A9, 48149, Münster, Germany
- Intercultural Business Psychology, Hamm-Lippstadt University of Applied Sciences, Hamm, Germany
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45
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Ferrer A, Labad J, Salvat-Pujol N, Monreal JA, Urretavizcaya M, Crespo JM, Menchón JM, Palao D, Soria V. Hypothalamic-pituitary-adrenal axis-related genes and cognition in major mood disorders and schizophrenia: a systematic review. Prog Neuropsychopharmacol Biol Psychiatry 2020; 101:109929. [PMID: 32197928 DOI: 10.1016/j.pnpbp.2020.109929] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 03/01/2020] [Accepted: 03/13/2020] [Indexed: 12/14/2022]
Abstract
Hypothalamic-pituitary-adrenal (HPA) axis dysregulation and cognitive deficits are two well-characterized endophenotypes present in different serious mental illnesses (SMIs), including major depressive disorder, bipolar disorder and schizophrenia. Our aim was to study the influence of genetic and epigenetic variations in HPA axis-related genes on cognitive performance in clinical samples, including patients with major mood disorders and schizophrenia. A systematic search was performed using PubMed (Medline), PsycINFO and Scopus databases. The systematic review identified 12 studies dealing with HPA-related genes and cognition in samples including patients with SMIs, focusing on single nucleotide polymorphism (SNP) variants, while no studies analysing epigenetic variations were found. The results suggest different and specific effects on the cognitive performance of SNP variants in the HPA axis-related genes studied, as well as interactions with traumatic experiences. There was high heterogeneity in the studied samples, genes analysed, and cognitive tasks evaluated. The relationship between HPA-related genes and cognition in SMIs is still largely unknown, and further studies including larger samples and epigenetic variations are needed.
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Affiliation(s)
- Alex Ferrer
- Department of Mental Health, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Spain; Department of Clinical Sciences, Universitat de Barcelona, Barcelona, Spain
| | - Javier Labad
- Department of Mental Health, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Spain
| | - Neus Salvat-Pujol
- Department of Mental Health, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Spain; Department of Clinical Sciences, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Spain
| | - José A Monreal
- Department of Mental Health, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Spain
| | - Mikel Urretavizcaya
- Department of Clinical Sciences, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group - Psychiatry and Mental Health, Barcelona, Spain
| | - José M Crespo
- Department of Clinical Sciences, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group - Psychiatry and Mental Health, Barcelona, Spain
| | - José M Menchón
- Department of Clinical Sciences, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group - Psychiatry and Mental Health, Barcelona, Spain
| | - Diego Palao
- Department of Mental Health, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Spain
| | - Virginia Soria
- Department of Clinical Sciences, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain; Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group - Psychiatry and Mental Health, Barcelona, Spain.
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46
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van der Kooij MA. The impact of chronic stress on energy metabolism. Mol Cell Neurosci 2020; 107:103525. [PMID: 32629109 DOI: 10.1016/j.mcn.2020.103525] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 06/02/2020] [Accepted: 06/16/2020] [Indexed: 01/21/2023] Open
Abstract
The brain is exceptionally demanding in terms of energy metabolism. Approximately 20% of the calories consumed are devoted to our cerebral faculties, with the lion's share provided in the form of glucose. The brain's stringent energy dependency requires a high degree of harmonization between the elements responsible for supplying- and metabolizing energetic substrates. However, chronic stress may jeopardize this homeostatic energy balance by disruption of critical metabolic processes. In agreement, stress-related mental disorders have been linked with perturbations in energy metabolism. Prominent stress-induced metabolic alterations include the actions of hormones, glucose uptake and mitochondrial adjustments. Importantly, fundamental stress-responsive metabolic adjustments in humans and animal models bear a striking resemblance. Here, an overview is provided of key findings, demonstrating the pervasive impact of chronic stress on energy metabolism. Furthermore, I argue that medications, aimed primarily at restoring metabolic homeostasis, may constitute a novel approach to treat mental disorders.
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47
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Connelly KL, Wolsh CC, Barr JL, Bauder M, Hausch F, Unterwald EM. Sex differences in the effect of the FKBP5 inhibitor SAFit2 on anxiety and stress-induced reinstatement following cocaine self-administration. Neurobiol Stress 2020; 13:100232. [PMID: 33344688 PMCID: PMC7739032 DOI: 10.1016/j.ynstr.2020.100232] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 04/14/2020] [Accepted: 05/05/2020] [Indexed: 01/30/2023] Open
Abstract
Cocaine use and withdrawal prompt stress system responses. Stress and the negative affective state produced by cocaine withdrawal are major triggers for relapse. FKBP5 is a co-chaperone of the glucocorticoid receptor and regulates HPA axis negative feedback. The role of FKBP5 in cocaine-related behaviors has not been studied. The FKBP5 inhibitor SAFit2 was used to examine the role of FKBP5 in anxiety-like behavior during early cocaine withdrawal and in stress-induced reinstatement following cocaine self-administration in male and female rats. Withdrawal from cocaine self-administration resulted in heightened anxiety-like behavior in female rats, which was significantly attenuated by SAFit2 administration. SAFit2 pretreatment prior to stress-induced reinstatement to cocaine seeking significantly reduced active lever presses of males. In female rats, SAFit2 administration prevented stress-induced reinstatement for rats in metestrus or diestrus, but not proestrus or estrus phases at the time of reinstatement. These data suggest an important role for FKBP5 in stress-related behaviors following cocaine self-administration, particularly in females.
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Affiliation(s)
- Krista L Connelly
- Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St. Philadelphia, PA, 19140, USA
| | - Cassandra C Wolsh
- Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St. Philadelphia, PA, 19140, USA
| | - Jeffrey L Barr
- Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St. Philadelphia, PA, 19140, USA
| | - Michael Bauder
- Clemens Schöpf Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss Str. 4, 64287, Darmstadt, Germany
| | - Felix Hausch
- Clemens Schöpf Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss Str. 4, 64287, Darmstadt, Germany
| | - Ellen M Unterwald
- Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St. Philadelphia, PA, 19140, USA.,Department of Pharmacology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St. Philadelphia, PA, 19140, USA
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Saman Y, Arshad Q, Dutia M, Rea P. Stress and the vestibular system. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 152:221-236. [PMID: 32450997 DOI: 10.1016/bs.irn.2020.03.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In this chapter we review the existing literature regarding the interactions between stress and the mechanisms that maintain balance. Evidence suggests that the interplay between neuro-endocrine and psychological factors may have a significant role in balance function. For example, in healthy individuals vestibular stimulation has been shown to trigger the stress response as indicated by increased blood cortisol levels, whereas in patients with vestibular pathology factors such as resilience and anxiety may be the key focus of interactions with stress. Critically, factors such as anxiety are known to influence clinical outcomes, despite our mechanistic understanding of these processes remaining in their infancy.
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Affiliation(s)
- Yougan Saman
- ENT Department, Leicester Royal Infirmary, Leicester, United Kingdom; inAmind Laboratory, Department of Psychology, Neuroscience and Behaviour, University of Leicester, Leicester, United Kingdom.
| | - Qadeer Arshad
- ENT Department, Leicester Royal Infirmary, Leicester, United Kingdom; inAmind Laboratory, Department of Psychology, Neuroscience and Behaviour, University of Leicester, Leicester, United Kingdom; Academic Department of Neuro-otology, Charing Cross Hospital Campus, Imperial College London, London, United Kingdom
| | - Mayank Dutia
- Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
| | - Peter Rea
- ENT Department, Leicester Royal Infirmary, Leicester, United Kingdom
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Kang C, Shi J, Gong Y, Wei J, Zhang M, Ding H, Wang K, Yu Y, Wang S, Han J. Interaction between FKBP5 polymorphisms and childhood trauma on depressive symptoms in Chinese adolescents: The moderating role of resilience. J Affect Disord 2020; 266:143-150. [PMID: 32056869 DOI: 10.1016/j.jad.2020.01.051] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 12/05/2019] [Accepted: 01/13/2020] [Indexed: 01/30/2023]
Abstract
BACKGROUND Previous gene-environment studies on depression have examined the interaction between FKBP5 gene and childhood trauma, but the results are inconsistent and few studies have focused on Asian adolescents. Psychological resilience may explain for the inconsistency. We examined the interaction between FKBP5 gene and childhood trauma on depressive symptoms in Chinese adolescents, and firstly explored the moderating role of resilience in the relationship. METHODS This study comprised 942 participants (448 males, 47.6%) randomly recruited from four senior schools in Wuhan, Hubei of China. Depressive symptoms, childhood trauma, and resilience were respectively evaluated by the Center for Epidemiological Studies Depression Scale (CES-D), the Childhood Trauma Questionnaire (CTQ) and the Connor-Davidson Resilience Scale (CD-RISC). Three potentially functional FKBP5 polymorphisms were selected for genotyping. RESULTS Participants carrying minor alleles of FKBP5 polymorphisms (rs3800373, rs1360780, and rs4713916) and a haplotype derived from these variants displayed higher CES-D scores when exposed to childhood physical abuse after adjusting for demographic characteristics and resilience (all P < 0.01). The three-way interactions of FKBP5 SNPs, physical abuse, and resilience on depressive symptoms all yielded statistical significance after adjusting for demographic characteristics (β = -0.282 to -0.236; all P < 0.001). LIMITATIONS Cross-sectional design, self- reported measurements and limited genotyped FKBP5 polymorphisms. CONCLUSION FKBP5 variants in combination with childhood physical abuse may increase more pronounced depressive symptoms among Chinese adolescents, while resilience plays a moderating role in the associations. Future research to examine the exact mechanism of resilience in these associations is needed.
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Affiliation(s)
- Chun Kang
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13Hangkong Road, Wuhan, China
| | - JunXin Shi
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13Hangkong Road, Wuhan, China
| | - Yusha Gong
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13Hangkong Road, Wuhan, China
| | - Jishan Wei
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13Hangkong Road, Wuhan, China
| | - Minli Zhang
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13Hangkong Road, Wuhan, China
| | - Huisi Ding
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13Hangkong Road, Wuhan, China
| | - Kaiqiao Wang
- Department of Education, Culture and Sports, East Lake New Technology Development Zone, Wuhan, China
| | - Yizhen Yu
- Department of Education, Culture and Sports, East Lake New Technology Development Zone, Wuhan, China
| | - Sichao Wang
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13Hangkong Road, Wuhan, China
| | - Juan Han
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13Hangkong Road, Wuhan, China.
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Disentangling genes, attachment, and environment: A systematic review of the developmental psychopathology literature on gene-environment interactions and attachment. Dev Psychopathol 2020; 32:357-381. [PMID: 30905328 DOI: 10.1017/s0954579419000142] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The role of genetics in relation to attachment is of continued interest to developmental psychology. Recent research has attempted to disentangle genetic main effects, environmental effects, and gene and environment (G × E) interactions in the development of attachment security/insecurity and disorganization. We systematically reviewed associations between gene markers and attachment, including G × E interactions, identifying 27 eligible studies. Inconsistent results emerged for associations between both gene effects and G × E interactions on attachment organization. Where G × E interactions used attachment as the environmental factor in the interaction, we observed more consistent results for differential susceptibility of G × E interactions on offspring behavior. Small sample size and heterogeneity in measurement of environmental factors impacted on comparability of studies. From these results, we propose that the future of research into the role of genetic effects in attachment lies in further exploration of G × E interactions, particularly where attachment acts as an environmental factor impacting on other child developmental outcomes emerging from the caregiving environment, consistent with differential susceptibility approaches to developmental psychopathology. In addition, from a methodological perspective, establishing the role of gene markers in such models will require a shift toward contemporary genomics, including genome-wide analysis (including novel genes and chromosomal loci), and epigenetic individual variations.
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