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Bordes J, Bajaj T, Miranda L, van Doeselaar L, Brix LM, Narayan S, Yang H, Mitra S, Kovarova V, Springer M, Kleigrewe K, Müller-Myhsok B, Gassen NC, Schmidt MV. Sex-specific fear acquisition following early life stress is linked to amygdala and hippocampal purine and glutamate metabolism. Commun Biol 2024; 7:1684. [PMID: 39702524 DOI: 10.1038/s42003-024-07396-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 12/11/2024] [Indexed: 12/21/2024] Open
Abstract
Early life stress (ELS) can negatively impact health, increasing the risk of stress-related disorders, such as post-traumatic stress disorder (PTSD). Importantly, PTSD disproportionately affects women, emphasizing the critical need to explore how sex differences influence the genetic and metabolic neurobiological pathways underlying trauma-related behaviors. This study uses the limited bedding and nesting (LBN) paradigm to model ELS and investigate its sex-specific effects on fear memory formation. Employing innovative unsupervised behavioral classification, the current study reveals distinct behavioral patterns associated with fear acquisition and retrieval in male and female mice following ELS. Females exposed to LBN display heightened active fear responses, contrasting with males. Furthermore, the study examined the crucial link between behavioral regulation and cellular metabolism in key brain regions involved in fear and stress processing. Sex-specific and stress-dependent alterations were observed in purine, pyrimidine, and glutamate metabolism within the basolateral amygdala, the dorsal hippocampus, and the ventral hippocampus. These findings provide crucial insights into the complex interplay between metabolic pathways, the neurobiological underpinnings of fear memory, and stress responses. Importantly, they emphasize the significance of considering sex-specific metabolic alterations when investigating stress-related disorders, opening potential avenues for the development of targeted interventions.
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Affiliation(s)
- Joeri Bordes
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany
| | - Thomas Bajaj
- Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, Bonn Clinical Center, University of Bonn, 53127, Bonn, Germany
| | - Lucas Miranda
- Research Group Statistical Genetics, Max Planck Institute of Psychiatry, 80804, Munich, Germany
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), 80804, Munich, Germany
| | - Lotte van Doeselaar
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), 80804, Munich, Germany
| | - Lea Maria Brix
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), 80804, Munich, Germany
| | - Sowmya Narayan
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), 80804, Munich, Germany
| | - Huanqing Yang
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany
| | - Shiladitya Mitra
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany
| | - Veronika Kovarova
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), 80804, Munich, Germany
| | - Margherita Springer
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany
| | - Karin Kleigrewe
- Bavarian Center for Biomolecular Mass Spectrometry, TUM School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Bertram Müller-Myhsok
- Research Group Statistical Genetics, Max Planck Institute of Psychiatry, 80804, Munich, Germany
| | - Nils C Gassen
- Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, Bonn Clinical Center, University of Bonn, 53127, Bonn, Germany
| | - Mathias V Schmidt
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany.
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Rajeswari JJ, Faught E, Santos H, Vijayan MM. Mineralocorticoid receptor activates postnatal adiposity in zebrafish lacking proopiomelanocortin. J Cell Physiol 2024; 239:e31428. [PMID: 39238189 PMCID: PMC11649959 DOI: 10.1002/jcp.31428] [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: 06/06/2024] [Revised: 08/14/2024] [Accepted: 08/26/2024] [Indexed: 09/07/2024]
Abstract
The proopiomelanocortin (Pomc)-derived peptides, including adrenocorticotropic hormone and α-melanocyte stimulating hormone (α-Msh), play both a central and a peripheral role in modulating the stress response. The central role is predominantly associated with nutrient homeostasis, while peripherally they play an important role in the synthesis of glucocorticoids (GCs) in response to stress. Pomc mutations are a major risk factor in the development of early-onset childhood obesity in humans. This is attributed primarily to their central effects on melanocortin receptor dysfunction leading to hyperphagia and reduced energy expenditure, while the peripheral mechanism contributing to obesity has largely been unexplored. Here, we tested the hypothesis that Pomc mutation-mediated adrenal insufficiency and the associated changes in GC signaling contribute to postnatal adiposity using zebrafish as a model. We generated a ubiquitous Pomc knockout zebrafish that mimicked the mammalian mutant phenotype of adrenal insufficiency and enhanced adiposity. The loss of Pomc inhibited stress-induced cortisol production and reprogrammed GC signaling by reducing glucocorticoid receptor responsiveness, whereas the mineralocorticoid receptor (Mr) signaling was enhanced. Larval feeding led to enhanced growth and adipogenesis in the Pomc mutants, and this was inhibited by eplerenone, an Mr antagonist. Altogether, our results underscore a key role for Mr signaling in early developmental adipogenesis and a possible target for therapeutic intervention for early-onset childhood obesity due to Pomc dysfunction.
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Affiliation(s)
| | - Erin Faught
- Department of Biological SciencesUniversity of CalgaryCalgaryAlbertaCanada
- Present address:
Institute of BiologyLeiden UniversityLeidenThe Netherlands
| | - Helio Santos
- Department of Biological SciencesUniversity of CalgaryCalgaryAlbertaCanada
- Present address:
Laboratório de Processamento de TecidosUniversidade Federal de São João Del Rei, Avenida Sebastião Gonçalves CoelhoDivinópolisBrazil
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Agusti A, Molina-Mendoza GV, Tamayo M, Rossini V, Cenit MC, Frances-Cuesta C, Tolosa-Enguis V, Gómez Del Pulgar EM, Flor-Duro A, Sanz Y. Christensenella minuta mitigates behavioral and cardiometabolic hallmarks of social defeat stress. Biomed Pharmacother 2024; 180:117377. [PMID: 39316970 DOI: 10.1016/j.biopha.2024.117377] [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: 05/10/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/26/2024] Open
Abstract
Psychological stress during early development and adolescence may increase the risk of psychiatric and cardiometabolic comorbidities in adulthood. The gut microbiota has been associated with mental health problems such as depression and anxiety and with cardiometabolic disease, but the potential role of the gut microbiota in their comorbidity is not well understood. We investigated the effects and mode of action of the intestinal bacterium Christensenella minuta DSM 32891 on stress-induced mental health and cardiometabolic disturbances in a mouse model of social defeat stress. We demonstrate that administered C. minuta alleviates chronic stress-induced depressive, anxiogenic and antisocial behavior. These effects are attributed to the bacterium's ability to modulate the hypothalamic-pituitary-adrenal axis, which mediates the stress response. This included the oversecretion of corticosterone and the overexpression of its receptors, as well as the metabolism of dopamine (DA) and the expression of its receptors (D1, D2L and D2S). Additionally, C. minuta administration reduced chronically induced inflammation in plasma, spleen and some brain areas, which likely contribute to the recovery of physical and behavioral function. Furthermore, C. minuta administration prevented chronic stress-induced cardiovascular damage by regulating key enzymes mediating liver fibrosis and oxidative stress. Finally, C. minuta increased the abundance of bacteria associated with mental health. Overall, our study highlights the potential of microbiota-directed interventions to alleviate both the physical and mental effects of chronic stress.
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Affiliation(s)
- A Agusti
- Microbiome, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia 46980, Spain.
| | - G V Molina-Mendoza
- Microbiome, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia 46980, Spain
| | - M Tamayo
- Microbiome, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia 46980, Spain; Department of Medicine, Autonomous University of Madrid, Madrid 28029, Spain
| | - V Rossini
- Microbiome, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia 46980, Spain
| | - M C Cenit
- Microbiome, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia 46980, Spain; Department of Medicine, Autonomous University of Madrid, Madrid 28029, Spain
| | - C Frances-Cuesta
- Microbiome, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia 46980, Spain
| | - V Tolosa-Enguis
- Microbiome, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia 46980, Spain
| | - E M Gómez Del Pulgar
- Microbiome, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia 46980, Spain
| | - A Flor-Duro
- Microbiome, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia 46980, Spain
| | - Y Sanz
- Microbiome, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia 46980, Spain.
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Suktas A, Ekalaksananan T, Aromseree S, Bumrungthai S, Songserm N, Pientong C. Genetic polymorphism involved in major depressive disorder: a systemic review and meta-analysis. BMC Psychiatry 2024; 24:716. [PMID: 39438912 PMCID: PMC11515766 DOI: 10.1186/s12888-024-06195-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND AND OBJECTIVE Genetic polymorphism studies in families and twins indicated the heritability of depression. However, the association between genes with genetic polymorphism and depression provides various findings and remains unclear. Therefore, we conducted a systematic review and meta-analysis to determine the genes with their polymorphism associated with the symptomatic depression known as major depressive disorder (MDD). MATERIALS AND METHODS PubMed and Scopus were searched for relevant studies published before May 22, 2023 (1968-2023), and 62 were selected for this review. The study's bias risk was investigated using the Newcastle-Ottawa scale. Gene functional enrichment analysis was investigated for molecular function (MF) and biological process (BP) and pathways. A meta-analysis of the studied genes that were replicative in the same single nucleotide polymorphism was conducted using a random-effect model. RESULTS The 49 genes involved in MDD were studied and engaged in several pathways, such as tryptophan metabolism or dopaminergic and serotonergic synapses. Based on gene overlapping in MF and BP, 13 genes with polymorphisms were identified as related to MDD. Most of them were only studied once. Solute carrier family 6 member 4 (SLC6A4) overlapping between MF and BP and brain-derived neurotrophic factor (BDNF) as unique to BP were replicative studied and used in the meta-analysis. The polymorphism of SLC6A4 SS and LS genotypes increased the occurrence of MDD development but not significantly [odd ratio (OR) = 1.39; 95% confidence interval (CI) = 0.87-2.22; P = 0.16 and OR = 1.13; 95% CI = 0.84-1.53; P = 0.42, respectively]. A similar result was observed for BDNF rs6265 GG (OR = 1.26; 95% CI = 0.78-2.06; P = 0.35) and BDNF rs6265 AA genotypes (OR = 1.12; 95% CI = 0.77-1.64; P = 0.56). These studies indicated low bias and significant heterogeneity. CONCLUSION At least 13 studied genes with polymorphisms were involved in MDD development according to MF and BP, but not significantly. These results suggest that MDD development risk factors might require genetic and other factors for interaction and induction.
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Grants
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
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Affiliation(s)
- Areeya Suktas
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Tipaya Ekalaksananan
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sirinart Aromseree
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sureewan Bumrungthai
- Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand
| | - Nopparat Songserm
- Faculty of Public Health, Ubon Ratchathani Rajabhat University, Ubon Ratchathani, Thailand
| | - Chamsai Pientong
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
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Uvnäs-Moberg K, Gross MM, Calleja-Agius J, Turner JD. The Yin and Yang of the oxytocin and stress systems: opposites, yet interdependent and intertwined determinants of lifelong health trajectories. Front Endocrinol (Lausanne) 2024; 15:1272270. [PMID: 38689729 PMCID: PMC11058227 DOI: 10.3389/fendo.2024.1272270] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 04/01/2024] [Indexed: 05/02/2024] Open
Abstract
During parturition and the immediate post-partum period there are two opposite, yet interdependent and intertwined systems that are highly active and play a role in determining lifelong health and behaviour in both the mother and her infant: the stress and the anti-stress (oxytocin) system. Before attempting to understand how the environment around birth determines long-term health trajectories, it is essential to understand how these two systems operate and how they interact. Here, we discuss together the hormonal and neuronal arms of both the hypothalamic-pituitary-adrenal (HPA) axis and the oxytocinergic systems and how they interact. Although the HPA axis and glucocorticoid stress axis are well studied, the role of oxytocin as an extremely powerful anti-stress hormone deserves more attention. It is clear that these anti-stress effects depend on oxytocinergic nerves emanating from the supraoptic nucleus (SON) and paraventricular nucleus (PVN), and project to multiple sites at which the stress system is regulated. These, include projections to corticotropin releasing hormone (CRH) neurons within the PVN, to the anterior pituitary, to areas involved in sympathetic and parasympathetic nervous control, to NA neurons in the locus coeruleus (LC), and to CRH neurons in the amygdala. In the context of the interaction between the HPA axis and the oxytocin system birth is a particularly interesting period as, for both the mother and the infant, both systems are very strongly activated within the same narrow time window. Data suggest that the HPA axis and the oxytocin system appear to interact in this early-life period, with effects lasting many years. If mother-child skin-to-skin contact occurs almost immediately postpartum, the effects of the anti-stress (oxytocin) system become more prominent, moderating lifelong health trajectories. There is clear evidence that HPA axis activity during this time is dependent on the balance between the HPA axis and the oxytocin system, the latter being reinforced by specific somatosensory inputs, and this has long-term consequences for stress reactivity.
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Affiliation(s)
- Kerstin Uvnäs-Moberg
- Department of Animal Environment and Health, Section of Anthrozoology and Applied Ethology, Swedish University of Agricultural Sciences, Skara, Sweden
| | - Mechthild M. Gross
- Midwifery Research and Education Unit, Hannover Medical School, Hannover, Germany
| | - Jean Calleja-Agius
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
| | - Jonathan D. Turner
- Immune Endocrine Epigenetics Research Group, Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg
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Kulakova E, Graumann L, Wingenfeld K. The Hypothalamus-Pituitary-Adrenal Axis and Social Cognition in Borderline Personality Disorder. Curr Neuropharmacol 2024; 22:378-394. [PMID: 37539934 PMCID: PMC10845078 DOI: 10.2174/1570159x21666230804085639] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 03/28/2023] [Accepted: 05/28/2023] [Indexed: 08/05/2023] Open
Abstract
Borderline personality disorder (BPD) is characterized by emotional instability, impulsivity and unstable interpersonal relationships. Patients experience discomforting levels of distress, inducing symptoms like dissociation, aggression or withdrawal. Social situations are particularly challenging, and acute social stress can reduce patients' cognitive and social functioning. In patients with Major Depressive Disorder or Posttraumatic Stress Disorder, which show high comorbidity with BPD, the endocrine stress response is characterized by Hypothalamus-Pituitary-Adrenal (HPA) axis dysfunction, which affects cognitive functioning. Compared to these clinical groups, research on HPA-axis function in BPD is relatively scarce, but evidence points towards a blunted cortisol reactivity to acute stress. Since BPD patients are particularly prone to social stress and experience high subjective difficulties in these situations, it seems plausible that HPA-axis dysregulation might contribute to decreased social cognition in BPD. The present review summarizes findings on the HPA-axis function in BPD and its association with social cognition following acute social stress. For this purpose, we review literature that employed a widely used social stressor (Trier Social Stress Test, TSST) to study the effects of acute social stress on social cognition and the HPA-axis response. We contrast these findings with studies on social cognition that employed Cyberball, another widely used social stressor that lacks HPA-axis involvement. We conclude that research on social cognition in BPD reveals heterogeneous results with no clear relationship between social functioning and HPA-axis response. More research is needed to better understand the psychophysiological underpinnings of impaired social cognition in BPD.
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Affiliation(s)
- Eugenia Kulakova
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Klinik für Psychiatrie und Psychotherapie, Campus Benjamin Franklin, Berlin, Germany
| | - Livia Graumann
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Klinik für Psychiatrie und Psychotherapie, Campus Benjamin Franklin, Berlin, Germany
| | - Katja Wingenfeld
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Klinik für Psychiatrie und Psychotherapie, Campus Benjamin Franklin, Berlin, Germany
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7
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de Kloet ER, Joëls M. The cortisol switch between vulnerability and resilience. Mol Psychiatry 2024; 29:20-34. [PMID: 36599967 DOI: 10.1038/s41380-022-01934-8] [Citation(s) in RCA: 46] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 12/14/2022] [Accepted: 12/16/2022] [Indexed: 01/06/2023]
Abstract
In concert with neuropeptides and transmitters, the end products of the hypothalamus-pituitary-adrenal (HPA) axis, the glucocorticoid hormones cortisol and corticosterone (CORT), promote resilience: i.e., the ability to cope with threats, adversity, and trauma. To exert this protective action, CORT activates mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) that operate in a complementary manner -as an on/off switch- to coordinate circadian events, stress-coping, and adaptation. The evolutionary older limbic MR facilitates contextual memory retrieval and supports an on-switch in the selection of stress-coping styles at a low cost. The rise in circulating CORT concentration after stress subsequently activates a GR-mediated off-switch underlying recovery of homeostasis by providing the energy for restraining the primary stress reactions and promoting cognitive control over emotional reactivity. GR activation facilitates contextual memory storage of the experience to enable future stress-coping. Such complementary MR-GR-mediated actions involve rapid non-genomic and slower gene-mediated mechanisms; they are time-dependent, conditional, and sexually dimorphic, and depend on genetic background and prior experience. If coping fails, GR activation impairs cognitive control and promotes emotional arousal which eventually may compromise resilience. Such breakdown of resilience involves a transition to a chronic stress construct, where information processing is crashed; it leads to an imbalanced MR-GR switch and hence increased vulnerability. Novel MR-GR modulators are becoming available that may reset a dysregulated stress response system to reinstate the cognitive flexibility required for resilience.
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Affiliation(s)
- E Ronald de Kloet
- Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
- Leiden/Amsterdam Center of Drug Research, Leiden University, Leiden, The Netherlands.
| | - Marian Joëls
- Dept. Translational Neuroscience, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Yang H, Narayan S, Schmidt MV. From Ligands to Behavioral Outcomes: Understanding the Role of Mineralocorticoid Receptors in Brain Function. Stress 2023; 26:2204366. [PMID: 37067948 DOI: 10.1080/10253890.2023.2204366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/18/2023] Open
Abstract
Stress is a normal response to situational pressures or demands. Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis and leads to the release of corticosteroids, which act in the brain via two distinct receptors: mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Persistent HPA axis overactivation or dysregulation can disrupt an individual's homeostasis, thereby contributing to an increased risk for mental illness. On the other hand, successful coping with stressful events involves adaptive and cognitive processes in the brain that render individuals more resilient to similar stressors in the future. Here we review the role of the MR in these processes, starting with an overview of the physiological structure, ligand binding, and expression of MR, and further summarizing its role in the brain, its relevance to psychiatric disorders, and related rodent studies. Given the central role of MR in cognitive and emotional functioning, and its importance as a target for promoting resilience, future research should investigate how MR modulation can be used to alleviate disturbances in emotion and behavior, as well as cognitive impairment, in patients with stress-related psychiatric disorders.
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Affiliation(s)
- Huanqing Yang
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
| | - Sowmya Narayan
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
- Department Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), 80804 Munich, Germany
| | - Mathias V Schmidt
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
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9
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Matcha Tea Powder's Antidepressant-like Effect through the Activation of the Dopaminergic System in Mice Is Dependent on Social Isolation Stress. Nutrients 2023; 15:nu15030581. [PMID: 36771286 PMCID: PMC9921318 DOI: 10.3390/nu15030581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/02/2023] [Accepted: 01/17/2023] [Indexed: 01/24/2023] Open
Abstract
Matcha tea powder is believed to have various physiological benefits; however, its detailed mechanism of action has been poorly understood. Here, we investigated whether the mental state of mice, due to social isolation stress, affects the antidepressant-like effect of Matcha tea powder by using the tail suspension test. Oral administration of Matcha tea powder reduced the duration of immobility in the stress-susceptible C57BL/6J strain, but not in BALB/c strain. In C57BL/6J mice, SCH23390, a dopamine D1 receptor blocker, prevented Matcha tea powder from exerting its antidepressant-like effect. Matcha tea powder also increased the number of c-Fos-positive cells in the prefrontal cortex (PFC) region and the nucleus accumbens (NAc) region in C57BL/6J mice, but not in BALB/c mice. In contrast, Matcha tea powder did not change the number of c-Fos-positive cells in the ventral tegmental area (VTA) region. Notably, C57BL/6J mice with a shorter immobility time had a higher number of c-Fos-positive cells in the PFC, NAc, and VTA regions. However, no such correlation was observed in the stress-tolerant BALB/c mice. These results suggest that Matcha tea powder exerts an antidepressant-like effect through the activation of the dopaminergic system including the PFC-NAc-VTA circuit and that mental states are important factors affecting the physiological benefits of Matcha tea powder.
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10
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Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies. Mol Psychiatry 2022; 27:4642-4652. [PMID: 36123420 DOI: 10.1038/s41380-022-01736-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 08/02/2022] [Accepted: 08/08/2022] [Indexed: 12/14/2022]
Abstract
Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solution without alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.
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11
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Engelmann J, Murck H, Wagner S, Zillich L, Streit F, Herzog DP, Braus DF, Tadic A, Lieb K, Műller MB. Routinely accessible parameters of mineralocorticoid receptor function, depression subtypes and response prediction: a post-hoc analysis from the early medication change trial in major depressive disorder. World J Biol Psychiatry 2022; 23:631-642. [PMID: 34985381 DOI: 10.1080/15622975.2021.2020334] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVES Previous studies indicated a relationship between aldosterone, the mineralocorticoid receptor (MR), and antidepressant treatment outcome. Physiological indicators of MR function (blood pressure and electrolytes) are easily accessible and may therefore serve as useful predictors. Thus, our aim was to investigate the predictive value of peripheral MR-related markers for antidepressant treatment outcomes. METHODS 826 MDD patients who had participated in the randomised-controlled Early Medication Change (EMC) trial were analysed. Depression severity and MR-related markers were assessed weekly. In 562 patients, genetic variation of five MR-related genes was determined. RESULTS Patients with blood pressure <120mmHg showed higher depression severity (p = 0.005) than patients with blood pressure ≥120mmHg. Patients with a melancholic subtype had significantly lower blood pressures (p = 0.004). Na+/K+ ratio was positively and K+-concentration was negatively correlated to depression severity and to relative changes in HAMD from baseline to day 14, and 56 respectively (p < 0.001). For none of the MR-related genes, genetic variation was associated with treatment outcomes. CONCLUSIONS We confirmed early observations of an altered peripheral MR sensitivity, reflected by lower blood pressure, low K+ or high Na+/K+ ratio in patients with more severe depression. These routinely collected biomarkers may potentially be useful for risk stratification in an early stage of treatment. Trial Registration: clinicaltrials.gov Identifier: NCT00974155; https://www.clinicaltrials.gov/ct2/results?term=NCT00974155.
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Affiliation(s)
- Jan Engelmann
- Department of Psychiatry and Psychotherapy, University Medical Center, Mainz, Germany.,Translational Psychiatry, Department of Psychiatry and Psychotherapy & Focus Program Translational Neuroscience, University Medical Center, Mainz, Germany
| | - Harald Murck
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.,Murck-Neuroscience, Westfield, NJ, United States.,Aptinyx Inc, Evanston, IL, USA
| | - Stefanie Wagner
- Department of Psychiatry and Psychotherapy, University Medical Center, Mainz, Germany
| | - Lea Zillich
- Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
| | - Fabian Streit
- Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
| | - David P Herzog
- Department of Psychiatry and Psychotherapy, University Medical Center, Mainz, Germany.,Translational Psychiatry, Department of Psychiatry and Psychotherapy & Focus Program Translational Neuroscience, University Medical Center, Mainz, Germany
| | - Dieter F Braus
- Department of Psychiatry and Psychotherapy, Eltville, Germany
| | - Andre Tadic
- Department of Psychiatry and Psychotherapy, University Medical Center, Mainz, Germany.,Department of Psychiatry, Psychosomatics, and Psychotherapy, DR. FONTHEIM Mentale Gesundheit, Liebenburg, Germany
| | - Klaus Lieb
- Department of Psychiatry and Psychotherapy, University Medical Center, Mainz, Germany
| | - Marianne B Műller
- Translational Psychiatry, Department of Psychiatry and Psychotherapy & Focus Program Translational Neuroscience, University Medical Center, Mainz, Germany
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12
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Paul SN, Wingenfeld K, Otte C, Meijer OC. Brain Mineralocorticoid receptor in health and disease: from molecular signaling to cognitive and emotional function. Br J Pharmacol 2022; 179:3205-3219. [PMID: 35297038 PMCID: PMC9323486 DOI: 10.1111/bph.15835] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 02/22/2022] [Accepted: 03/08/2022] [Indexed: 11/27/2022] Open
Abstract
Brain mineralocorticoid receptors (MR) mediate effects of glucocorticoid hormones in stress adaptation, as well as the effects of aldosterone itself in relation to salt homeostasis. Brain stem MRs respond to aldosterone, whereas forebrain MRs mediate rapid and delayed glucocorticoid effects in conjunction with the glucocorticoid receptor (GR). MR‐mediated effects depend on age, gender, genetic variations, and environmental influences. Disturbed MR activity through chronic stress, certain (endocrine) diseases or during glucocorticoid therapy can cause deleterious effects on affective state, cognitive and behavioural function in susceptible individuals. Considering the important role MR plays in cognition and emotional function in health and disease, MR modulation by pharmacological intervention could relieve stress‐ and endocrine‐related symptoms. Here, we discuss recent pharmacological interventions in the clinic and genetic developments in the molecular underpinnings of MR signalling. Further understanding of MR‐dependent pathways may help to improve psychiatric symptoms in a diversity of settings.
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Affiliation(s)
- Susana N Paul
- Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Katja Wingenfeld
- Klinik für Psychiatrie und Psychotherapie, Charité Universitätsmedizin Campus Benjamin Franklin, Berlin, Germany
| | - Christian Otte
- Klinik für Psychiatrie und Psychotherapie, Charité Universitätsmedizin Campus Benjamin Franklin, Berlin, Germany.,NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Onno C Meijer
- Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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13
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Wang H, Kan WJ, Feng Y, Feng L, Yang Y, Chen P, Xu JJ, Si TM, Zhang L, Wang G, Du J. Nuclear receptors modulate inflammasomes in the pathophysiology and treatment of major depressive disorder. World J Psychiatry 2021; 11:1191-1205. [PMID: 35070770 PMCID: PMC8717028 DOI: 10.5498/wjp.v11.i12.1191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/29/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023] Open
Abstract
Major depressive disorder (MDD) is highly prevalent and is a significant cause of mortality and morbidity worldwide. Currently, conventional pharmacological treatments for MDD produce temporary remission in < 50% of patients; therefore, there is an urgent need for a wider spectrum of novel antidepressants to target newly discovered underlying disease mechanisms. Accumulated evidence has shown that immune inflammation, particularly inflammasome activity, plays an important role in the pathophysiology of MDD. In this review, we summarize the evidence on nuclear receptors (NRs), such as glucocorticoid receptor, mineralocorticoid receptor, estrogen receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor, in modulating the inflammasome activity and depression-associated behaviors. This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology of MDD, and to provide insight for the discovery of antidepressants with novel mechanisms for this devastating disorder.
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Affiliation(s)
- Han Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Wei-Jing Kan
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Yuan Feng
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Lei Feng
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Yang Yang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Pei Chen
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Jing-Jie Xu
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Tian-Mei Si
- Department of Clinical Psychopharmacology, Peking University Institute of Mental Health, Beijing 100191, Beijing Province, China
| | - Ling Zhang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Gang Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Jing Du
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
- State Key Laboratory for Conservation and Utilization of Bio-resources in Yunnan, Yunnan University, Kunming 650091, Yunnan Province, China
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14
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Hippocampal neuropathology in suicide: Gaps in our knowledge and opportunities for a breakthrough. Neurosci Biobehav Rev 2021; 132:542-552. [PMID: 34906612 DOI: 10.1016/j.neubiorev.2021.12.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 12/03/2021] [Accepted: 12/10/2021] [Indexed: 01/27/2023]
Abstract
Suicide is a major global hazard. There is a need for increasing suicide awareness and effective and evidence-based interventions, targeting both suicidal ideation and conduct. However, anti-suicide pharmacological effects are unsatisfactory. The human hippocampus is vulnerable to neuropsychiatric damages and subsequently releases psychobiological signals. Human hippocampal studies of suicide completers have shown mechanistic changes in neurobiology, which, however, could not reflect the neuropathological 'fingerprints' of fatal suicide ideations and suicide attempts. In this review, we provide several leading theories of suicide, including the serotoninergic system, Wnt pathway and brain-derived neurotrophic factor/tropomyosin receptor kinase B signalling, and discuss the evidence for their roles in suicide and treatment. Moreover, the cognitive dysfunctions associated with suicide risk are discussed, as well as the novel evidence on cognitive therapies that decrease suicidal ideation. We highlight the need to apply multi-omics techniques (including single-nucleus RNA sequencing and mass spectrometry histochemistry) on hippocampal samples from donors who died by suicide or legal euthanasia, to clarify the aetiology of suicide and propose novel therapeutic strategies.
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15
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Zhang Y, Zhou T, Feng S, Liu X, Wang F, Sha Z, Yu X. A voxel-level brain-wide association study of cortisol at 8 a.m.: Evidence from Cushing's disease. Neurobiol Stress 2021; 15:100414. [PMID: 34786440 PMCID: PMC8578035 DOI: 10.1016/j.ynstr.2021.100414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 10/16/2021] [Accepted: 10/24/2021] [Indexed: 11/28/2022] Open
Abstract
Cortisol, the end product of the hypothalamic–pituitary–adrenal axis, regulates cognitive function and emotion processing. Cushing's disease, which is characterized by a unique excess of cortisol upon clinical diagnosis, serve as an excellent in vivo “hyperexpression” model to investigate the neurobiological mechanisms of cortisol in the human brain. Previous studies have shown the association between cortisol and functional connectivity within an a priori brain network. However, the whole-brain connectivity pattern that accompanies endogenous cortisol variation is still unclear, as are its associated genetic underpinnings. Here, using resting-state functional magnetic resonance imaging in 112 subjects (60 patients with Cushing's disease and 52 healthy subjects), we performed a voxel-level brain-wide association analysis to investigate the functional connectivity pattern associated with a wide variation in cortisol levels at 8 a.m. The results showed that the regions associated with cortisol as of 8 a.m. were primarily distributed in brain functional hubs involved in self-referential processing, such as the medial prefrontal cortex, anterior and posterior cingulate cortex, and caudate. We also found that regions in the middle temporal, inferior parietal and ventrolateral prefrontal cortex, which is important for social communication tasks, and in the visual and supplementary motor cortex, which is involved in primary sensorimotor perception, were adversely affected by excessive cortisol. The connectivity between these regions was also significantly correlated with neuropsychiatric profiles, such anxiety and depression. Finally, combined neuroimaging and transcriptome analysis showed that functional cortisol-sensitive brain variations were significantly coupled to regional expression of glucocorticoid and mineralocorticoid receptors. These findings reveal cortisol-biased functional signatures in the human brain and shed light on the transcriptional regulation constraints on the cortisol-related brain network.
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Affiliation(s)
- Yanyang Zhang
- Department of Neurosurgery, The First Medical Center of Chinese PLA General Hospital, Beijing, PR China
| | - Tao Zhou
- Department of Neurosurgery, The First Medical Center of Chinese PLA General Hospital, Beijing, PR China
| | - Shiyu Feng
- Department of Neurosurgery, The First Medical Center of Chinese PLA General Hospital, Beijing, PR China
| | - Xinyun Liu
- Department of Radiology, The First Medical Center of Chinese PLA General Hospital, Beijing, PR China
| | - Fuyu Wang
- Department of Neurosurgery, The First Medical Center of Chinese PLA General Hospital, Beijing, PR China
| | - Zhiqiang Sha
- Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Xinguang Yu
- Department of Neurosurgery, The First Medical Center of Chinese PLA General Hospital, Beijing, PR China
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16
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Medina J, De Guzman RM, Workman JL. Lactation is not required for maintaining maternal care and active coping responses in chronically stressed postpartum rats: Interactions between nursing demand and chronic variable stress. Horm Behav 2021; 136:105035. [PMID: 34488064 DOI: 10.1016/j.yhbeh.2021.105035] [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] [Received: 01/27/2021] [Revised: 06/11/2021] [Accepted: 07/04/2021] [Indexed: 10/20/2022]
Abstract
Women who do not breastfeed or discontinue breastfeeding early are more likely to develop postpartum depression (PPD) and stress is a significant risk factor for depression, including PPD. Using a rat model, we investigated whether the absence of nursing would increase the susceptibility to chronic stress-related behavioral and neural changes during the postpartum period. Adult female rats underwent thelectomy (thel; removal of teats), sham surgery, or no surgery (control) and were paired with males for breeding. All litters were rotated twice daily until postpartum day (PD) 26. Sham rats served as surrogates for thel litters, yielding a higher nursing demand for sham rats. Concurrently, rats received either no stress or chronic variable stress until PD 25. Rats were observed for maternal behaviors and tested in a series of tasks including open field, sucrose preference, and forced swim. We used immunohistochemistry (IHC) for doublecortin (DCX; to label immature neurons) or for mineralocorticoid receptor (MR). Contrary to our expectations, non-nursing thel rats were resistant to the effects of stress in all dependent measures. Our data indicate that even in chronic adverse conditions, nursing is not required for maintaining stable care to offspring or active coping responses in an acutely stressful task. We discuss the possible role of offspring contact and consider future directions for biomedical and clinical research. In rats with high nursing demand, however, chronic stress increased immobility, hippocampal neurogenesis, and MR expression (largely in opposition to the effects of stress in rats with typical nursing demand). We discuss these patterns in the context of energetics and allostatic load. This research highlights the complexity in relationships between stress, nursing, and neurobehavioral outcomes in the postpartum period and underscores the need for additional biomedical and clinical research geared toward optimizing treatments and interventions for women with PPD, regardless of breastfeeding status. SIGNIFICANCE STATEMENT: The goal of this research was to determine how the absence of nursing and higher nursing demand impact stress-coping behaviors and neural changes associated with chronic stress in order to disentangle the complex interplay of factors that contribute to psychological illness during the postpartum period.
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Affiliation(s)
- Joanna Medina
- Department of Psychology, University at Albany, State University of New York, 1400 Washington Ave., Albany, NY 12222, United States of America
| | - Rose M De Guzman
- Department of Psychology, University at Albany, State University of New York, 1400 Washington Ave., Albany, NY 12222, United States of America
| | - Joanna L Workman
- Department of Psychology, University at Albany, State University of New York, 1400 Washington Ave., Albany, NY 12222, United States of America; Center for Neuroscience Research, University at Albany, State University of New York, 1400 Washington Ave., Albany, NY 12222, United States of America.
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17
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van Hulst AM, Verwaaijen EJ, Fiocco MF, Pluijm SMF, Grootenhuis MA, Pieters R, van den Akker ELT, van den Heuvel-Eibrink MM. Study protocol: DexaDays-2, hydrocortisone for treatment of dexamethasone-induced neurobehavioral side effects in pediatric leukemia patients: a double-blind placebo controlled randomized intervention study with cross-over design. BMC Pediatr 2021; 21:427. [PMID: 34579671 PMCID: PMC8474814 DOI: 10.1186/s12887-021-02896-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 09/15/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Dexamethasone, a highly effective drug in treating pediatric acute lymphoblastic leukemia (ALL), can induce serious neurobehavioral side effects. These side effects are experienced by patients and parents as detrimental with respect to health related quality of life (HRQoL). Based on previous studies, it has been suggested that neurobehavioral side effects are associated to cortisol depletion of the mineralocorticoid receptor in the brain. Our previously reported randomized controlled trial, the Dexadagen study (NTR3280), suggests that physiological hydrocortisone addition during dexamethasone treatment may overcome clinically relevant neurobehavioral problems in patients who experience these problems during dexamethasone treatment. With our current study, we aim to replicate these results in a targeted larger sample before further implementing this intervention into standard of care. METHODS In a national center setting, pediatric ALL patients between 3 and 18 years are enrolled in an Identification study, which identifies patients with clinically relevant dexamethasone-induced neurobehavioral side effects using the Strengths and Difficulties Questionnaire (SDQ). Contributing factors, such as genetic susceptibility, dexamethasone pharmacokinetics as well as psychosocial and family factors are studied to determine their influence in the inter-patient variability for developing dexamethasone-induced neurobehavioral side effects. Patients with clinically relevant problems (i.e. a rise of ≥ 5 points on the SDQ Total Difficulties Score after 5 days of dexamethasone) are subsequently included in a randomized double-blind placebo-controlled trial with a cross-over design. They receive two courses placebo followed by two courses hydrocortisone during dexamethasone treatment, or vice versa, each time at least 16 days without study medication in between. The primary endpoint is change in SDQ score. The secondary endpoints are sleep (measured with actigraphy and the Sleep Disturbance Scale for Children) and HRQoL (Pediatric Quality of Life Questionnaire). DISCUSSION The results of our current study may contribute to the management of future ALL patients who experience dexamethasone-induced neuropsychological problems as it may improve HRQoL for patients who suffer most from dexamethasone-induced neurobehavioral side effects. Furthermore, by investigating multiple risk factors that could be related to inter-patient variability in developing these side effects, we might be able to identify and treat patients who are at risk earlier during treatment. TRIAL REGISTRATION Medical Ethical Committee approval number: NL62388.078.17. Affiliation: Erasmus Medical Centre. Netherlands Trial Register: NL6507 ( NTR6695 ). Registered 5 September 2017.
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Affiliation(s)
- A. M. van Hulst
- Princess Maxima Center, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands
| | - E. J. Verwaaijen
- Princess Maxima Center, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands
| | - M. F. Fiocco
- Princess Maxima Center, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands
- Mathematical Institute Leiden University, Niels Bohrweg 1, 2333 CA Leiden, The Netherlands
| | - S. M. F. Pluijm
- Princess Maxima Center, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands
| | - M. A. Grootenhuis
- Princess Maxima Center, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands
| | - R. Pieters
- Princess Maxima Center, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands
| | - E. L. T. van den Akker
- Erasmus MC- Sophia Children’s Hospital, Wytemaweg 80, 3015 CE Rotterdam, The Netherlands
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18
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Rivera-Bonet CN, Birn RM, Ladd CO, Meyerand ME, Abercrombie HC. Cortisol effects on brain functional connectivity during emotion processing in women with depression. J Affect Disord 2021; 287:247-254. [PMID: 33799044 PMCID: PMC8128282 DOI: 10.1016/j.jad.2021.03.034] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/10/2021] [Accepted: 03/15/2021] [Indexed: 01/30/2023]
Abstract
BACKGROUND Depression is associated with altered functional connectivity and altered cortisol sensitivity, but the effects of cortisol on functional connectivity in depression are unknown. Previous research shows that brief cortisol augmentation (CORT) has beneficial neurocognitive effects in depression. METHODS We investigated the effects of CORT (20mg oral cortisol) on functional connectivity during emotion processing in women with depression. Participants included 75 women with no depression or a depressive disorder. In a double-blind, crossover study, we used functional magnetic resonance imaging to measure effects of CORT vs. placebo on task-based functional connectivity during presentation of emotionally-laden images. We performed psychophysiological interaction (PPI) to test interactions among depression severity, cortisol administration, and task-dependent functional connectivity using the hippocampus and amygdala as seeds. RESULTS During the presentation of negative images, CORT (vs. placebo) increased functional connectivity between the hippocampus and putamen in association with depression severity. During the presentation of positive pictures CORT increased functional connectivity between the hippocampus and middle frontal gyrus as well as superior temporal gyrus in association with depression. LIMITATIONS Because cortisol was pharmacologically manipulated, results cannot be extrapolated to endogenous increases in cortisol levels. The sample did not permit investigation of differences due to race, ethnicity, or sex. Co-morbidities such as anxiety or PTSD were not accounted for. CONCLUSIONS The results suggest that CORT has normalizing effects on task-dependent functional connectivity in women with depression during emotion processing. Increasing cortisol availability or signaling may have therapeutic benefits within affective disorders.
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Affiliation(s)
| | - Rasmus M Birn
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, United States; Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, United States; Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, United States
| | - Charlotte O Ladd
- Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, United States
| | - Mary E Meyerand
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, United States; Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, United States; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States
| | - Heather C Abercrombie
- Center for Healthy Minds, University of Wisconsin-Madison, Madison, WI, United States
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19
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Abstract
Treatment for critical illness typically focuses on a patient's short-term physical recovery; however, recent work has broadened our understanding of the long-term implications of illness and treatment strategies. In particular, survivors of critical illness have significantly elevated risk of developing lasting cognitive impairment and psychiatric disorders. In this review, we examine the role of endogenous and exogenous glucocorticoids in neuropsychiatric outcomes following critical illness. Illness is marked by acute elevation of free cortisol and adrenocorticotropic hormone suppression, which typically normalize after recovery; however, prolonged dysregulation can sometimes occur. High glucocorticoid levels can cause lasting alterations to the plasticity and structural integrity of the hippocampus and prefrontal cortex, and this mechanism may plausibly contribute to impaired memory and cognition in critical illness survivors, though specific evidence is lacking. Glucocorticoids may also exacerbate inflammation-associated neural damage. Conversely, current evidence indicates that glucocorticoids during illness may protect against the development of post-traumatic stress disorder. We propose future directions for research in this field, including determining the role of persistent glucocorticoid elevations after illness in neuropsychiatric outcomes, the role of systemic vs neuroinflammation, and probing unexplored lines of investigation on the role of mineralocorticoid receptors and the gut-brain axis. Progress toward personalized medicine in this area has the potential to produce tangible improvements to the lives patients after a critical illness, including Coronavirus Disease 2019.
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Affiliation(s)
- Alice R Hill
- Undergraduate Program in Neuroscience, University of Michigan, Ann Arbor, MI, USA
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | - Joanna L Spencer-Segal
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
- Deparment of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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20
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HUZARD D, RAPPENEAU V, MEIJER OC, TOUMA C, ARANGO-LIEVANO M, GARABEDIAN MJ, JEANNETEAU F. Experience and activity-dependent control of glucocorticoid receptors during the stress response in large-scale brain networks. Stress 2021; 24:130-153. [PMID: 32755268 PMCID: PMC7907260 DOI: 10.1080/10253890.2020.1806226] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The diversity of actions of the glucocorticoid stress hormones among individuals and within organs, tissues and cells is shaped by age, gender, genetics, metabolism, and the quantity of exposure. However, such factors cannot explain the heterogeneity of responses in the brain within cells of the same lineage, or similar tissue environment, or in the same individual. Here, we argue that the stress response is continuously updated by synchronized neural activity on large-scale brain networks. This occurs at the molecular, cellular and behavioral levels by crosstalk communication between activity-dependent and glucocorticoid signaling pathways, which updates the diversity of responses based on prior experience. Such a Bayesian process determines adaptation to the demands of the body and external world. We propose a framework for understanding how the diversity of glucocorticoid actions throughout brain networks is essential for supporting optimal health, while its disruption may contribute to the pathophysiology of stress-related disorders, such as major depression, and resistance to therapeutic treatments.
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Affiliation(s)
- Damien HUZARD
- Department of Neuroscience and Physiology, University of Montpellier, CNRS, INSERM, Institut de Génomique Fonctionnelle, Montpellier, France
| | - Virginie RAPPENEAU
- Department of Behavioural Biology, University of Osnabrück, Osnabrück, Germany
| | - Onno C. MEIJER
- Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden University, Leiden, the Netherlands
| | - Chadi TOUMA
- Department of Behavioural Biology, University of Osnabrück, Osnabrück, Germany
| | - Margarita ARANGO-LIEVANO
- Department of Neuroscience and Physiology, University of Montpellier, CNRS, INSERM, Institut de Génomique Fonctionnelle, Montpellier, France
| | | | - Freddy JEANNETEAU
- Department of Neuroscience and Physiology, University of Montpellier, CNRS, INSERM, Institut de Génomique Fonctionnelle, Montpellier, France
- Corresponding author:
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21
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Long Q, Wang R, Feng M, Zhao X, Liu Y, Ma X, Yu L, Li S, Guo Z, Zhu Y, Teng Z, Zeng Y. Construction and Analysis of a Diagnostic Model Based on Differential Expression Genes in Patients With Major Depressive Disorder. Front Psychiatry 2021; 12:762683. [PMID: 34955918 PMCID: PMC8695921 DOI: 10.3389/fpsyt.2021.762683] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/09/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Major depressive disorder (MDD) is a common and severe psychiatric disorder with a heavy burden on the individual and society. However, the prevalence varies significantly owing to the lack of auxiliary diagnostic biomarkers. To identify the shared differential expression genes (DEGs) with potential diagnostic value in both the hippocampus and whole blood, a systematic and integrated bioinformatics analysis was carried out. Methods: Two datasets from the Gene Expression Omnibus database (GSE53987 and GSE98793) were downloaded and analyzed separately. A weighted gene co-expression network analysis was performed to construct the co-expression gene network of DEGs from GSE53987, and the most disease-related module was extracted. The shared DEGs from the module and GSE98793 were identified using a Venn diagram. Functional pathway prediction was used to identify the most disease-related DEGs. Finally, several DEGs were chosen, and their potential diagnostic value was determined by receiver operating characteristic curve analysis. Results: After weighted gene co-expression network analysis, the most MDD-related module (MEgrey) was identified, and 623 DEGs were extracted from this module. The intersection between MEgrey and GSE98793 was calculated, and 163 common DEGs were identified. The co-expression network of 163 DEGs from these was then reconstructed. All hub genes were identified based on the connective degree of the reconstructed co-expression network. Based on the results of functional pathway enrichment, 17 candidate hub genes were identified. Finally, logistic regression and receiver operating characteristic curves showed that three candidate hub genes (CEP350, SMAD5, and HSPG2) had relatively high auxiliary value in the diagnosis of MDD. Conclusion: Our results showed that the combination of CEP350, SMAD5, and HSPG2 has a relatively high diagnostic value for MDD. Pathway enrichment analysis also showed that these genes may play an important role in the pathogenesis of MDD. These results suggest a potentially important role for this gene combination in clinical practice.
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Affiliation(s)
- Qing Long
- Sixth Affiliated Hospital of Kunming Medical University, Yuxi, China
| | - Rui Wang
- Institute for Health Sciences, Kunming Medical University, Kunming, China
| | - Maoyang Feng
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xinling Zhao
- Sixth Affiliated Hospital of Kunming Medical University, Yuxi, China
| | - Yilin Liu
- Sixth Affiliated Hospital of Kunming Medical University, Yuxi, China
| | - Xiao Ma
- Sixth Affiliated Hospital of Kunming Medical University, Yuxi, China
| | - Lei Yu
- Sixth Affiliated Hospital of Kunming Medical University, Yuxi, China
| | - Shujun Li
- Sixth Affiliated Hospital of Kunming Medical University, Yuxi, China
| | - Zeyi Guo
- Sixth Affiliated Hospital of Kunming Medical University, Yuxi, China
| | - Yun Zhu
- Sixth Affiliated Hospital of Kunming Medical University, Yuxi, China
| | - Zhaowei Teng
- First People's Hospital of Yunnan Province, Kunming, China
| | - Yong Zeng
- Sixth Affiliated Hospital of Kunming Medical University, Yuxi, China
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Cognitive and emotional empathy after stimulation of brain mineralocorticoid and NMDA receptors in patients with major depression and healthy controls. Neuropsychopharmacology 2020; 45:2155-2161. [PMID: 32722659 PMCID: PMC7785026 DOI: 10.1038/s41386-020-0777-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/19/2020] [Accepted: 07/10/2020] [Indexed: 02/06/2023]
Abstract
Mineralocorticoid receptors (MR) are predominantly expressed in the hippocampus and prefrontal cortex. Both brain areas are associated with social cognition, which includes cognitive empathy (ability to understand others' emotions) and emotional empathy (ability to empathize with another person). MR stimulation improves memory and executive functioning in patients with major depressive disorder (MDD) and healthy controls, and leads to glutamate-mediated N-methyl-D-aspartate receptor (NMDA-R) signaling. We examined whether the beneficial effects of MR stimulation can be extended to social cognition (empathy), and whether DCS would have additional beneficial effects. In this double-blind placebo-controlled single-dose study, we randomized 116 unmedicated MDD patients (mean age 34 years, 78% women) and 116 age-, sex-, and education years-matched healthy controls to four conditions: MR stimulation (fludrocortisone (0.4 mg) + placebo), NMDA-R stimulation (placebo + D-cycloserine (250 mg)), MR and NMDA-R stimulation (both drugs), or placebo. Cognitive and emotional empathy were assessed by the Multifaceted Empathy Test. The study was registered on clinicaltrials.gov (NCT03062150). MR stimulation increased cognitive empathy across groups, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients only. Independent of receptor stimulation, cognitive empathy did not differ between groups. Emotional empathy was not affected by MR or NMDA-R stimulation. However, MDD patients showed decreased emotional empathy compared with controls but, according to exploratory analyses, only for positive emotions. We conclude that MR stimulation has beneficial effects on cognitive empathy in MDD patients and healthy controls, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients. It appears that MR rather than NMDA-R are potential treatment targets to modulate cognitive empathy in MDD.
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23
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Qing L, Liu L, Zhou L, Zhang F, Gao C, Hu L, Nie S. Sex-dependent association of mineralocorticoid receptor gene (NR3C2) DNA methylation and schizophrenia. Psychiatry Res 2020; 292:113318. [PMID: 32712448 DOI: 10.1016/j.psychres.2020.113318] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 07/07/2020] [Accepted: 07/19/2020] [Indexed: 12/20/2022]
Abstract
Schizophrenia is a complex disease caused by genetic and environmental factors. Epigenetic regulation mediates gene-environment interactions by modulating gene expression. Abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis has been widely reported in schizophrenia patients. The DNA methylation levels of critical genes are associated with HPA axis activity, which is linked to schizophrenia pathogenesis. The mineralocorticoid receptor gene NR3C2 regulates HPA axis activity. However, how NR3C2 methylation affects the development of schizophrenia remains unknown. Here, we investigated the DNA methylation state of NR3C2, including the promoter P1 (NR3C2-1, NR3C2-2 and NR3C2-3) and exon 1α and its downstream sequence (NR3C2-4), in schizophrenia. Peripheral blood DNA from 80 schizophrenia patients and 128 healthy controls was used to assess NR3C2 DNA methylation via sodium bisulfite treatment and the MethylTarget method. NR3C2-4 region was hypermethylated in schizophrenia patients compared with healthy controls in the female group. Specific CpG sites in P1 and NR3C2-4 region were associated with schizophrenia, with sex-specific effects. These findings showed a relationship between NR3C2 DNA methylation and schizophrenia, revealing that epigenetic processes may mediate schizophrenia pathophysiology. Further research should address the potential epigenetic mechanisms of the relationship between NR3C2 and schizophrenia.
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Affiliation(s)
- Lili Qing
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, People's Republc of China
| | - Linlin Liu
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, People's Republc of China
| | - Li Zhou
- Mental Health Center of Yunnan Province, Kunming, Yunnan Province, People's Republc of China
| | - Fan Zhang
- Mental Health Center of Yunnan Province, Kunming, Yunnan Province, People's Republc of China
| | - Changqing Gao
- Mental Health Center of Yunnan Province, Kunming, Yunnan Province, People's Republc of China.
| | - Liping Hu
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, People's Republc of China.
| | - Shengjie Nie
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, People's Republc of China.
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You X, Zhang Y, Long Q, Liu Z, Feng Z, Zhang W, Teng Z, Zeng Y. Does single gene expression omnibus data mining analysis apply for only tumors and not mental illness? A preliminary study on bipolar disorder based on bioinformatics methodology. Medicine (Baltimore) 2020; 99:e21989. [PMID: 32871949 PMCID: PMC7458177 DOI: 10.1097/md.0000000000021989] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Bipolar disorder (BD), a common kind of mood disorder with frequent recurrence, high rates of additional comorbid conditions and poor compliance, has an unclear pathogenesis. The Gene Expression Omnibus (GEO) database is a gene expression database created and maintained by the National Center for Biotechnology Information. Researchers can download expression data online for bioinformatics analysis, especially for cancer research. However, there is little research on the use of such bioinformatics analysis methodologies for mental illness by downloading differential expression data from the GEO database. METHODS Publicly available data were downloaded from the GEO database (GSE12649, GSE5388 and GSE5389), and differentially expressed genes (DEGs) were extracted by using the online tool GEO2R. A Venn diagram was used to screen out common DEGs between postmortem brain tissues and normal tissues. Functional annotation and pathway enrichment analysis of DEGs were performed by using Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. Furthermore, a protein-protein interaction network was constructed to identify hub genes. RESULTS A total of 289 DEGs were found, among which 5 of 10 hub genes [HSP90AA1, HSP90AB 1, UBE2N, UBE3A, and CUL1] were identified as susceptibility genes whose expression was downregulated. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that variations in these 5 hub genes were obviously enriched in protein folding, protein polyubiquitination, apoptotic process, protein binding, the ubiquitin-mediated proteolysis pathway, and protein processing in the endoplasmic reticulum pathway. These findings strongly suggested that HSP90AA1, UBE3A, and CUL 1, which had large areas under the curve in receiver operator curves (P < .05), were potential diagnostic markers for BD. CONCLUSION Although there are 3 hub genes [HSP90AA1, UBE3A, and CUL 1] that are tightly correlated with the occurrence of BD, mainly based on routine bioinformatics methods for cancer-related disease, the feasibility of applying this single GEO bioinformatics approach for mental illness is questionable, given the significant differences between mental illness and cancer-related diseases.
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25
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Revisiting the Stress Concept: Implications for Affective Disorders. J Neurosci 2020; 40:12-21. [PMID: 31896560 DOI: 10.1523/jneurosci.0733-19.2019] [Citation(s) in RCA: 302] [Impact Index Per Article: 60.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 11/24/2019] [Accepted: 11/29/2019] [Indexed: 12/18/2022] Open
Abstract
Over the last 50 years, the concept of stress has evolved significantly, and our understanding of the underlying neurobiology has expanded dramatically. Rather than consider stress biology to be relevant only under unusual and threatening conditions, we conceive of it as an ongoing, adaptive process of assessing the environment, coping with it, and enabling the individual to anticipate and deal with future challenges. Though much remains to be discovered, the fundamental neurocircuitry that underlies these processes has been broadly delineated, key molecular players have been identified, and the impact of this system on neuroplasticity has been well established. More recently, we have come to appreciate the critical interaction between the brain and the rest of the body as it pertains to stress responsiveness. Importantly, this system can become overloaded due to ongoing environmental demands on the individual, be they physical, physiological, or psychosocial. The impact of this overload is deleterious to brain health, and it results in vulnerability to a range of brain disorders, including major depression and cognitive deficits. Thus, stress biology is one of the best understood systems in affective neuroscience and is an ideal target for addressing the pathophysiology of many brain-related diseases. The story we present began with the discovery of glucocorticoid receptors in hippocampus and has extended to other brain regions in both animal models and the human brain with the further discovery of structural and functional adaptive plasticity in response to stressful and other experiences.
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D'Alessio L, Mesarosova L, Anink JJ, Kochen S, Solís P, Oddo S, Konopka H, Iyer AM, Mühlebner A, Lucassen PJ, Aronica E, van Vliet EA. Reduced expression of the glucocorticoid receptor in the hippocampus of patients with drug-resistant temporal lobe epilepsy and comorbid depression. Epilepsia 2020; 61:1595-1605. [PMID: 32652588 PMCID: PMC7496961 DOI: 10.1111/epi.16598] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 05/16/2020] [Accepted: 06/11/2020] [Indexed: 12/23/2022]
Abstract
Objective Depressive disorders are common among about 50% of the patients with drug‐resistant temporal lobe epilepsy (TLE). The underlying etiology remains elusive, but hypothalamus‐pituitary‐adrenal (HPA) axis activation due to changes in glucocorticoid receptor (GR) protein expression could play an important role. Therefore, we set out to investigate expression of the GR in the hippocampus, an important brain region for HPA axis feedback, of patients with drug‐resistant TLE, with and without comorbid depression. Methods GR expression was studied using immunohistochemistry on hippocampal sections from well‐characterized TLE patients with depression (TLE + D, n = 14) and without depression (TLE − D, n = 12) who underwent surgery for drug‐resistant epilepsy, as well as on hippocampal sections from autopsy control cases (n = 9). Video–electroencephalography (EEG), magnetic resonance imaging (MRI), and psychiatric and memory assessments were performed prior to surgery. Results Abundant GR immunoreactivity was present in dentate gyrus granule cells and CA1 pyramidal cells of controls. In contrast, neuronal GR expression was lower in patients with TLE, particularly in the TLE + D group. Quantitative analysis showed a smaller GR+ area in TLE + D as compared to TLE − D patients and controls. Furthermore, the ratio between the number of GR+/NeuN+ cells was lower in patients with TLE + D as compared to TLE − D and correlated negatively with the depression severity based on psychiatric history. The expression of the GR was also lower in glial cells of TLE + D compared to TLE − D patients and correlated negatively to the severity of depression. Significance Reduced hippocampal GR expression may be involved in the etiology of depression in patients with TLE and could constitute a biological marker of depression in these patients.
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Affiliation(s)
- Luciana D'Alessio
- Universidad de Buenos Aires, IBCN-CONICET, Centro de Epilepsia Hospital Ramos Mejía y Hospital El Cruce, ENyS-CONICET, Buenos Aires, Argentina
| | - Lucia Mesarosova
- Amsterdam UMC, University of Amsterdam, Department of (Neuro) Pathology, Amsterdam Neuroscience, Amsterdam, the Netherlands
| | - Jasper J Anink
- Amsterdam UMC, University of Amsterdam, Department of (Neuro) Pathology, Amsterdam Neuroscience, Amsterdam, the Netherlands
| | - Silvia Kochen
- Universidad de Buenos Aires, IBCN-CONICET, Centro de Epilepsia Hospital Ramos Mejía y Hospital El Cruce, ENyS-CONICET, Buenos Aires, Argentina
| | - Patricia Solís
- Universidad de Buenos Aires, IBCN-CONICET, Centro de Epilepsia Hospital Ramos Mejía y Hospital El Cruce, ENyS-CONICET, Buenos Aires, Argentina
| | - Silvia Oddo
- Universidad de Buenos Aires, IBCN-CONICET, Centro de Epilepsia Hospital Ramos Mejía y Hospital El Cruce, ENyS-CONICET, Buenos Aires, Argentina
| | - Hector Konopka
- Universidad de Buenos Aires, IBCN-CONICET, Centro de Epilepsia Hospital Ramos Mejía y Hospital El Cruce, ENyS-CONICET, Buenos Aires, Argentina
| | - Anand M Iyer
- Amsterdam UMC, University of Amsterdam, Department of (Neuro) Pathology, Amsterdam Neuroscience, Amsterdam, the Netherlands
| | - Angelika Mühlebner
- Amsterdam UMC, University of Amsterdam, Department of (Neuro) Pathology, Amsterdam Neuroscience, Amsterdam, the Netherlands
| | - Paul J Lucassen
- Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands
| | - Eleonora Aronica
- Amsterdam UMC, University of Amsterdam, Department of (Neuro) Pathology, Amsterdam Neuroscience, Amsterdam, the Netherlands.,Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands
| | - Erwin A van Vliet
- Amsterdam UMC, University of Amsterdam, Department of (Neuro) Pathology, Amsterdam Neuroscience, Amsterdam, the Netherlands.,Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands
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Cortisol secretion predicts functional macro-scale connectivity of the visual cortex: A data-driven Multivoxel Pattern Analysis (MVPA). Psychoneuroendocrinology 2020; 117:104695. [PMID: 32361170 DOI: 10.1016/j.psyneuen.2020.104695] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 01/30/2020] [Accepted: 04/11/2020] [Indexed: 11/21/2022]
Abstract
BACKGROUND Functional connectivity is a fundamental principle of brain organization. Cortisol, the end product of the hypothalamic-pituitary-adrenal axis, is a potent modulator of brain functions. Previous studies investigating the association between cortisol levels on brain connectivity are, however, limited to specifica priori defined brain networks. Such hypothesis-driven approaches only partly capture the full extent of spatial modulatory effects that cortisol exerts on brain connectivity. Consequently, the aim of this study was a data-driven identification of brain regions where connectivity patterns covary significantly with cortisol levels. METHODS Eighty-eight healthy right-handed individuals participated in a task-independent fMRI-resting-state functional connectivity (rsFC) measurement. The cortisol concentrations in saliva were measured at eight points in time around the resting state measurement. Using a multi-voxel pattern analysis (MVPA), seed regions were identified whose activity covaried strongest with cortisol levels. Seed-to-voxel analyses were then performed to isolate corresponding networks affected by cortisol variation. RESULTS The MVPA identified three regions in the primary and secondary visual cortex where connectivity patterns were associated with cortisol secretion. Seed-to-voxel analysis revealed large lateral connectivity clusters that mainly correspond to the salience and control network, but also to auditory and pericentral regions. Subsequent dose-response analysis suggests that cortisol levels below ∼10 nmol/L weakly influenced connectivity between the identified regions. DISCUSSION The results indicate a dose-dependent association between cortisol levels and the rsFC of the visual cortex to several lateral brain regions associated with perception, attention, cognition, salience mapping and motor actions. It is possible that the effects of cortisol on cognitive functions may be (at least partially) mediated by cortisol effects on the underlying sensory processes.
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Lambert K, Hunter RG, Bartlett AA, Lapp HE, Kent M. In search of optimal resilience ratios: Differential influences of neurobehavioral factors contributing to stress-resilience spectra. Front Neuroendocrinol 2020; 56:100802. [PMID: 31738947 DOI: 10.1016/j.yfrne.2019.100802] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 09/07/2019] [Accepted: 10/29/2019] [Indexed: 12/14/2022]
Abstract
The ability to adapt to stressful circumstances, known as emotional resilience, is a key factor in the maintenance of mental health. Several individual biomarkers of the stress response (e.g., corticosterone) that influence an animal's position along the continuum that ranges from adaptive allostasis to maladaptive allostatic load have been identified. Extending beyond specific biomarkers of stress responses, however, it is also important to consider stress-related responses relative to other relevant responses for a thorough understanding of the underpinnings of adaptive allostasis. In this review, behavioral, neurobiological, developmental and genomic variables are considered in the context of emotional resilience [e.g., explore/exploit behavioral tendencies; DHEA/CORT ratios and relative proportions of protein-coding/nonprotein-coding (transposable) genomic elements]. As complex and multifaceted relationships between pertinent allostasis biomediators are identified, translational applications for optimal resilience are more likely to emerge as effective therapeutic strategies.
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Affiliation(s)
- Kelly Lambert
- Dept of Psychology, B326 Gottwald Science Center, University of Richmond, VA 23173, United States.
| | - Richard G Hunter
- Dept of Psychology, University of Massachusetts-Boston, 100 Morrissey Blvd., Boston, MA 00252, United States
| | - Andrew A Bartlett
- Dept of Psychology, University of Massachusetts-Boston, 100 Morrissey Blvd., Boston, MA 00252, United States
| | - Hannah E Lapp
- Dept of Psychology, University of Massachusetts-Boston, 100 Morrissey Blvd., Boston, MA 00252, United States
| | - Molly Kent
- Dept of Psychology, B326 Gottwald Science Center, University of Richmond, VA 23173, United States
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Kokras N, Hodes GE, Bangasser DA, Dalla C. Sex differences in the hypothalamic-pituitary-adrenal axis: An obstacle to antidepressant drug development? Br J Pharmacol 2019; 176:4090-4106. [PMID: 31093959 PMCID: PMC6877794 DOI: 10.1111/bph.14710] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 04/11/2019] [Accepted: 04/23/2019] [Indexed: 12/30/2022] Open
Abstract
Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has long been implicated in the pathophysiology of depression, and HPA axis-based compounds have served as potential new therapeutic targets, but with no success. This review details sex differences from animal and human studies in the function of HPA axis elements (glucocorticoids, corticotropin releasing factor, and vasopressin) and related compounds tested as candidate antidepressants. We propose that sex differences contribute to the failure of novel HPA axis-based drugs in clinical trials. Compounds studied preclinically in males were tested in clinical trials that recruited more, if not exclusively, women, and did not control, but rather adjusted, for potential sex differences. Indeed, clinical trials of antidepressants are usually not stratified by sex or other important factors, although preclinical and epidemiological data support such stratification. In conclusion, we suggest that clinical testing of HPA axis-related compounds creates an opportunity for targeted, personalized antidepressant treatments based on sex. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.
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Affiliation(s)
- Nikolaos Kokras
- Department of PharmacologyNational and Kapodistrian University of AthensAthensGreece
- First Department of Psychiatry, Eginition HospitalNational and Kapodistrian University of AthensAthensGreece
| | - Georgia E. Hodes
- School of NeuroscienceVirginia Polytechnic Institute and State UniversityBlacksburgVirginia
| | | | - Christina Dalla
- Department of PharmacologyNational and Kapodistrian University of AthensAthensGreece
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Wingenfeld K, Otte C. Mineralocorticoid receptor function and cognition in health and disease. Psychoneuroendocrinology 2019; 105:25-35. [PMID: 30243757 DOI: 10.1016/j.psyneuen.2018.09.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 09/06/2018] [Accepted: 09/10/2018] [Indexed: 02/04/2023]
Abstract
The steroid hormone cortisol is released in response to stress and exerts its effects in the brain via two different receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). This review - dedicated to Dirk Hellhammer - focusses on the role of MR on cognitive and emotional function in healthy individuals and in stress-associated disorders such as major depressive disorder (MDD) or borderline personality disorder (BPD). Animal data and studies from healthy individuals converge such that MR play an important role in the appraisal of new situations and the following response selection. Decision-making and empathy are important determinants of this response selection and both are affected by MR function. Furthermore, MR are crucially involved in visuospatial navigation and memory in young and elderly healthy individuals whereas the exact physiological role of MR in verbal learning and verbal memory needs to be further characterized. In contrast to studies in healthy participants, age played a moderating role on the effects of MR stimulation on cognition in depressed patients. In young depressed patients, MR stimulation exerted beneficial effects on verbal memory and executive function, whereas in elderly depressed patients MR stimulation led to impaired verbal learning and visuospatial memory. Similar to healthy controls, BPD patients showed enhanced emotional empathy but not cognitive empathy after MR stimulation. Accordingly, this make MR an interesting target for potential pharmacological augmentation of psychotherapy in BPD. Given the important role MR play in cognitive and emotional function in health and disease, further studies should examine whether MR modulation can alleviate cognitive and emotional problems in patients with stress-associated disorders.
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Affiliation(s)
- Katja Wingenfeld
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Psychiatrie und Psychotherapie, Campus Benjamin Franklin, Berlin, Germany.
| | - Christian Otte
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Psychiatrie und Psychotherapie, Campus Benjamin Franklin, Berlin, Germany
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31
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Holm SK, Madsen KS, Vestergaard M, Born AP, Paulson OB, Siebner HR, Uldall P, Baaré WFC. Previous glucocorticoid treatment in childhood and adolescence is associated with long-term differences in subcortical grey matter volume and microstructure. NEUROIMAGE-CLINICAL 2019; 23:101825. [PMID: 31004915 PMCID: PMC6475768 DOI: 10.1016/j.nicl.2019.101825] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 03/24/2019] [Accepted: 04/10/2019] [Indexed: 11/17/2022]
Abstract
BACKGROUND Glucocorticoids are widely used in the treatment of several pediatric diseases with undisputed disease-related benefits. Perinatal exposure to high levels of glucocorticoids can have long-term adverse cerebral effects. In adults, glucocorticoid treatment has been associated with smaller volumes of subcortical grey matter structures. Recently, we observed smaller total brain volumes in children and adolescents treated with glucocorticoid during childhood compared to healthy controls. The possible long-term effects of glucocorticoid treatment during childhood on subcortical brain volume and microstructure remain unknown. METHOD We examined 30 children and adolescents, who had previously been treated with glucocorticoids for nephrotic syndrome or rheumatic disease, and 30 healthy volunteers. Patients and healthy control groups were matched by age, gender, and level of parent education. Participants underwent 3 T magnetic resonance (MR) brain imaging. T1-weighted and diffusion-weighted images were acquired. Volume and mean diffusivity (MD) measures were extracted for hippocampus, amygdala, nucleus accumbens, caudate nucleus and putamen. Multiple linear regression analyses were used to assess differences between patients and controls, and to evaluate possible dose-response relationships. A priori, we expected patients to display lower hippocampal and amygdala volumes. RESULTS While children previously treated with glucocorticoids displayed smaller right hippocampal volumes than controls, this difference did not survive correction for multiple comparisons. Furthermore, patients as compared to controls showed lower right hippocampal MD, which remained when correcting for global changes in MD. The longer the time between the glucocorticoid treatment termination and MR-scan, the more right hippocampal MD values resembled that of healthy controls. Patient and controls did not differ in amygdala volume or MD. Analyses of the nucleus accumbens, caudate nucleus and putamen only revealed smaller putamen volumes in patients compared to controls, which remained significant when controlling for total brain volume. CONCLUSION The results suggest that extra-cerebral diseases during childhood treated with glucocorticoids may be associated with reduced subcortical grey matter volumes and lower right hippocampal mean diffusivity later in life. Our findings warrant replication and elaboration in larger, preferably prospective and longitudinal studies. Such studies may also allow disentangling disease-specific effects from possible glucocorticoid treatment effects.
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Affiliation(s)
- Sara Krøis Holm
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark; Department of Paediatrics and Adolescent Medicine, Neuropaediatric Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Kathrine Skak Madsen
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark; Radiography, Department of Technology, University College Copenhagen, Copenhagen, Denmark
| | - Martin Vestergaard
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark
| | - Alfred Peter Born
- Department of Paediatrics and Adolescent Medicine, Neuropaediatric Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Olaf B Paulson
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Hartwig Roman Siebner
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark; Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - Peter Uldall
- Department of Paediatrics and Adolescent Medicine, Neuropaediatric Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - William F C Baaré
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark.
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de Kloet ER, de Kloet SF, de Kloet CS, de Kloet AD. Top-down and bottom-up control of stress-coping. J Neuroendocrinol 2019; 31:e12675. [PMID: 30578574 PMCID: PMC6519262 DOI: 10.1111/jne.12675] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 12/12/2018] [Accepted: 12/12/2018] [Indexed: 12/17/2022]
Abstract
In this 30th anniversary issue review, we focus on the glucocorticoid modulation of limbic-prefrontocortical circuitry during stress-coping. This action of the stress hormone is mediated by mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) that are co-expressed abundantly in these higher brain regions. Via both receptor types, the glucocorticoids demonstrate, in various contexts, rapid nongenomic and slower genomic actions that coordinate consecutive stages of information processing. MR-mediated action optimises stress-coping, whereas, in a complementary fashion, the memory storage of the selected coping strategy is promoted via GR. We highlight the involvement of adipose tissue in the allocation of energy resources to central regulation of stress reactions, point to still poorly understood neuronal ensembles in the prefrontal cortex that underlie cognitive flexibility critical for effective coping, and evaluate the role of cortisol as a pleiotropic regulator in vulnerability to, and treatment of, trauma-related psychiatric disorders.
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Affiliation(s)
- Edo R. de Kloet
- Division of EndocrinologyDepartment of MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Sybren F. de Kloet
- Department of Integrative NeurophysiologyCenter for Neurogenomics and Cognitive ResearchVU‐University of AmsterdamAmsterdamThe Netherlands
| | | | - Annette D. de Kloet
- Department of Physiology and Functional GenomicsUniversity of FloridaGainesvilleFlorida
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Epigenetic and Neurological Impairments Associated with Early Life Exposure to Persistent Organic Pollutants. Int J Genomics 2019; 2019:2085496. [PMID: 30733955 PMCID: PMC6348822 DOI: 10.1155/2019/2085496] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 09/14/2018] [Accepted: 10/31/2018] [Indexed: 12/31/2022] Open
Abstract
The incidence of neurodevelopmental and neurodegenerative diseases worldwide has dramatically increased over the last decades. Although the aetiology remains uncertain, evidence is now growing that exposure to persistent organic pollutants during sensitive neurodevelopmental periods such as early life may be a strong risk factor, predisposing the individual to disease development later in life. Epidemiological studies have associated environmentally persistent organic pollutant exposure to brain disorders including neuropathies, cognitive, motor, and sensory impairments; neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD); and neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). In many ways, this expands the classical “Developmental Origins of Health and Disease” paradigm to include exposure to pollutants. This model has been refined over the years to give the current “three-hit” model that considers the individual's genetic factors as a first “hit.” It has an immediate interaction with the early-life exposome (including persistent organic pollutants) that can be considered to be a second “hit.” Together, these first two “hits” produce a quiescent or latent phenotype, most probably encoded in the epigenome, which has become susceptible to a third environmental “hit” in later life. It is only after the third “hit” that the increased risk of disease symptoms is crystallised. However, if the individual is exposed to a different environment in later life, they would be expected to remain healthy. In this review, we examine the effect of exposure to persistent organic pollutants and particulate matters in early life and the relationship to subsequent neurodevelopmental and neurodegenerative disorders. The roles of those environmental factors which may affect epigenetic DNA methylation and therefore influence normal neurodevelopment are then evaluated.
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Goncharova N, Chigarova O, Rudenko N, Oganyan T. Glucocorticoid Negative Feedback in Regulation of the Hypothalamic-Pituitary-Adrenal Axis in Rhesus Monkeys With Various Types of Adaptive Behavior: Individual and Age-Related Differences. Front Endocrinol (Lausanne) 2019; 10:24. [PMID: 30814974 PMCID: PMC6381009 DOI: 10.3389/fendo.2019.00024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 01/14/2019] [Indexed: 12/27/2022] Open
Abstract
The study of the mechanisms underlying the increased vulnerability of the individual to stressful environmental factors in different age periods is of great relevance for prevention and effective treatment of stress-dependent diseases that are widespread in the population of aging individuals. The purpose of our study was to investigate the individual and age-related features of the glucocorticoid negative feedback in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, the key adaptive neuroendocrine system, in experiments with physically healthy young and old female rhesus monkeys with administration of mineracorticoid receptor (fludrocortisone) and glucocorticoid receptor (dexamethasone) agonists. We studied the monkeys with increased trait anxiety and depression-like behavior (DAB) characterized, as previously was shown, by the increased vulnerability to acute stress and the animals with normal standard behavior (SB) as the control. The pronounced individual differences in the reaction of HPA axis to fludrocortisone and dexamethasone in young animals were found. Young animals with DAB showed a lower sensitivity of HPA axis to the inhibitory effect of both fludrocortisone and dexamethasone compared with young animals with SB. At the same time, there were no significant intergroup differences in the concentration of ACTH and cortisol in response to placebo injection, i.e., in basal conditions. The old individuals with DAB demonstrated the essential relative resistance of HPA axis to fludrocortisone test and higher basal plasma levels of cortisol and ACTH in the evening (the period of HPA axis low circadian activity) compared to old SB animals. In the same time, the intergroup differences in the response of HPA axis to dexamethasone administration were leveled due to age-related increase in sensitivity of HPA axis to dexamethasone in animals with DAB. These data testify the pronounced intergroup and age differences in the feedback regulation of HPA axis, presumably resulting from unequal individual, and age-related changes in the activity of mineralcorticoid and glucocorticoid receptors in the brain structures supporting the functions of HPA axis. The maximum age disorders in functioning of the negative feedback mechanism in the regulation of HPA axis are characteristic of animals with DAB, which, apparently, underlie the increased vulnerability of these animals to stress exposure.
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Brain Mineralocorticoid Receptors and Resilience to Stress. VITAMINS AND HORMONES 2019; 109:341-359. [DOI: 10.1016/bs.vh.2018.11.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/26/2023]
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Meijer OC, Buurstede JC, Schaaf MJM. Corticosteroid Receptors in the Brain: Transcriptional Mechanisms for Specificity and Context-Dependent Effects. Cell Mol Neurobiol 2018; 39:539-549. [PMID: 30291573 PMCID: PMC6469829 DOI: 10.1007/s10571-018-0625-2] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 09/25/2018] [Indexed: 12/22/2022]
Abstract
Corticosteroid hormones act in the brain to support adaptation to stress via binding to mineralocorticoid and glucocorticoid receptors (MR and GR). These receptors act in large measure as transcription factors. Corticosteroid effects can be highly divergent, depending on the receptor type, but also on brain region, cell type, and physiological context. These differences ultimately depend on differential interactions of MR and GR with other proteins, which determine ligand binding, nuclear translocation, and transcriptional activities. In this review, we discuss established and potential mechanisms that confer receptor and cell type-specific effects of the MR and GR-mediated transcriptional effects in the brain.
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Affiliation(s)
- Onno C Meijer
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. .,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
| | - J C Buurstede
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
| | - Marcel J M Schaaf
- Department of Animal Sciences and Health (M.J.M.S.), Institute of Biology, Leiden University, 2333 CC, Leiden, The Netherlands
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Ren H, Fabbri C, Uher R, Rietschel M, Mors O, Henigsberg N, Hauser J, Zobel A, Maier W, Dernovsek MZ, Souery D, Cattaneo A, Breen G, Craig IW, Farmer AE, McGuffin P, Lewis CM, Aitchison KJ. Genes associated with anhedonia: a new analysis in a large clinical trial (GENDEP). Transl Psychiatry 2018; 8:150. [PMID: 30104601 PMCID: PMC6089928 DOI: 10.1038/s41398-018-0198-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 02/17/2018] [Accepted: 03/26/2018] [Indexed: 12/14/2022] Open
Abstract
A key feature of major depressive disorder (MDD) is anhedonia, which is a predictor of response to antidepressant treatment. In order to shed light on its genetic underpinnings, we conducted a genome-wide association study (GWAS) followed by investigation of biological pathway enrichment using an anhedonia dimension for 759 patients with MDD in the GENDEP study. The GWAS identified 18 SNPs associated at genome-wide significance with the top one being an intronic SNP (rs9392549) in PRPF4B (pre-mRNA processing factor 4B) located on chromosome 6 (P = 2.07 × 10-9) while gene-set enrichment analysis returned one gene ontology term, axon cargo transport (GO: 0008088) with a nominally significant P value (1.15 × 10-5). Furthermore, our exploratory analysis yielded some interesting, albeit not statistically significant genetic correlation with Parkinson's Disease and nucleus accumbens gray matter. In addition, polygenic risk scores (PRSs) generated from our association analysis were found to be able to predict treatment efficacy of the antidepressants in this study. In conclusion, we found some markers significantly associated with anhedonia, and some suggestive findings of related pathways and biological functions, which could be further investigated in other studies.
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Affiliation(s)
- Hongyan Ren
- Psychiatry and Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Chiara Fabbri
- MRC Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK
| | - Rudolf Uher
- Psychiatry Department, Dalhousie University, Halifax, NS, Canada
| | - Marcella Rietschel
- Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany
| | - Ole Mors
- Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Neven Henigsberg
- Croatian Institute for Brain Research, University of Zagreb, Zagreb, Croatia
| | - Joanna Hauser
- Psychiatry Department, University of Poznan, Poznan, Poland
| | - Astrid Zobel
- Psychiatry Department, University of Bonn, Bonn, Germany
| | - Wolfgang Maier
- Psychiatry Department, University of Bonn, Bonn, Germany
| | - Mojca Z Dernovsek
- University Psychiatric Clinic, University of Ljubliana, Ljubljana, Slovenia
| | - Daniel Souery
- Psychological Medicine, Free University of Brussels, Brussels, Belgium
| | | | - Gerome Breen
- MRC Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK
| | - Ian W Craig
- MRC Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK
| | - Anne E Farmer
- MRC Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK
| | - Peter McGuffin
- MRC Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK
| | - Cathryn M Lewis
- MRC Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK
| | - Katherine J Aitchison
- Psychiatry and Medical Genetics, University of Alberta, Edmonton, AB, Canada.
- MRC Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
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Jiménez JP, Botto A, Herrera L, Leighton C, Rossi JL, Quevedo Y, Silva JR, Martínez F, Assar R, Salazar LA, Ortiz M, Ríos U, Barros P, Jaramillo K, Luyten P. Psychotherapy and Genetic Neuroscience: An Emerging Dialog. Front Genet 2018; 9:257. [PMID: 30065751 PMCID: PMC6056612 DOI: 10.3389/fgene.2018.00257] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 06/26/2018] [Indexed: 12/21/2022] Open
Abstract
Recent research in psychiatric genetics has led to a move away from simple diathesis-stress models to more complex models of psychopathology incorporating a focus on gene–environment interactions and epigenetics. Our increased understanding of the way biology encodes the impact of life events on organisms has also generated more sophisticated theoretical models concerning the molecular processes at the interface between “nature” and “nurture.” There is also increasing consensus that psychotherapy entails a specific type of learning in the context of an emotional relationship (i.e., the therapeutic relationship) that may also lead to epigenetic modifications across different therapeutic treatment modalities. This paper provides a systematic review of this emerging body of research. It is concluded that, although the evidence is still limited at this stage, extant research does indeed suggest that psychotherapy may be associated with epigenetic changes. Furthermore, it is argued that epigenetic studies may play a key role in the identification of biomarkers implicated in vulnerability for psychopathology, and thus may improve diagnosis and open up future research opportunities regarding the mechanism of action of psychotropic drugs as well as psychotherapy. We review evidence suggesting there may be important individual differences in susceptibility to environmental input, including psychotherapy. In addition, given that there is increasing evidence for the transgenerational transmission of epigenetic modifications in animals and humans exposed to trauma and adversity, epigenetic changes produced by psychotherapy may also potentially be passed on to the next generation, which opens up new perspective for prevention science. We conclude this paper stressing the limitations of current research and by proposing a set of recommendations for future research in this area.
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Affiliation(s)
- Juan P Jiménez
- Department of Psychiatry and Mental Health - East, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Alberto Botto
- Department of Psychiatry and Mental Health - East, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Luisa Herrera
- Human Genetics Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Caroline Leighton
- Department of Psychiatry and Mental Health - East, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - José L Rossi
- Department of Psychology, Faculty of Social Sciences, Universidad de Chile, Santiago, Chile
| | - Yamil Quevedo
- Department of Psychiatry and Mental Health - East, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Jaime R Silva
- Center for Attachment and Emotional Regulation (CARE), Faculty of Psychology, Universidad del Desarrollo, Santiago, Chile
| | - Felipe Martínez
- Center for Intercultural and Indigenous Research, Anthropology Program, Institute of Sociology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rodrigo Assar
- ICBM Human Genetics Program, Centre for Medical Informatics and Telemedicine, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Luis A Salazar
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile
| | - Manuel Ortiz
- Department of Psychology, Faculty of Education, Social Sciences and Humanities, Universidad de La Frontera, Temuco, Chile
| | - Ulises Ríos
- Department of Psychiatry, Universidad de Valparaíso, Valparaíso, Chile
| | - Paulina Barros
- Department of Psychiatry and Mental Health - East, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Karina Jaramillo
- Ph.D. Program in Public Health, School of Public Health, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Patrick Luyten
- Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium.,Research Department of Clinical, Educational and Health Psychology, University College London, London, United Kingdom
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Hacimusalar Y, Eşel E. Suggested Biomarkers for Major Depressive Disorder. ACTA ACUST UNITED AC 2018; 55:280-290. [PMID: 30224877 DOI: 10.5152/npa.2017.19482] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 06/08/2017] [Indexed: 12/21/2022]
Abstract
Currently, the diagnosis of major depressive disorder (MDD) mainly relies on clinical examination and subjective evaluation of depressive symptoms. There is no non-invasive, quantitative test available today for the diagnosis of MDD. In MDD, exploration of biomarkers will be helpful in diagnosing the disorder as well as in choosing a treatment, and predicting the treatment response. In this article, it is aimed to review the findings of suggested biomarkers such as growth factors, cytokines and other inflammatory markers, oxidative stress markers, endocrine markers, energy balance hormones, genetic and epigenetic features, and neuroimaging in MDD and to evaluate how these findings contribute to the pathophysiology of MDD, the prediction of treatment response, severity of the disorder, and identification of subtypes. Among these, the findings related to the brain-derived neurotrophic factor, the hypothalamo-pituitary-adrenal axis, cytokines, and neuroimaging may be strong candidates for being biomarkers MDD, and may provide critical information in understanding biological etiology of depression. Although the findings are not sufficient yet, we think that the results of epigenetic studies will also provide very important contributions to the biomarker research in MDD. The availability of biomarkers in MDD will be an advancement that will facilitate the diagnosis of the disorder, treatment choices in the early stages, and prediction of the course of the disorder.
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Affiliation(s)
- Yunus Hacimusalar
- Department of Psychiatry, Kayseri Training and Research Hospital, Kayseri, Turkey
| | - Ertuğrul Eşel
- Department of Psychiatry, Erciyes University Faculty of Medicine, Kayseri, Turkey
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40
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de Kloet ER, Meijer OC, de Nicola AF, de Rijk RH, Joëls M. Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation. Front Neuroendocrinol 2018; 49:124-145. [PMID: 29428549 DOI: 10.1016/j.yfrne.2018.02.003] [Citation(s) in RCA: 163] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 01/25/2018] [Accepted: 02/07/2018] [Indexed: 01/14/2023]
Abstract
Bruce McEwen's discovery of receptors for corticosterone in the rat hippocampus introduced higher brain circuits in the neuroendocrinology of stress. Subsequently, these receptors were identified as mineralocorticoid receptors (MRs) that are involved in appraisal processes, choice of coping style, encoding and retrieval. The MR-mediated actions on cognition are complemented by slower actions via glucocorticoid receptors (GRs) on contextualization, rationalization and memory storage of the experience. These sequential phases in cognitive performance depend on synaptic metaplasticity that is regulated by coordinate MR- and GR activation. The receptor activation includes recruitment of coregulators and transcription factors as determinants of context-dependent specificity in steroid action; they can be modulated by genetic variation and (early) experience. Interestingly, inflammatory responses to damage seem to be governed by a similarly balanced MR:GR-mediated action as the initiating, terminating and priming mechanisms involved in stress-adaptation. We conclude with five questions challenging the MR:GR balance hypothesis.
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Affiliation(s)
- E R de Kloet
- Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
| | - O C Meijer
- Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
| | - A F de Nicola
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina.
| | - R H de Rijk
- Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands & Department of Clinical Psychology, Leiden University, The Netherlands.
| | - M Joëls
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands; University of Groningen, University Medical Center Groningen, The Netherlands.
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41
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Shadrina M, Bondarenko EA, Slominsky PA. Genetics Factors in Major Depression Disease. Front Psychiatry 2018; 9:334. [PMID: 30083112 PMCID: PMC6065213 DOI: 10.3389/fpsyt.2018.00334] [Citation(s) in RCA: 152] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 07/02/2018] [Indexed: 12/22/2022] Open
Abstract
Depressive disorders (DDs) are one of the most widespread forms of psychiatric pathology. According to the World Health Organization, about 350 million people in the world are affected by this condition. Family and twin studies have demonstrated that the contribution of genetic factors to the risk of the onset of DDs is quite large. Various methodological approaches (analysis of candidate genes, genome-wide association analysis, genome-wide sequencing) have been used, and a large number of the associations between genes and different clinical DD variants and DD subphenotypes have been published. However, in most cases, these associations have not been confirmed in replication studies, and only a small number of genes have been proven to be associated with DD development risk. To ascertain the role of genetic factors in DD pathogenesis, further investigations of the relevant conditions are required. Special consideration should be given to the polygenic characteristics noted in whole-genome studies of the heritability of the disorder without a pronounced effect of the major gene. These observations accentuate the relevance of the analysis of gene-interaction roles in DD development and progression. It is important that association studies of the inherited variants of the genome should be supported by analysis of dynamic changes during DD progression. Epigenetic changes that cause modifications of a gene's functional state without changing its coding sequence are of primary interest. However, the opportunities for studying changes in the epigenome, transcriptome, and proteome during DD are limited by the nature of the disease and the need for brain tissue analysis, which is possible only postmortem. Therefore, any association studies between DD pathogenesis and epigenetic factors must be supplemented through the use of different animal models of depression. A threefold approach comprising the combination of gene association studies, assessment of the epigenetic state in DD patients, and analysis of different "omic" changes in animal depression models will make it possible to evaluate the contribution of genetic, epigenetic, and environmental factors to the development of different forms of depression and to help develop ways to decrease the risk of depression and improve the treatment of DD.
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Affiliation(s)
- Maria Shadrina
- Laboratory of Molecular Genetics of Hereditary Diseases, Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia
| | - Elena A Bondarenko
- Laboratory of Molecular Genetics of Hereditary Diseases, Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia
| | - Petr A Slominsky
- Laboratory of Molecular Genetics of Hereditary Diseases, Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia
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Joëls M, de Kloet ER. 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The brain mineralocorticoid receptor: a saga in three episodes. J Endocrinol 2017. [PMID: 28634266 DOI: 10.1530/joe-16-0660] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
In 1968, Bruce McEwen discovered that 3H-corticosterone administered to adrenalectomised rats is retained in neurons of hippocampus rather than those of hypothalamus. This discovery signalled the expansion of endocrinology into the science of higher brain regions. With this in mind, our contribution highlights the saga of the brain mineralocorticoid receptor (MR) in three episodes. First, the precloning era dominated by the conundrum of two types of corticosterone-binding receptors in the brain, which led to the identification of the high-affinity corticosterone receptor as the 'promiscuous' MR cloned in 1987 by Jeff Arriza and Ron Evans in addition to the classical glucocorticoid receptor (GR). Then, the post-cloning period aimed to disentangle the function of the brain MR from that of the closely related GR on different levels of biological complexity. Finally, the synthesis section that highlights the two faces of brain MR: Salt and Stress. 'Salt' refers to the regulation of salt appetite, and reciprocal arousal, motivation and reward, by a network of aldosterone-selective MR-expressing neurons projecting from nucleus tractus solitarii (NTS) and circumventricular organs. 'Stress' is about the limbic-forebrain nuclear and membrane MRs, which act as a switch in the selection of the best response to cope with a stressor. For this purpose, activation of the limbic MR promotes selective attention, memory retrieval and the appraisal process, while driving emotional expressions of fear and aggression. Subsequently, rising glucocorticoid concentrations activate GRs in limbic-forebrain circuitry underlying executive functions and memory storage, which contribute in balance with MR-mediated actions to homeostasis, excitability and behavioural adaptation.
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Affiliation(s)
- Marian Joëls
- Department of Translational NeuroscienceBrain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands
- University of GroningenUniversity Medical Center, Groningen, The Netherlands
| | - E Ronald de Kloet
- Division of EndocrinologyDepartment of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Kanatsou S, Karst H, Kortesidou D, van den Akker RA, den Blaauwen J, Harris AP, Seckl JR, Krugers HJ, Joels M. Overexpression of Mineralocorticoid Receptors in the Mouse Forebrain Partly Alleviates the Effects of Chronic Early Life Stress on Spatial Memory, Neurogenesis and Synaptic Function in the Dentate Gyrus. Front Cell Neurosci 2017; 11:132. [PMID: 28611594 PMCID: PMC5447008 DOI: 10.3389/fncel.2017.00132] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 04/19/2017] [Indexed: 11/13/2022] Open
Abstract
Evidence from human studies suggests that high expression of brain mineralocorticoid receptors (MR) may promote resilience against negative consequences of stress exposure, including childhood trauma. We examined, in mice, whether brain MR overexpression can alleviate the effects of chronic early life stress (ELS) on contextual memory formation under low and high stress conditions, and neurogenesis and synaptic function of dentate gyrus granular cells. Male mice were exposed to ELS by housing the dam with limited nesting and bedding material from postnatal day (PND) 2 to 9. We investigated the moderating role of MRs by using forebrain-specific transgenic MR overexpression (MR-tg) mice. Low-stress contextual (i.e., object relocation) memory formation was hampered by ELS in wildtype but not MR-tg mice. Anxiety like behavior and high-stress contextual (i.e., fear) memory formation were unaffected by ELS and/or MR expression level. At the cellular level, an interaction effect was observed between ELS and MR overexpression on the number of doublecortin-positive cells, with a significant difference between the wildtype ELS and MR-tg ELS groups. No interaction was found regarding Ki-67 and BrdU staining. A significant interaction between ELS and MR expression was further observed with regard to mEPSCs and mIPSC frequency. The ratio of evoked EPSC/IPSC or NMDA/AMPA responses was unaffected. Overall, these results suggest that ELS affects contextual memory formation under low stress conditions as well as neurogenesis and synaptic transmission in dentate granule cells, an effect that can be alleviated by MR-overexpression.
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Affiliation(s)
- Sofia Kanatsou
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center UtrechtUtrecht, Netherlands.,Swammerdam Institute for Life Sciences - Center for Neuroscience, University of AmsterdamAmsterdam, Netherlands
| | - Henk Karst
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center UtrechtUtrecht, Netherlands
| | - Despoina Kortesidou
- Swammerdam Institute for Life Sciences - Center for Neuroscience, University of AmsterdamAmsterdam, Netherlands
| | - Rachelle A van den Akker
- Swammerdam Institute for Life Sciences - Center for Neuroscience, University of AmsterdamAmsterdam, Netherlands
| | - Jan den Blaauwen
- Swammerdam Institute for Life Sciences - Center for Neuroscience, University of AmsterdamAmsterdam, Netherlands
| | - Anjanette P Harris
- Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of EdinburghEdinburgh, United Kingdom
| | - Jonathan R Seckl
- Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of EdinburghEdinburgh, United Kingdom
| | - Harm J Krugers
- Swammerdam Institute for Life Sciences - Center for Neuroscience, University of AmsterdamAmsterdam, Netherlands
| | - Marian Joels
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center UtrechtUtrecht, Netherlands.,University of Groningen, University Medical Center GroningenGroningen, Netherlands
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44
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Ebner K, Singewald N. Individual differences in stress susceptibility and stress inhibitory mechanisms. Curr Opin Behav Sci 2017. [DOI: 10.1016/j.cobeha.2016.11.016] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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45
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Sarubin N, Hilbert S, Naumann F, Zill P, Wimmer AM, Nothdurfter C, Rupprecht R, Baghai TC, Bühner M, Schüle C. The sex-dependent role of the glucocorticoid receptor in depression: variations in the NR3C1 gene are associated with major depressive disorder in women but not in men. Eur Arch Psychiatry Clin Neurosci 2017; 267:123-133. [PMID: 27549215 DOI: 10.1007/s00406-016-0722-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Accepted: 08/04/2016] [Indexed: 12/14/2022]
Abstract
Genetic variations in the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) have been associated with maladaptive stress responses and major depressive disorder (MDD). In a case-control study design, we examined whether single nucleotide polymorphisms (SNPs) and haploid genotype (haplotype) associations of MR gene NR3C2, GR gene NR3C1 and genes of GR chaperone molecules FK506 binding protein 5 (FKBP5) and corticotrophin-releasing hormone receptor 1 (CRHR1) differed between healthy subjects (n = 634) and inpatients with major depressive disorder (n = 412). All analyses were conducted for women and men separately. After conservative correction of Type-I-error to obtain reliable p values, one SNP in the NR3C1 gene, namely rs6195, showed a significant association with the presence of a major depression (p = 0.048) in females. In contrast, NR3C2, FKBP5 and CRHR1 polymorphisms were not significantly associated with MDD. No haplotype effects could be identified. Our results support the notion of an association between variants of GR-related genes in women and the pathophysiology of depression: females suffering from MDD showed a more than three times higher frequency of the T/C polymorphism compared to controls, which thus seems to increase the vulnerability to depression in females.
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Affiliation(s)
- Nina Sarubin
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, 80336, Munich, Germany.
- Department of Psychological Methodology and Assessment, Ludwig-Maximilians-University Munich, Munich, Germany.
- Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
- Hochschule Fresenius, University of Applied Sciences, Munich, Germany.
| | - Sven Hilbert
- Department of Psychological Methodology and Assessment, Ludwig-Maximilians-University Munich, Munich, Germany
- Faculty of Psychology, Educational Science and Sport Science, University of Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany
| | - Felix Naumann
- Department of Psychological Methodology and Assessment, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Peter Zill
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, 80336, Munich, Germany
| | - Anna-Maria Wimmer
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, 80336, Munich, Germany
| | - Caroline Nothdurfter
- Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany
| | - Rainer Rupprecht
- Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany
| | - Thomas C Baghai
- Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany
| | - Markus Bühner
- Department of Psychological Methodology and Assessment, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Cornelius Schüle
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, 80336, Munich, Germany
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46
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Krugers HJ, Arp JM, Xiong H, Kanatsou S, Lesuis SL, Korosi A, Joels M, Lucassen PJ. Early life adversity: Lasting consequences for emotional learning. Neurobiol Stress 2017; 6:14-21. [PMID: 28229105 PMCID: PMC5314442 DOI: 10.1016/j.ynstr.2016.11.005] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 11/22/2016] [Accepted: 11/23/2016] [Indexed: 02/02/2023] Open
Abstract
The early postnatal period is a highly sensitive time period for the developing brain, both in humans and rodents. During this time window, exposure to adverse experiences can lastingly impact cognitive and emotional development. In this review, we briefly discuss human and rodent studies investigating how exposure to adverse early life conditions - mainly related to quality of parental care - affects brain activity, brain structure, cognition and emotional responses later in life. We discuss the evidence that early life adversity hampers later hippocampal and prefrontal cortex functions, while increasing amygdala activity, and the sensitivity to stressors and emotional behavior later in life. Exposure to early life stress may thus on the one hand promote behavioral adaptation to potentially threatening conditions later in life -at the cost of contextual memory formation in less threatening situations- but may on the other hand also increase the sensitivity to develop stress-related and anxiety disorders in vulnerable individuals.
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Affiliation(s)
- Harm J. Krugers
- SILS-Center for Neuroscience, University of Amsterdam, The Netherlands
| | - J. Marit Arp
- SILS-Center for Neuroscience, University of Amsterdam, The Netherlands
| | - Hui Xiong
- SILS-Center for Neuroscience, University of Amsterdam, The Netherlands
| | - Sofia Kanatsou
- SILS-Center for Neuroscience, University of Amsterdam, The Netherlands
- Dept. Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands
| | - Sylvie L. Lesuis
- SILS-Center for Neuroscience, University of Amsterdam, The Netherlands
| | - Aniko Korosi
- SILS-Center for Neuroscience, University of Amsterdam, The Netherlands
| | - Marian Joels
- Dept. Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands
- University of Groningen, University Medical Center Groningen, The Netherlands
| | - Paul J. Lucassen
- SILS-Center for Neuroscience, University of Amsterdam, The Netherlands
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de Kloet ER, Joëls M. Brain mineralocorticoid receptor function in control of salt balance and stress-adaptation. Physiol Behav 2017; 178:13-20. [PMID: 28089704 DOI: 10.1016/j.physbeh.2016.12.045] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 12/14/2016] [Accepted: 12/20/2016] [Indexed: 12/13/2022]
Abstract
We will highlight in honor of Randall Sakai the peculiar characteristics of the brain mineralocorticoid receptor (MR) in its response pattern to the classical mineralocorticoid aldosterone and the naturally occurring glucocorticoids corticosterone and cortisol. Neurons in the nucleus tractus solitarii (NTS) and circumventricular organs express MR, which mediate selectively the action of aldosterone on salt appetite, sympathetic outflow and volume regulation. The MR-containing NTS neurons innervate limbic-forebrain circuits enabling aldosterone to also modulate reciprocally arousal, motivation, fear and reward. MR expressed in abundance in this limbic-forebrain circuitry, is target of cortisol and corticosterone in modulation of appraisal processes, memory performance and selection of coping strategy. Complementary to this role of limbic MR is the action mediated by the lower affinity glucocorticoid receptors (GR), which promote subsequently memory storage of the experience and facilitate behavioral adaptation. Current evidence supports the hypothesis that an imbalance between MR- and GR-mediated actions compromises resilience and adaptation to stress.
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Affiliation(s)
- Edo Ronald de Kloet
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
| | - Marian Joëls
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands; University of Groningen, University Medical Center Groningen, The Netherlands
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48
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Chen C, Nakagawa S, An Y, Ito K, Kitaichi Y, Kusumi I. The exercise-glucocorticoid paradox: How exercise is beneficial to cognition, mood, and the brain while increasing glucocorticoid levels. Front Neuroendocrinol 2017; 44:83-102. [PMID: 27956050 DOI: 10.1016/j.yfrne.2016.12.001] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 11/26/2016] [Accepted: 12/01/2016] [Indexed: 11/26/2022]
Abstract
Exercise is known to have beneficial effects on cognition, mood, and the brain. However, exercise also activates the hypothalamic-pituitary-adrenal axis and increases levels of the glucocorticoid cortisol (CORT). CORT, also known as the "stress hormone," is considered a mediator between chronic stress and depression and to link various cognitive deficits. Here, we review the evidence that shows that while both chronic stress and exercise elevate basal CORT levels leading to increased secretion of CORT, the former is detrimental to cognition/memory, mood/stress coping, and brain plasticity, while the latter is beneficial. We propose three preliminary answers to the exercise-CORT paradox. Importantly, the elevated CORT, through glucocorticoid receptors, functions to elevate dopamine in the medial prefrontal cortex under chronic exercise but not chronic stress, and the medial prefrontal dopamine is essential for active coping. Future inquiries may provide further insights to promote our understanding of this paradox.
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Affiliation(s)
- Chong Chen
- Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Shin Nakagawa
- Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
| | - Yan An
- Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Koki Ito
- Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Yuji Kitaichi
- Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Ichiro Kusumi
- Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
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49
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Hamstra DA, de Kloet ER, Tollenaar M, Verkuil B, Manai M, Putman P, Van der Does W. Mineralocorticoid receptor haplotype moderates the effects of oral contraceptives and menstrual cycle on emotional information processing. J Psychopharmacol 2016; 30:1054-61. [PMID: 27222270 DOI: 10.1177/0269881116647504] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
RATIONALE The processing of emotional information is affected by menstrual cycle phase and by the use of oral contraceptives (OCs). The stress hormone cortisol is known to affect emotional information processing via the limbic mineralocorticoid receptor (MR). OBJECTIVES We investigated in an exploratory study whether the MR-genotype moderates the effect of both OC-use and menstrual cycle phase on emotional cognition. METHODS Healthy premenopausal volunteers (n=93) of West-European descent completed a battery of emotional cognition tests. Forty-nine participants were OC users and 44 naturally cycling, 21 of whom were tested in the early follicular (EF) and 23 in the mid-luteal (ML) phase of the menstrual cycle. RESULTS In MR-haplotype 1/3 carriers, ML women gambled more than EF women when their risk to lose was relatively small. In MR-haplotype 2, ML women gambled more than EF women, regardless of their odds of winning. OC-users with MR-haplotype 1/3 recognised fewer facial expressions than ML women with MR-haplotype 1/3. CONCLUSION MR-haplotype 1/3 carriers may be more sensitive to the influence of their female hormonal status. MR-haplotype 2 carriers showed more risky decision-making. As this may reflect optimistic expectations, this finding may support previous observations in female carriers of MR-haplotype 2 in a naturalistic cohort study.
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Affiliation(s)
- Danielle A Hamstra
- Institute of Psychology, Leiden University, Leiden, the Netherlands Leiden Institute of Brain and Cognition, Leiden University, Leiden, the Netherlands
| | - E Ronald de Kloet
- Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
| | - Marieke Tollenaar
- Institute of Psychology, Leiden University, Leiden, the Netherlands Leiden Institute of Brain and Cognition, Leiden University, Leiden, the Netherlands
| | - Bart Verkuil
- Institute of Psychology, Leiden University, Leiden, the Netherlands Leiden Institute of Brain and Cognition, Leiden University, Leiden, the Netherlands
| | - Meriem Manai
- Institute of Psychology, Leiden University, Leiden, the Netherlands Leiden Institute of Brain and Cognition, Leiden University, Leiden, the Netherlands
| | - Peter Putman
- Institute of Psychology, Leiden University, Leiden, the Netherlands Leiden Institute of Brain and Cognition, Leiden University, Leiden, the Netherlands
| | - Willem Van der Does
- Institute of Psychology, Leiden University, Leiden, the Netherlands Leiden Institute of Brain and Cognition, Leiden University, Leiden, the Netherlands Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands
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50
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Schultebraucks K, Deuter CE, Duesenberg M, Schulze L, Hellmann-Regen J, Domke A, Lockenvitz L, Kuehl LK, Otte C, Wingenfeld K. Selective attention to emotional cues and emotion recognition in healthy subjects: the role of mineralocorticoid receptor stimulation. Psychopharmacology (Berl) 2016; 233:3405-15. [PMID: 27422567 DOI: 10.1007/s00213-016-4380-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 07/06/2016] [Indexed: 11/30/2022]
Abstract
RATIONALE Selective attention toward emotional cues and emotion recognition of facial expressions are important aspects of social cognition. Stress modulates social cognition through cortisol, which acts on glucocorticoid (GR) and mineralocorticoid receptors (MR) in the brain. OBJECTIVES We examined the role of MR activation on attentional bias toward emotional cues and on emotion recognition. METHODS We included 40 healthy young women and 40 healthy young men (mean age 23.9 ± 3.3), who either received 0.4 mg of the MR agonist fludrocortisone or placebo. A dot-probe paradigm was used to test for attentional biases toward emotional cues (happy and sad faces). Moreover, we used a facial emotion recognition task to investigate the ability to recognize emotional valence (anger and sadness) from facial expression in four graded categories of emotional intensity (20, 30, 40, and 80 %). RESULTS In the emotional dot-probe task, we found a main effect of treatment and a treatment × valence interaction. Post hoc analyses revealed an attentional bias away from sad faces after placebo intake and a shift in selective attention toward sad faces compared to placebo. We found no attentional bias toward happy faces after fludrocortisone or placebo intake. In the facial emotion recognition task, there was no main effect of treatment. CONCLUSIONS MR stimulation seems to be important in modulating quick, automatic emotional processing, i.e., a shift in selective attention toward negative emotional cues. Our results confirm and extend previous findings of MR function. However, we did not find an effect of MR stimulation on emotion recognition.
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Affiliation(s)
- Katharina Schultebraucks
- Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany.
| | - Christian E Deuter
- Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany
| | - Moritz Duesenberg
- Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany
| | - Lars Schulze
- Department of Clinical Psychology and Psychotherapy, Freie Universität Berlin, Berlin, Germany
| | - Julian Hellmann-Regen
- Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany
| | - Antonia Domke
- Department of Clinical Psychology and Psychotherapy, Freie Universität Berlin, Berlin, Germany
| | - Lisa Lockenvitz
- Department of Psychology, Universität Potsdam, Potsdam, Germany
| | - Linn K Kuehl
- Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany
| | - Christian Otte
- Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany
| | - Katja Wingenfeld
- Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany
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