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Tedla A, Asnakew S, Legas G, Beyene GM, Shiferaw K, Belete A, Birhan Z, Munie BM. Suicidal ideation among medical and surgical inpatients at South Gondar Public Hospitals, Northwest Ethiopia, 2023: a multicenter institution-based cross-sectional study. Eur Arch Psychiatry Clin Neurosci 2025:10.1007/s00406-025-01963-8. [PMID: 39903264 DOI: 10.1007/s00406-025-01963-8] [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] [Received: 09/25/2024] [Accepted: 01/16/2025] [Indexed: 02/06/2025]
Abstract
Suicide is a significant global public health issue impacting individuals, families, and communities across the world. People with medical and surgical conditions are at an elevated risk of experiencing suicidal thoughts. However, to the best of our knowledge, in Ethiopia, there has not been any published research that examines the magnitude and associated factors of suicidal ideation in this context. The objective of this study was to assess the prevalence of suicidal ideation among medical and surgically admitted patients in South Gondar public hospitals, Northwest Ethiopia, 2023. A multi-center institutional-based cross-sectional study was conducted in South Gondar public hospitals. A systematic random sampling technique was used to select 616 individuals with a response rate of 98.2%. Suicidal ideation was measured using the World Health Organization's Composite International Diagnostic Interview suicide module. Descriptive, bivariate, and multivariate binary logistic regressions were employed, with odds ratios and 95% confidence intervals. The significance of the association was determined with a p-value of less than 0.05. The prevalence of suicidal ideation in this study was 24.7% (95% CI: 20.8, 27.7). Poor life satisfaction (AOR = 2.64, 95% CI, 1.63, 4.3), poor social support (AOR: 3.38; 95% CI; 1.97, 5.8), being female (AOR: 1.98; 95% CI; 1.19, 3.3), depression (AOR: 2.67; 95% CI; 1.67, 4.22), prior suicidal ideation and/or attempt (AOR = 2.73, 95% CI; 1.47, 5.1), having high perceived threat (AOR = 3.0; 95% CI; 1.69, 5.29), and having poor sleep quality (AOR: 2.54; 95% CI 1.5, 4.25) were significantly associated with suicidal ideation at p-value < 0.05. The prevalence of suicidal ideation is notably high among patients hospitalized in surgical and medical wards. Effective screening, timely intervention, and enhanced support systems are essential for individuals, particularly for females, with poor social support, high perceived threat, prior suicidal ideation and/or attempt, poor sleep quality, depression, and low life satisfaction.
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Affiliation(s)
- Assasahegn Tedla
- Department of Psychiatry, School of Medicine, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia.
| | - Sintayehu Asnakew
- Department of Psychiatry, School of Medicine, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Getasew Legas
- Department of Psychiatry, School of Medicine, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Getnet Mihretie Beyene
- Department of Psychiatry, School of Medicine, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Kirubel Shiferaw
- Department of Psychiatry, School of Medicine, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Amsalu Belete
- Department of Psychiatry, School of Medicine, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Zelalem Birhan
- Department of Psychiatry, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
| | - Birhanu Mengist Munie
- Department of Psychiatry, School of Medicine, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
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Alabdali R, Franchini L, Orlandi C. G α Protein Signaling Bias at Serotonin 1A Receptor. Mol Pharmacol 2023; 104:230-238. [PMID: 37567783 PMCID: PMC10586511 DOI: 10.1124/molpharm.123.000722] [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: 05/18/2023] [Revised: 07/11/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Serotonin 1A receptor (5-HT1AR) is a clinically relevant target because of its involvement in several central and peripheral functions, including sleep, temperature homeostasis, processing of emotions, and response to stress. As a G protein coupled receptor (GPCR) activating numerous Gα i/o/z family members, 5-HT1AR can potentially modulate multiple intracellular signaling pathways in response to different therapeutics. Here, we applied a cell-based bioluminescence resonance energy transfer assay to quantify how ten structurally diverse 5-HT1AR agonists exert biased signaling by differentially stimulating Gα i/o/z family members. Our concentration-response analysis of the activation of each Gα i/o/z protein revealed unique potency and efficacy profiles of selected agonists when compared with the reference 5-hydroxytryptamine, serotonin. Overall, our analysis of signaling bias identified groups of ligands sharing comparable G protein activation selectivity and also drugs with unique selectivity profiles. We observed, for example, a strong bias of F-15599 toward the activation of Gα i3 that was unique among the agonists tested: we found a biased factor of +2.19 when comparing the activation of Gα i3 versus Gα i2 by F-15599, while it was -0.29 for 8-hydroxy-2-(di-n-propylamino) tetralin. Similarly, vortioxetine showed a biased factor of +1.06 for Gα z versus Gα oA, while it was -1.38 for vilazodone. Considering that alternative signaling pathways are regulated downstream of each Gα protein, our data suggest that the unique pharmacological properties of the tested agonists could result in multiple unrelated cellular outcomes. Further investigation is needed to reveal how this type of ligand bias could affect cellular responses and to illuminate the molecular mechanisms underlying therapeutic profile and side effects of each drug. SIGNIFICANCE STATEMENT: Serotonin 1a receptor (5-HT1AR) activates several members of the Gi/o/z protein family. Here, we examined ten structurally diverse and clinically relevant agonists acting on 5-HT1AR and identified distinctive bias patterns among G proteins. Considering the diversity of their intracellular effectors and signaling properties, this data reveal novel mechanisms underlying both therapeutic and undesirable effects.
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Affiliation(s)
- Rana Alabdali
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY
| | - Luca Franchini
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY
| | - Cesare Orlandi
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY
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Benhadda A, Delhaye C, Moutkine I, Marques X, Russeau M, Le Magueresse C, Roumier A, Lévi S, Maroteaux L. 5-HT 1A and 5-HT 2B receptor interaction and co-clustering regulate serotonergic neuron excitability. iScience 2023; 26:107401. [PMID: 37575185 PMCID: PMC10415917 DOI: 10.1016/j.isci.2023.107401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/26/2023] [Accepted: 07/12/2023] [Indexed: 08/15/2023] Open
Abstract
Many psychiatric diseases have been associated with serotonin (5-HT) neuron dysfunction. The firing of 5-HT neurons is known to be under 5-HT1A receptor-mediated autoinhibition, but functional consequences of coexpressed receptors are unknown. Using co-immunoprecipitation, BRET, confocal, and super-resolution microscopy in hippocampal and 5-HT neurons, we present evidence that 5-HT1A and 5-HT2B receptors can form heterodimers and co-cluster at the plasma membrane of dendrites. Selective agonist stimulation of coexpressed 5-HT1A and 5-HT2B receptors prevents 5-HT1A receptor internalization and increases 5-HT2B receptor membrane clustering. Current clamp recordings of 5-HT neurons revealed that 5-HT1A receptor stimulation of acute slices from mice lacking 5-HT2B receptors in 5-HT neurons increased their firing activity trough Ca2+-activated potassium channel inhibition compared to 5-HT neurons from control mice. This work supports the hypothesis that the relative expression of 5-HT1A and 5-HT2B receptors tunes the neuronal excitability of serotonergic neurons through potassium channel regulation.
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Affiliation(s)
- Amina Benhadda
- Institut du Fer à Moulin, U1270 INSERM, Sorbonne Université, 17 rue du Fer à Moulin, 75005 Paris, France
| | - Célia Delhaye
- Institut du Fer à Moulin, U1270 INSERM, Sorbonne Université, 17 rue du Fer à Moulin, 75005 Paris, France
| | - Imane Moutkine
- Institut du Fer à Moulin, U1270 INSERM, Sorbonne Université, 17 rue du Fer à Moulin, 75005 Paris, France
| | - Xavier Marques
- Institut du Fer à Moulin, U1270 INSERM, Sorbonne Université, 17 rue du Fer à Moulin, 75005 Paris, France
| | - Marion Russeau
- Institut du Fer à Moulin, U1270 INSERM, Sorbonne Université, 17 rue du Fer à Moulin, 75005 Paris, France
| | - Corentin Le Magueresse
- Institut du Fer à Moulin, U1270 INSERM, Sorbonne Université, 17 rue du Fer à Moulin, 75005 Paris, France
| | - Anne Roumier
- Institut du Fer à Moulin, U1270 INSERM, Sorbonne Université, 17 rue du Fer à Moulin, 75005 Paris, France
| | - Sabine Lévi
- Institut du Fer à Moulin, U1270 INSERM, Sorbonne Université, 17 rue du Fer à Moulin, 75005 Paris, France
| | - Luc Maroteaux
- Institut du Fer à Moulin, U1270 INSERM, Sorbonne Université, 17 rue du Fer à Moulin, 75005 Paris, France
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4
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Plausible Role of Stem Cell Types for Treating and Understanding the Pathophysiology of Depression. Pharmaceutics 2023; 15:pharmaceutics15030814. [PMID: 36986674 PMCID: PMC10058940 DOI: 10.3390/pharmaceutics15030814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/09/2023] [Accepted: 02/17/2023] [Indexed: 03/06/2023] Open
Abstract
Major Depressive Disorder (MDD), colloquially known as depression, is a debilitating condition affecting an estimated 3.8% of the population globally, of which 5.0% are adults and 5.7% are above the age of 60. MDD is differentiated from common mood changes and short-lived emotional responses due to subtle alterations in gray and white matter, including the frontal lobe, hippocampus, temporal lobe, thalamus, striatum, and amygdala. It can be detrimental to a person’s overall health if it occurs with moderate or severe intensity. It can render a person suffering terribly to perform inadequately in their personal, professional, and social lives. Depression, at its peak, can lead to suicidal thoughts and ideation. Antidepressants manage clinical depression and function by modulating the serotonin, norepinephrine, and dopamine neurotransmitter levels in the brain. Patients with MDD positively respond to antidepressants, but 10–30% do not recuperate or have a partial response accompanied by poor life quality, suicidal ideation, self-injurious behavior, and an increased relapse rate. Recent research shows that mesenchymal stem cells and iPSCs may be responsible for lowering depression by producing more neurons with increased cortical connections. This narrative review discusses the plausible functions of various stem cell types in treating and understanding depression pathophysiology.
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Bassil K, Krontira AC, Leroy T, Escoto AIH, Snijders C, Pernia CD, Pasterkamp RJ, de Nijs L, van den Hove D, Kenis G, Boks MP, Vadodaria K, Daskalakis NP, Binder EB, Rutten BPF. In vitro modeling of the neurobiological effects of glucocorticoids: A review. Neurobiol Stress 2023; 23:100530. [PMID: 36891528 PMCID: PMC9986648 DOI: 10.1016/j.ynstr.2023.100530] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 02/15/2023] [Accepted: 02/16/2023] [Indexed: 02/25/2023] Open
Abstract
Hypothalamic-pituitary adrenal (HPA)axis dysregulation has long been implicated in stress-related disorders such as major depression and post-traumatic stress disorder. Glucocorticoids (GCs) are released from the adrenal glands as a result of HPA-axis activation. The release of GCs is implicated with several neurobiological changes that are associated with negative consequences of chronic stress and the onset and course of psychiatric disorders. Investigating the underlying neurobiological effects of GCs may help to better understand the pathophysiology of stress-related psychiatric disorders. GCs impact a plethora of neuronal processes at the genetic, epigenetic, cellular, and molecular levels. Given the scarcity and difficulty in accessing human brain samples, 2D and 3D in vitro neuronal cultures are becoming increasingly useful in studying GC effects. In this review, we provide an overview of in vitro studies investigating the effects of GCs on key neuronal processes such as proliferation and survival of progenitor cells, neurogenesis, synaptic plasticity, neuronal activity, inflammation, genetic vulnerability, and epigenetic alterations. Finally, we discuss the challenges in the field and offer suggestions for improving the use of in vitro models to investigate GC effects.
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Affiliation(s)
- Katherine Bassil
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Anthi C Krontira
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.,International Max Planck Research School for Translational Psychiatry, Munich, Germany
| | - Thomas Leroy
- Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium
| | - Alana I H Escoto
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Clara Snijders
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA
| | - Cameron D Pernia
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA
| | - R Jeroen Pasterkamp
- Department of Translational Neuroscience, University Medical Center (UMC) Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands
| | - Laurence de Nijs
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Daniel van den Hove
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Gunter Kenis
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Marco P Boks
- Psychiatry, UMC Utrecht Brain Center, Utrecht, the Netherlands
| | - Krishna Vadodaria
- Salk Institute for Biological Studies, La Jolla, San Diego, United States
| | | | - Elisabeth B Binder
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.,International Max Planck Research School for Translational Psychiatry, Munich, Germany
| | - Bart P F Rutten
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
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6
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Dorsal raphe serotonergic neurons preferentially reactivate dorsal dentate gyrus cell ensembles associated with positive experience. Cell Rep 2023; 42:112149. [PMID: 36821440 DOI: 10.1016/j.celrep.2023.112149] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 11/24/2022] [Accepted: 02/06/2023] [Indexed: 02/24/2023] Open
Abstract
Major depressive disorder (MDD) is among the most common mental illnesses. Serotonergic (5-HT) neurons are central to the pathophysiology and treatment of MDD. Repeatedly recalling positive episodes is effective for MDD. Stimulating 5-HT neurons of the dorsal raphe nucleus (DRN) or neuronal ensembles in the dorsal dentate gyrus (dDG) associated with positive memories reverses the stress-induced behavioral abnormalities. Despite this phenotypic similarity, their causal relationship is unclear. This study revealed that the DRN 5-HT neurons activate dDG neurons; surprisingly, this activation was specifically observed in positive memory ensembles rather than neutral or negative ensembles. Furthermore, we revealed that dopaminergic signaling induced by activation of DRN 5-HT neurons projecting to the ventral tegmental area mediates an increase in active coping behavior and positive dDG ensemble reactivation. Our study identifies a role of DRN 5-HT neurons as specific reactivators of positive memories and provides insights into how serotonin elicits antidepressive effects.
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Zhang Y, Huang CC, Zhao J, Liu Y, Xia M, Wang X, Wei D, Chen Y, Liu B, Zheng Y, Wu Y, Chen T, Cheng Y, Xu X, Gong Q, Si T, Qiu S, Cheng J, Tang Y, Wang F, Qiu J, Xie P, Li L, He Y, Lin CP, Zac Lo CY. Resting-state functional connectivity of the raphe nuclei in major depressive Disorder: A Multi-site study. Neuroimage Clin 2023; 37:103359. [PMID: 36878150 PMCID: PMC9999207 DOI: 10.1016/j.nicl.2023.103359] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 11/06/2022] [Accepted: 02/20/2023] [Indexed: 03/06/2023]
Abstract
Accumulating evidence showed that major depressive disorder (MDD) is characterized by a dysfunction of serotonin neurotransmission. Raphe nuclei are the sources of most serotonergic neurons that project throughout the brain. Incorporating measurements of activity within the raphe nuclei into the analysis of connectivity characteristics may contribute to understanding how neurotransmitter synthesized centers are involved in thepathogenesisof MDD. Here, we analyzed the resting-state functional magnetic resonance imaging (RS-fMRI) dataset from 1,148 MDD patients and 1,079 healthy individuals recruited across nine centers. A seed-based analysis with the dorsal raphe and median raphe nuclei was performed to explore the functional connectivity (FC) alterations. Compared to controls, for dorsal raphe, the significantly decreased FC linking with the right precuneus and median cingulate cortex were found; for median raphe, the increased FC linking with right superior cerebellum (lobules V/VI) was found in MDD patients. In further exploratory analyzes, MDD-related connectivity alterations in dorsal and median raphe nuclei in different clinical factors remained highly similar to the main findings, indicating these abnormal connectivities are a disease-related alteration. Our study highlights a functional dysconnection pattern of raphe nuclei in MDD with multi-site big data. These findings help improve our understanding of the pathophysiology of depression and provide evidence of the theoretical foundation for the development of novel pharmacotherapies.
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Affiliation(s)
- Yajuan Zhang
- Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China; School of Biomedical Engineering, ShanghaiTech University, Shanghai, China
| | - Chu-Chung Huang
- Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Affiliated Mental Health Center (ECNU), School of Psychology and Cognitive Science, East China Normal University, Shanghai, China; Shanghai Changning Mental Health Center, Shanghai, China.
| | - Jiajia Zhao
- Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China
| | - Yuchen Liu
- Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China
| | - Mingrui Xia
- State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China; Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China; IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China
| | - Xiaoqin Wang
- Key Laboratory of Cognition and Personality (SWU), Ministry of Education, Chongqing, China; Department of Psychology, Southwest University, Chongqing, China
| | - Dongtao Wei
- Key Laboratory of Cognition and Personality (SWU), Ministry of Education, Chongqing, China; Department of Psychology, Southwest University, Chongqing, China
| | - Yuan Chen
- Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bangshan Liu
- Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Mental Health Institute of Central South University, China National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Hunan Medical Center for Mental Health, Changsha, Hunan, China
| | - Yanting Zheng
- Department of Radiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yankun Wu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Taolin Chen
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu, China; Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, Sichuan, China
| | - Yuqi Cheng
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xiufeng Xu
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qiyong Gong
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu, China; Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, Sichuan, China
| | - Tianmei Si
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Shijun Qiu
- Department of Radiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingliang Cheng
- Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanqing Tang
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Fei Wang
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jiang Qiu
- Key Laboratory of Cognition and Personality (SWU), Ministry of Education, Chongqing, China; Department of Psychology, Southwest University, Chongqing, China
| | - Peng Xie
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Neurobiology, Chongqing, China
| | - Lingjiang Li
- Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Mental Health Institute of Central South University, China National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Hunan Medical Center for Mental Health, Changsha, Hunan, China
| | - Yong He
- State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China; Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China; IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China; Institute for Brain Research, Beijing, China
| | - Ching-Po Lin
- Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | | | - Chun-Yi Zac Lo
- Department of Biomedical Engineering, Chung Yuan Christian University, Taoyuan, 32023, Taiwan.
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Xu C, Su L, Qiu N, Hou M, Yu F, Zou X, Wang J. The Effect of Unpredictable Chronic Stress on Rare Minnow ( Gobiocypris rarus): Growth, Behaviour and Physiology. BIOLOGY 2022; 11:1755. [PMID: 36552265 PMCID: PMC9775413 DOI: 10.3390/biology11121755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/28/2022] [Accepted: 11/30/2022] [Indexed: 12/05/2022]
Abstract
Fishes often adjust their behaviour patterns and physiological responses to cope with changing environments, and different life experiences affect them differently. Fishes might adapt to short-term stress, whereas long-term unpredictable stress may lead to various adverse effects. Although some studies have constructed unpredictable stress models of fish, the effect of unpredictable chronic stress (UCS) in the laboratory is poorly understood in fishes. In the current study, we exposed adult rare minnow to an unpredictable chronic stress protocol over 7 and 14 days and measured their response in terms of growth performance, cortisol, neurotransmitter levels (DA, 5-HT, and related metabolites), and behaviour patterns to comprehensively assess the effects of UCS on laboratory rare minnow. We discovered that specific growth rates were significantly decreased, and cortisol levels were lowered in both 7-days and 14-days stress groups. In the behaviour test, the activity level of the 14-days stress group increased, but there was no significant difference in the number of crossings to the center areas, time spent in the center areas, or the speed. In addition, the levels of DA and 5-HT did not change in the stress groups, but the DOPAC and 5-HIAA levels in the 14 days stress group were significantly higher than those in the control group. These results suggested that UCS influences rare minnow growth performance, behaviour patterns, and cortisol levels, and similar stress should be minimised in the laboratory.
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Affiliation(s)
- Chunsen Xu
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Liangxia Su
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Ning Qiu
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Miaomiao Hou
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fandong Yu
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xinhua Zou
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianwei Wang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- National Aquatic Biological Resource Center, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430070, China
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Claudio A, Andrea F. Circadian neuromarkers of mood disorders. JOURNAL OF AFFECTIVE DISORDERS REPORTS 2022. [DOI: 10.1016/j.jadr.2022.100384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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10
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Zhao Q, Pan W, Shi H, Qi F, Liu Y, Yang T, Si H, Si G. Network pharmacology and molecular docking analysis on the mechanism of Baihe Zhimu decoction in the treatment of postpartum depression. Medicine (Baltimore) 2022; 101:e29323. [PMID: 36316904 PMCID: PMC9622608 DOI: 10.1097/md.0000000000029323] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Baihe Zhimu decoction (BZD) has significant antidepressant properties and is widely used to treat mental diseases. However, the multitarget mechanism of BZD in postpartum depression (PPD) remains to be elucidated. Therefore, the aim of this study was to explore the molecular mechanisms of BDZ in treating PPD using network pharmacology and molecular docking. Active components and their target proteins were screened from the traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The PPD-related targets were obtained from the OMIM, CTD, and GeneCards databases. After overlap, the targets of BZD against PPD were collected. Protein-protein interaction (PPI) network and core target analyses were conducted using the STRING network platform and Cytoscape software. Moreover, molecular docking methods were used to confirm the high affinity between BZD and targets. Finally, the DAVID online tool was used to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of overlapping targets. The TCMSP database showed that BZD contained 23 active ingredients in PPD. KEGG analysis showed that overlapping genes were mainly enriched in HIF-1, dopaminergic synapses, estrogen, and serotonergic synaptic signalling pathways. Combining the PPI network and KEGG enrichment analysis, we found that ESR1, MAOA, NR3C1, VEGFA, and mTOR were the key targets of PPD. In addition, molecular docking confirmed the high affinity between BZD and the PPD target. Verified by a network pharmacology approach based on data mining and molecular docking methods, the multi-target drug BZD may serve as a promising therapeutic candidate for PPD, but further in vivo/in vitro experiments are needed.
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Affiliation(s)
- Qiong Zhao
- School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Wengu Pan
- Department of Kidney transplantation, The second hospital of Shandong University, Jinan, China
| | - Hongshuo Shi
- School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fanghua Qi
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Yuan Liu
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Tiantian Yang
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Hao Si
- Ai Kunwei Pharmaceutical Technology Co, Ltd, Shanghai, China
| | - Guomin Si
- School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- *Correspondence: Guomin Si, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China (e-mail: )
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11
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Stoliker D, Egan GF, Friston KJ, Razi A. Neural Mechanisms and Psychology of Psychedelic Ego Dissolution. Pharmacol Rev 2022; 74:876-917. [PMID: 36786290 DOI: 10.1124/pharmrev.121.000508] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 06/26/2022] [Accepted: 06/29/2022] [Indexed: 11/22/2022] Open
Abstract
Neuroimaging studies of psychedelics have advanced our understanding of hierarchical brain organization and the mechanisms underlying their subjective and therapeutic effects. The primary mechanism of action of classic psychedelics is binding to serotonergic 5-HT2A receptors. Agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy that can have a profound effect on hierarchical message-passing in the brain. Here, we review the cognitive and neuroimaging evidence for the effects of psychedelics: in particular, their influence on selfhood and subject-object boundaries-known as ego dissolution-surmised to underwrite their subjective and therapeutic effects. Agonism of 5-HT2A receptors, located at the apex of the cortical hierarchy, may have a particularly powerful effect on sentience and consciousness. These effects can endure well after the pharmacological half-life, suggesting that psychedelics may have effects on neural plasticity that may play a role in their therapeutic efficacy. Psychologically, this may be accompanied by a disarming of ego resistance that increases the repertoire of perceptual hypotheses and affords alternate pathways for thought and behavior, including those that undergird selfhood. We consider the interaction between serotonergic neuromodulation and sentience through the lens of hierarchical predictive coding, which speaks to the value of psychedelics in understanding how we make sense of the world and specific predictions about effective connectivity in cortical hierarchies that can be tested using functional neuroimaging. SIGNIFICANCE STATEMENT: Classic psychedelics bind to serotonergic 5-HT2A receptors. Their agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy, resulting in a profound effect on information processing in the brain. Here, we synthesize an abundance of brain imaging research with pharmacological and psychological interpretations informed by the framework of predictive coding. Moreover, predictive coding is suggested to offer more sophisticated interpretations of neuroimaging findings by bridging the role between the 5-HT2A receptors and large-scale brain networks.
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Affiliation(s)
- Devon Stoliker
- Turner Institute for Brain and Mental Health (D.S., G.F.E., A.R.) and Monash Biomedical Imaging (G.F.E., A.R.), Monash University, Clayton, Victoria, Australia; Wellcome Centre for Human Neuroimaging, UCL, London, United Kingdom (K.J.F., A.R.); and CIFAR Azrieli Global Scholar, CIFAR, Toronto, Canada (A.R.)
| | - Gary F Egan
- Turner Institute for Brain and Mental Health (D.S., G.F.E., A.R.) and Monash Biomedical Imaging (G.F.E., A.R.), Monash University, Clayton, Victoria, Australia; Wellcome Centre for Human Neuroimaging, UCL, London, United Kingdom (K.J.F., A.R.); and CIFAR Azrieli Global Scholar, CIFAR, Toronto, Canada (A.R.)
| | - Karl J Friston
- Turner Institute for Brain and Mental Health (D.S., G.F.E., A.R.) and Monash Biomedical Imaging (G.F.E., A.R.), Monash University, Clayton, Victoria, Australia; Wellcome Centre for Human Neuroimaging, UCL, London, United Kingdom (K.J.F., A.R.); and CIFAR Azrieli Global Scholar, CIFAR, Toronto, Canada (A.R.)
| | - Adeel Razi
- Turner Institute for Brain and Mental Health (D.S., G.F.E., A.R.) and Monash Biomedical Imaging (G.F.E., A.R.), Monash University, Clayton, Victoria, Australia; Wellcome Centre for Human Neuroimaging, UCL, London, United Kingdom (K.J.F., A.R.); and CIFAR Azrieli Global Scholar, CIFAR, Toronto, Canada (A.R.)
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12
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Hilz EN, Gore AC. Sex-specific Effects of Endocrine-disrupting Chemicals on Brain Monoamines and Cognitive Behavior. Endocrinology 2022; 163:bqac128. [PMID: 35939362 PMCID: PMC9419695 DOI: 10.1210/endocr/bqac128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Indexed: 11/19/2022]
Abstract
The period of brain sexual differentiation is characterized by the development of hormone-sensitive neural circuits that govern the subsequent presentation of sexually dimorphic behavior in adulthood. Perturbations of hormones by endocrine-disrupting chemicals (EDCs) during this developmental period interfere with an organism's endocrine function and can disrupt the normative organization of male- or female-typical neural circuitry. This is well characterized for reproductive and social behaviors and their underlying circuitry in the hypothalamus and other limbic regions of the brain; however, cognitive behaviors are also sexually dimorphic, with their underlying neural circuitry potentially vulnerable to EDC exposure during critical periods of brain development. This review provides recent evidence for sex-specific changes to the brain's monoaminergic systems (dopamine, serotonin, norepinephrine) after developmental EDC exposure and relates these outcomes to sex differences in cognition such as affective, attentional, and learning/memory behaviors.
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Affiliation(s)
- Emily N Hilz
- Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, Texas, 78712, USA
| | - Andrea C Gore
- Correspondence: Andrea C. Gore, PhD, College of Pharmacy, The University of Texas at Austin, 107 W Dean Keeton St, Box C0875, Austin, TX, 78712, USA.
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13
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Jeoung SW, Park HS, Ryoo ZY, Cho DH, Lee HS, Ryu HY. SUMOylation and Major Depressive Disorder. Int J Mol Sci 2022; 23:8023. [PMID: 35887370 PMCID: PMC9316168 DOI: 10.3390/ijms23148023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/19/2022] [Accepted: 07/19/2022] [Indexed: 12/04/2022] Open
Abstract
Since the discovery of the small ubiquitin-like modifier (SUMO) protein in 1995, SUMOylation has been considered a crucial post-translational modification in diverse cellular functions. In neurons, SUMOylation has various roles ranging from managing synaptic transmitter release to maintaining mitochondrial integrity and determining neuronal health. It has been discovered that neuronal dysfunction is a key factor in the development of major depressive disorder (MDD). PubMed and Google Scholar databases were searched with keywords such as 'SUMO', 'neuronal plasticity', and 'depression' to obtain relevant scientific literature. Here, we provide an overview of recent studies demonstrating the role of SUMOylation in maintaining neuronal function in participants suffering from MDD.
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Affiliation(s)
- Seok-Won Jeoung
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, College of National Sciences, Kyungpook National University, Daegu 41566, Korea; (S.-W.J.); (Z.Y.R.); (D.-H.C.); (H.-S.L.)
- Brain Science and Engineering Institute, Kyungpook National University, Daegu 41566, Korea
| | - Hyun-Sun Park
- Department of Biochemistry, Inje University College of Medicine, Busan 50834, Korea;
| | - Zae Young Ryoo
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, College of National Sciences, Kyungpook National University, Daegu 41566, Korea; (S.-W.J.); (Z.Y.R.); (D.-H.C.); (H.-S.L.)
| | - Dong-Hyung Cho
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, College of National Sciences, Kyungpook National University, Daegu 41566, Korea; (S.-W.J.); (Z.Y.R.); (D.-H.C.); (H.-S.L.)
| | - Hyun-Shik Lee
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, College of National Sciences, Kyungpook National University, Daegu 41566, Korea; (S.-W.J.); (Z.Y.R.); (D.-H.C.); (H.-S.L.)
| | - Hong-Yeoul Ryu
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, College of National Sciences, Kyungpook National University, Daegu 41566, Korea; (S.-W.J.); (Z.Y.R.); (D.-H.C.); (H.-S.L.)
- Brain Science and Engineering Institute, Kyungpook National University, Daegu 41566, Korea
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14
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Karimi R, Mallah N, Nedjat S, Beasley MJ, Takkouche B. Association between alcohol consumption and chronic pain: a systematic review and meta-analysis. Br J Anaesth 2022; 129:355-365. [DOI: 10.1016/j.bja.2022.03.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/27/2022] [Accepted: 03/10/2022] [Indexed: 12/20/2022] Open
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15
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Marks RB, Wee JY, Jacobson SV, Hashimoto K, O’Connell KL, Golden SA, Baker PM, Law KC. The Role of the Lateral Habenula in Suicide: A Call for Further Exploration. Front Behav Neurosci 2022; 16:812952. [PMID: 35359586 PMCID: PMC8964288 DOI: 10.3389/fnbeh.2022.812952] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/15/2022] [Indexed: 11/29/2022] Open
Abstract
Despite decades of significant effort in research, policy, and prevention, suicide rates have continued to rise to the current peak of 14.6 per 100,000 deaths. This has resulted in a concerted effort to identify biomarkers associated with suicidal behavior in the brain, to provide predictions that are better than the chance of discerning who will die by suicide. We propose that the lateral habenula (LHb), and its dysfunction during a suicidal crisis, is a critical component of the transition from suicidal ideations to self-harm. Moreover, the LHb—a key functional node in brain reward circuitry—has not been ascribed a contributory role in suicidal behavior. We argue that the LHb anchors a “suicide circuit” and call for suicide researchers to directly examine the role of the LHb, and its long-term modulation, in response to the negative affect in suicidal behavior. Discerning the neural mechanisms of this contribution will require the collaboration of neuroscientists and psychologists. Consequently, we highlight and discuss research on LHb as it relates to suicidal ideation, suicidal behavior, or death by suicide. In so doing we hope to address the bench-to-bedside translational issues currently involved in suicide research and suggest a developmental framework that focuses on specific structures motivated by theoretical anchors as a way to incorporate neurobiological findings within the context of clinical theory.
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Affiliation(s)
- Rocky B. Marks
- Department of Clinical Psychology, Seattle Pacific University, Seattle, WA, United States
- Correspondence: Rocky B. Marks Keyne Catherine Law
| | - Janelle Y. Wee
- Department of Clinical Psychology, Seattle Pacific University, Seattle, WA, United States
| | - Samantha V. Jacobson
- Department of Clinical Psychology, Seattle Pacific University, Seattle, WA, United States
| | - Kimi Hashimoto
- Department of Clinical Psychology, Seattle Pacific University, Seattle, WA, United States
| | - Katherine L. O’Connell
- Department of Clinical Psychology, Seattle Pacific University, Seattle, WA, United States
| | - Sam Adler Golden
- Department of Biological Structure, University of Washington, Seattle, WA, United States
| | | | - Keyne Catherine Law
- Department of Clinical Psychology, Seattle Pacific University, Seattle, WA, United States
- Correspondence: Rocky B. Marks Keyne Catherine Law
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16
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Miyagishi H, Tsuji M, Miyagawa K, Kurokawa K, Mochida-Saito A, Takahashi K, Kosuge Y, Ishige K, Takeda H. Possible role of transcriptional regulation of 5-HT 1A receptor in the midbrain on unadaptation to stress in mice. Brain Res 2022; 1783:147859. [PMID: 35245487 DOI: 10.1016/j.brainres.2022.147859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/04/2022] [Accepted: 02/28/2022] [Indexed: 11/17/2022]
Abstract
The ability to adapt to stress is an essential defensive function of a living body, and disturbance of this ability in the brain may contribute to the development of affective illness. Previously, we reported that mice exposed to unadaptable restraint stress show emotional abnormality. Moreover, this emotional abnormality was alleviated by chronic treatment with flesinoxan, a serotonin (5-HT)1A receptor agonist. 5-HT1A receptor expression is regulated by several transcription factors such as nuclear deformed epidermal autoregulatory factor (NUDR/Deaf-1) and five prime repressors under dual repression binding protein 1 (Freud-1). The present study was designed to investigate the expression levels of 5-HT1A receptor and its transcription factors in the midbrain and hippocampus of stress-adaptive and -unadaptive mice. Mice were exposed to 14 days of repeated adaptable (1 h/day) or repeated unadaptable (4 h/day) restraint stress, or were left in their home cage (non-stressed groups). In a western blot analysis, a significant increase in the expression levels of 5HT1A receptor protein were observed in the hippocampal membrane fraction in stress-adaptive mice. In contrast, the expression levels of 5-HT1A receptor protein in stress-unadaptive mice were significantly increased in both cytoplasmic and membrane fraction of the midbrain. Furthermore, real-time PCR analysis revealed that, in the midbrain of stress-unadaptive mice, the expression levels of 5-HT1A receptor mRNA and Freud-1 or NUDR mRNA were significantly increased and decreased, respectively. These results suggest that increased expression of 5-HT1A receptor due to decrease in the expression of Freud-1 and NUDR in the midbrain may play a pivotal role in the emotional abnormality of stress-unadaptive mice.
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Affiliation(s)
- Hiroko Miyagishi
- Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan; Laboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
| | - Minoru Tsuji
- Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan.
| | - Kazuya Miyagawa
- Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan
| | - Kazuhiro Kurokawa
- Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan
| | - Atsumi Mochida-Saito
- Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan
| | - Kohei Takahashi
- Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan
| | - Yasuhiro Kosuge
- Laboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
| | - Kumiko Ishige
- Laboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
| | - Hiroshi Takeda
- Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan
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17
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The Effect of Environmental Enrichment on Laboratory Rare Minnows (Gobiocypris rarus): Growth, Physiology, and Behavior. Animals (Basel) 2022; 12:ani12040514. [PMID: 35203222 PMCID: PMC8868387 DOI: 10.3390/ani12040514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/15/2022] [Accepted: 02/18/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Environmental enrichment is an important part of animal welfare. In this study, rare minnow in different rearing conditions underwent comprehensive evaluation regarding growth, anxiety-like behavior, and physiology parameters. Results showed that there were no differences in SGR, anxiety-like behavior, DA, DOPAC, and 5-HIAA levels between control and enriched groups. However, the enriched group had higher cortisol and 5-HT levels. Therefore, researchers should focus on the effect of environmental enrichment regarding the welfare of rare minnow and how it effects the validity of data from laboratory studies. Abstract Environmental enrichment is a method to increase environmental heterogeneity, which may reduce stress and improve animal welfare. Previous studies have shown that environmental enrichment can increase the growth rate, decrease aggressive and anxiety-like behaviors, improve learning ability and agility, and reduce cortisol levels in animals. These effects usually differ between species. Unfortunately, habitat enrichment on laboratory fish is poorly studied and seldom adopted in care guidance. Rare minnows (Gobiocypris rarus) have been cultured as a native laboratory fish in China in barren banks without environmental enrichment since 1990; they have been widely used in studies on ecotoxicology, environmental science, and other topics. The purpose of this study was to investigate the effect of environment enrichment on the growth, physiological status, and anxiety-like behavior of laboratory rare minnows. We observed and analyzed SGR, cortisol levels, DA, DOPAC, 5-HT and 5-HIAA, and anxiety-like behavior indexes after one month of treatment in barren (control) and enrichment tanks. We found that there were no significant differences in SGR, anxiety-like behavior, DA, DOPAC, or 5-HIAA levels between the two treatments. However, higher cortisol and 5-HT levels were observed in the enrichment tanks. This study suggests that rare minnows might be influenced by their living environment, and future related studies should consider their environmental enrichment.
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18
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McGuinness AJ, Davis JA, Dawson SL, Loughman A, Collier F, O’Hely M, Simpson CA, Green J, Marx W, Hair C, Guest G, Mohebbi M, Berk M, Stupart D, Watters D, Jacka FN. A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia. Mol Psychiatry 2022; 27:1920-1935. [PMID: 35194166 PMCID: PMC9126816 DOI: 10.1038/s41380-022-01456-3] [Citation(s) in RCA: 252] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 12/22/2021] [Accepted: 01/18/2022] [Indexed: 02/07/2023]
Abstract
The emerging understanding of gut microbiota as 'metabolic machinery' influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to 'healthy' controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (β-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota.
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Affiliation(s)
- A. J. McGuinness
- grid.1021.20000 0001 0526 7079The Institute for Mental and Physical Health and Clinical Translation (IMPACT), Food & Mood Centre, School of Medicine and Barwon Health, Deakin University, Geelong, VIC Australia
| | - J. A. Davis
- grid.1021.20000 0001 0526 7079The Institute for Mental and Physical Health and Clinical Translation (IMPACT), Food & Mood Centre, School of Medicine and Barwon Health, Deakin University, Geelong, VIC Australia
| | - S. L. Dawson
- grid.1021.20000 0001 0526 7079The Institute for Mental and Physical Health and Clinical Translation (IMPACT), Food & Mood Centre, School of Medicine and Barwon Health, Deakin University, Geelong, VIC Australia ,grid.1058.c0000 0000 9442 535XMurdoch Children’s Research Institute, Parkville, VIC Australia
| | - A. Loughman
- grid.1021.20000 0001 0526 7079The Institute for Mental and Physical Health and Clinical Translation (IMPACT), Food & Mood Centre, School of Medicine and Barwon Health, Deakin University, Geelong, VIC Australia
| | - F. Collier
- grid.1021.20000 0001 0526 7079The Institute for Mental and Physical Health and Clinical Translation (IMPACT), Food & Mood Centre, School of Medicine and Barwon Health, Deakin University, Geelong, VIC Australia
| | - M. O’Hely
- grid.1021.20000 0001 0526 7079The Institute for Mental and Physical Health and Clinical Translation (IMPACT), Food & Mood Centre, School of Medicine and Barwon Health, Deakin University, Geelong, VIC Australia ,grid.1058.c0000 0000 9442 535XMurdoch Children’s Research Institute, Parkville, VIC Australia
| | - C. A. Simpson
- grid.1008.90000 0001 2179 088XMelbourne School of Psychological Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC Australia ,grid.1008.90000 0001 2179 088XMelbourne Neuropsychiatry Centre, Department of Medicine, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne and Melbourne Health, Melbourne, VIC Australia
| | - J. Green
- grid.1021.20000 0001 0526 7079The Institute for Mental and Physical Health and Clinical Translation (IMPACT), Food & Mood Centre, School of Medicine and Barwon Health, Deakin University, Geelong, VIC Australia ,grid.1002.30000 0004 1936 7857Monash Alfred Psychiatry Research Centre (MAPcr), Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Parkville, VIC Australia ,grid.466993.70000 0004 0436 2893Department of Psychiatry, Peninsula Health, Frankston, VIC Australia
| | - W. Marx
- grid.1021.20000 0001 0526 7079The Institute for Mental and Physical Health and Clinical Translation (IMPACT), Food & Mood Centre, School of Medicine and Barwon Health, Deakin University, Geelong, VIC Australia
| | - C. Hair
- grid.1021.20000 0001 0526 7079Deakin University, School of Medicine, Geelong, VIC Australia ,grid.414257.10000 0004 0540 0062Department of Gastroenterology, Barwon Health, Geelong, VIC Australia
| | - G. Guest
- grid.1021.20000 0001 0526 7079Deakin University, School of Medicine, Geelong, VIC Australia ,grid.415335.50000 0000 8560 4604Department of Surgery, University Hospital Geelong, Barwon Health, Geelong, VIC Australia
| | - M. Mohebbi
- grid.1021.20000 0001 0526 7079Biostatistics Unit, Faculty of Health, Deakin University, Melbourne, VIC Australia
| | - M. Berk
- grid.1021.20000 0001 0526 7079The Institute for Mental and Physical Health and Clinical Translation (IMPACT), Food & Mood Centre, School of Medicine and Barwon Health, Deakin University, Geelong, VIC Australia ,grid.1021.20000 0001 0526 7079Deakin University, School of Medicine, Geelong, VIC Australia ,grid.1008.90000 0001 2179 088XOrygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia
| | - D. Stupart
- grid.1021.20000 0001 0526 7079Deakin University, School of Medicine, Geelong, VIC Australia ,grid.415335.50000 0000 8560 4604Department of Surgery, University Hospital Geelong, Barwon Health, Geelong, VIC Australia
| | - D. Watters
- grid.1021.20000 0001 0526 7079Deakin University, School of Medicine, Geelong, VIC Australia ,grid.415335.50000 0000 8560 4604Department of Surgery, University Hospital Geelong, Barwon Health, Geelong, VIC Australia
| | - F. N. Jacka
- grid.1021.20000 0001 0526 7079The Institute for Mental and Physical Health and Clinical Translation (IMPACT), Food & Mood Centre, School of Medicine and Barwon Health, Deakin University, Geelong, VIC Australia ,grid.1058.c0000 0000 9442 535XCentre for Adolescent Health, Murdoch Children’s Research Institute, Melbourne, VIC Australia ,grid.418393.40000 0001 0640 7766Black Dog Institute, Sydney, NSW Australia ,grid.1011.10000 0004 0474 1797College of Public Health, Medical & Veterinary Sciences, James Cook University, Townsville, QLD Australia
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Lozano AFQ, Moura MS, Tavares BM, Kempinas WDG. Exposure of pregnant rats to stress and/or sertraline: Side effects on maternal health and neurobehavioral development of male offspring. Life Sci 2021; 285:119960. [PMID: 34536495 DOI: 10.1016/j.lfs.2021.119960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 09/01/2021] [Accepted: 09/09/2021] [Indexed: 11/25/2022]
Abstract
AIMS Sertraline (SE) is one of the most prescribed medications for treating gestational depression, anxiety and stress. However, little is known about its effects on nervous-system development in offspring. Therefore, this study investigated the somatic, reflex and neurobehavioral development of rats exposed to SE during pregnancy, associated or not with stress. MAIN METHODS Pregnant Wistar rats were assigned to the following groups (n = 10-8 rats/group): CO - control animals administered filtered water by gavage; SE - animals administered 20 mg/kg SE by gavage; ST - animals subjected to restraining stress and administered filtered water; ST/SE - animals subjected to restraining stress and administered 20 mg/kg SE. The treatment was administered between gestational days (GD) 13 to 20. Somatic and reflex developments were investigated in the male offspring from postnatal day (PND) 1 to 21. The elevated plus maze was performed on PND 25 and 80. The open field and light/dark box test were performed on PND 90 and 100, respectively. KEY FINDINGS Body weight reduction and vaginal bleeding were observed in pregnant rats exposed to SE. The male offspring of the SE group showed delay in incisor eruption, fur development and negative geotaxis. In addition, the SE group was less exploratory (anxious personality) compared to the CO and ST groups. SIGNIFICANCE The results obtained in the present study demonstrate that sertraline not only impairs maternal health, but also, associated or not with stress, can compromise the somatic, reflex and neurobehavioral development of male rats.
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Affiliation(s)
- Ana Flávia Quiarato Lozano
- Graduate Program in General and Applied Biology, São Paulo State University (UNESP), Institute of Biosciences, Botucatu, SP, Brazil; Laboratory of Reproductive and Developmental Biology and Toxicology, Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP, Brazil.
| | - Mayara Silva Moura
- Graduate Program in General and Applied Biology, São Paulo State University (UNESP), Institute of Biosciences, Botucatu, SP, Brazil; Laboratory of Reproductive and Developmental Biology and Toxicology, Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Bruna Marques Tavares
- Laboratory of Reproductive and Developmental Biology and Toxicology, Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Wilma De Grava Kempinas
- Laboratory of Reproductive and Developmental Biology and Toxicology, Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP, Brazil
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Lam LT, Lam MK. Sleep Disorders in Early Childhood and the Development of Mental Health Problems in Adolescents: A Systematic Review of Longitudinal and Prospective Studies. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:11782. [PMID: 34831538 PMCID: PMC8621806 DOI: 10.3390/ijerph182211782] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/08/2021] [Accepted: 11/08/2021] [Indexed: 11/27/2022]
Abstract
The association between sleep problems, particularly sleep disorders, and mental health has long been studied and recognized. However, the causal relationship between sleep disorders, particularly during early childhood, on mental health problems in adolescence are yet to be established. From a preventive perspective, it is important to understand the causality of mental health problems in adolescents so that intervention measures can be derived and implemented as early as possible for maximum effectiveness. To provide more precise information on the effect of early childhood sleep disorders on mental health problems during adolescence, a systematic review was conducted on longitudinal and prospective studies reported in the literature. Following the PRISMA guidelines with an extensive search of the literature 26 studies were identified. Seven of these identified studies satisfied all selection criteria with sufficient data on the effect of early childhood sleep disorders and mental health problems in adolescence. Information was extracted and analyzed systematically from each study and tabulated. The overall results obtained from these studies indicate a significant and possible causal relationship between early childhood sleep disorders and the development of mental health problems, such as anxiety, depression, and ADHD in adolescence. These results are discussed with regards to the theoretical and practical implications as well as preventive strategies.
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Affiliation(s)
- Lawrence T Lam
- Tung Wah College, Hong Kong, China
- Faculty of Health, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Mary K Lam
- RMIT University, Melbourne, VIC 3083, Australia;
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21
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Sex-based changes in rat brain serotonin and behavior in a model of altitude-related vulnerability to treatment-resistant depression. Psychopharmacology (Berl) 2021; 238:2867-2881. [PMID: 34159421 DOI: 10.1007/s00213-021-05902-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 06/08/2021] [Indexed: 01/03/2023]
Abstract
RATIONALE Rates of depression and suicide increase with altitude. In our animal model, rats housed at moderate altitude vs. at sea level exhibit increased depressive symptoms in the forced swim test (FST) and lack of response to selective serotonin reuptake inhibitors (SSRIs). Depression and SSRI resistance are linked to disrupted serotonergic function, and hypobaric hypoxia may reduce the oxygen-dependent synthesis of serotonin. We therefore tested brain serotonin in rats housed at altitude. METHODS Sprague-Dawley rats were housed at altitude (4,500 ft, 10,000 ft) vs. sea level for 7-36 days. Brain serotonin was measured by ELISA, or behavior evaluated in the FST, sucrose preference (SPT), or open-field tests (OFT). RESULTS After 2 weeks at 4,500 ft or 10,000ft vs. sea level, serotonin levels decreased significantly at altitude in the female prefrontal cortex, striatum, hippocampus, and brainstem, but increased with altitude in the male hippocampus and brainstem. Female brain serotonin decreased from 7 to 36 days at 4,500 ft, but males did not vary. At 2 weeks and 24 days, females at altitude exhibit lower brain serotonin and increased depressive symptoms in the FST and SPT, with motor behavior unaltered. In males, serotonin, passive coping in the FST and OFT immobility increased with altitude at 2 weeks, but not at 24 days. Male SPT behavior did not change with altitude. CONCLUSIONS Females may be more vulnerable to depressive symptoms at altitude, while males may be resilient. Chronic hypoxic stress at altitudes as low as 4,500 ft may cause a brain serotonin imbalance to worsen vulnerability to depression and SSRI resistance, and potentially worsen suicide risk.
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Shi B, Ogden RT. Inference in functional mixed regression models with applications to Positron Emission Tomography imaging data. Stat Med 2021; 40:4640-4659. [PMID: 34405911 DOI: 10.1002/sim.9087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 05/01/2021] [Accepted: 05/09/2021] [Indexed: 11/06/2022]
Abstract
In a function-on-scalar regression framework, we present some modeling strategies for functional mixed models and also some approaches for making inference about various aspects of the fixed effects. This is presented in the context of modeling positron emission tomography (PET) data in order to explore the density of various proteins of interest throughout the human brain. For this application, information about the density of the target protein in a given brain region is encapsulated in the impulse response function (IRF) of the region. Previous work on nonparametric estimation of the IRF is limited in that it is only able to model a single brain region at a time. We propose an extension, based on principles of functional data analysis, that will allow modeling of multiple brain regions simultaneously. Applicable more broadly to functional mixed regression modeling, we discuss two general approaches for permutation testing and describe valid strategies for identifying exchangeable units within the model and building corresponding permutation tests. We illustrate our methods with an application to PET data and explore the effects of depression and sex on the IRF.
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Affiliation(s)
- Baoyi Shi
- Department of Biostatistics, Columbia University, New York, New York, USA
| | - R Todd Ogden
- Department of Biostatistics, Columbia University, New York, New York, USA
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23
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Neurotoxic Effects of Neonicotinoids on Mammals: What Is There beyond the Activation of Nicotinic Acetylcholine Receptors?-A Systematic Review. Int J Mol Sci 2021; 22:ijms22168413. [PMID: 34445117 PMCID: PMC8395098 DOI: 10.3390/ijms22168413] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/29/2021] [Accepted: 08/02/2021] [Indexed: 02/07/2023] Open
Abstract
Neonicotinoids are a class of insecticides that exert their effect through a specific action on neuronal nicotinic acetylcholine receptors (nAChRs). The success of these insecticides is due to this mechanism of action, since they act as potent agonists of insect nAChRs, presenting low affinity for vertebrate nAChRs, which reduces potential toxic risk and increases safety for non-target species. However, although neonicotinoids are considered safe, their presence in the environment could increase the risk of exposure and toxicity. On the other hand, although neonicotinoids have low affinity for mammalian nAChRs, the large quantity, variety, and ubiquity of these receptors, combined with its diversity of functions, raises the question of what effects these insecticides can produce in non-target species. In the present systematic review, we investigate the available evidence on the biochemical and behavioral effects of neonicotinoids on the mammalian nervous system. In general, exposure to neonicotinoids at an early age alters the correct neuronal development, with decreases in neurogenesis and alterations in migration, and induces neuroinflammation. In adulthood, neonicotinoids induce neurobehavioral toxicity, these effects being associated with their modulating action on nAChRs, with consequent neurochemical alterations. These alterations include decreased expression of nAChRs, modifications in acetylcholinesterase activity, and significant changes in the function of the nigrostriatal dopaminergic system. All these effects can lead to the activation of a series of intracellular signaling pathways that generate oxidative stress, neuroinflammation and, finally, neuronal death. Neonicotinoid-induced changes in nAChR function could be responsible for most of the effects observed in the different studies.
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24
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Gu M, Li X, Yan L, Zhang Y, Yang L, Li S, Song C. Endogenous ω-3 fatty acids in Fat-1 mice attenuated depression-like behaviors, spatial memory impairment and relevant changes induced by olfactory bulbectomy. Prostaglandins Leukot Essent Fatty Acids 2021; 171:102313. [PMID: 34246927 DOI: 10.1016/j.plefa.2021.102313] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 06/12/2021] [Accepted: 06/17/2021] [Indexed: 11/21/2022]
Abstract
OBJECTIVES Olfactory bulbectomy (OB) induced behaviors, hypercortisolism, inflammation and neurotrophin dysfunctions are similar to those observed in depressed patients. Omega (n)-3 polyunsaturated fatty acids (PUFAs) can effectively treat depression via anti-inflammatory and neuroprotective effects. However, n-3 PUFA purities, caloric contents, and ratios in different diets often cause contradictive results. This study used Fat-1 mice, which can convert n-6 to n-3 PUFAs in the brain, to study the effect of n-3 PUFAs on OB-induced behaviors and related changes. METHODS Fat-1 and wild-type littermates were fed safflower oil for 3 months. Behaviors were tested on day 21 after surgery. Monoamine neurotransmitters were measured by HPLC. Macrophage activity was measured by MTT assay. Astrocyte phenotypes A1 S100β, A2 BDNF and cholesterol level were measured by ELISA and total cholesterol assay kits respectively. PUFA profile and membrane fluidity were detected by GC and DPH fluorescence probe respectively. RESULTS OB significantly induced animal hyperactivity and spatial memory impairment, while decreased sucrose consumption and social contact with decreased 5-HT turnover, increased the macrophage activity and S100β/BDNF ratio. Meanwhile, n-3/n-6 PUFAs ratio and total cholesterol level were reduced in OB mice. Whereas, OB-induced behavioral changes were attenuated, which were associated with increasing 5-HT turnover, decrease macrophage activity, restored S100β/BDNF and n-3/n-6 PUFAs ratios, and total cholesterol concentrations in Fat-1 mice. CONCLUSION The present study for the first time demonstrated that endogenous n-3 PUFAs attenuated OB-induced depression-like behaviors and spatial memory impairment through modulating serotonergic and immune function, balancing the astrocyte A1/A2 phenotypes, and normalizing PUFAs profile and membrane function.
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Affiliation(s)
- Minqing Gu
- Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China
| | - Xiaohong Li
- Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China
| | - Ling Yan
- Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China; Institute of Biomedicine and Translation Medicine, Department of Physiology, Faculty of Medicine, University of Tartu, Tartu, Estonia
| | - Yongping Zhang
- Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China; Shenzhen Institute of Guangdong Ocean University, Shenzhen, China
| | - Longen Yang
- Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China
| | - Shurui Li
- Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China
| | - Cai Song
- Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China; Shenzhen Institute of Guangdong Ocean University, Shenzhen, China.
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25
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Hersey M, Hashemi P, Reagan LP. Integrating the monoamine and cytokine hypotheses of depression: Is histamine the missing link? Eur J Neurosci 2021; 55:2895-2911. [PMID: 34265868 DOI: 10.1111/ejn.15392] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 06/26/2021] [Accepted: 07/06/2021] [Indexed: 12/28/2022]
Abstract
Psychiatric diseases, like depression, largely affect the central nervous system (CNS). While the underlying neuropathology of depressive illness remains to be elucidated, several hypotheses have been proposed as molecular underpinnings for major depressive disorder, including the monoamine hypothesis and the cytokine hypothesis. The monoamine hypothesis has been largely supported by the pharmaceuticals that target monoamine neurotransmitters as a treatment for depression. However, these antidepressants have come under scrutiny due to their limited clinical efficacy, side effects, and delayed onset of action. The more recent, cytokine hypothesis of depression is supported by the ability of immune-active agents to induce "sickness behaviour" akin to that seen with depression. However, treatments that more selectively target inflammation have yielded inconsistent antidepressive results. As such, neither of these hypotheses can fully explain depressive illness pathology, implying that the underlying neuropathological mechanisms may encompass aspects of both theories. The goal of the current review is to integrate these two well-studied hypotheses and to propose a role for histamine as a potential unifying factor that links monoamines to cytokines. Additionally, we will focus on stress-induced depression, to provide an updated perspective of depressive illness research and thereby identify new potential targets for the treatment of major depressive disorder.
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Affiliation(s)
- Melinda Hersey
- Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina, USA.,Department of Chemistry & Biochemistry, University of South Carolina, Columbia, South Carolina, USA
| | - Parastoo Hashemi
- Department of Chemistry & Biochemistry, University of South Carolina, Columbia, South Carolina, USA.,Department of Bioengineering, Imperial College, London, UK
| | - Lawrence P Reagan
- Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina, USA.,WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA
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Melo L, Mosayebi-Samani M, Ghanavati E, Nitsche MA, Kuo MF. Dosage-Dependent Impact of Acute Serotonin Enhancement on Transcranial Direct Current Stimulation Effects. Int J Neuropsychopharmacol 2021; 24:787-797. [PMID: 34106250 PMCID: PMC8538892 DOI: 10.1093/ijnp/pyab035] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 05/27/2021] [Accepted: 06/07/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The serotonergic system has an important impact on basic physiological and higher brain functions. Acute and chronic enhancement of serotonin levels via selective serotonin reuptake inhibitor administration impacts neuroplasticity in humans, as shown by its effects on cortical excitability alterations induced by non-invasive brain stimulation, including transcranial direct current stimulation (tDCS). Nevertheless, the interaction between serotonin activation and neuroplasticity is not fully understood, particularly considering dose-dependent effects. Our goal was to explore dosage-dependent effects of acute serotonin enhancement on stimulation-induced plasticity in healthy individuals. METHODS Twelve healthy adults participated in 7 sessions conducted in a crossover, partially double-blinded, randomized, and sham-controlled study design. Anodal and cathodal tDCS was applied to the motor cortex under selective serotonin reuptake inhibitor (20 mg/40 mg citalopram) or placebo medication. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation. RESULTS Under placebo medication, anodal tDCS enhanced, and cathodal tDCS reduced, excitability for approximately 60-120 minutes after the intervention. Citalopram enhanced and prolonged the facilitation induced by anodal tDCS regardless of the dosage while turning cathodal tDCS-induced excitability diminution into facilitation. For the latter, prolonged effects were observed when 40 mg was administrated. CONCLUSIONS Acute serotonin enhancement modulates tDCS after-effects and has largely similar modulatory effects on motor cortex neuroplasticity regardless of the specific dosage. A minor dosage-dependent effect was observed only for cathodal tDCS. The present findings support the concept of boosting the neuroplastic effects of anodal tDCS by serotonergic enhancement, a potential clinical approach for the treatment of neurological and psychiatric disorders.
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Affiliation(s)
- Lorena Melo
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany,International Graduate School of Neuroscience (IGSN), Ruhr-University Bochum, Germany
| | - Mohsen Mosayebi-Samani
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany
| | - Elham Ghanavati
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany
| | - Michael A Nitsche
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany,Department of Neurology, University Medical Hospital Bergmannsheil, Bochum, Germany
| | - Min-Fang Kuo
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany,Correspondence: Min-Fang Kuo, MD, PhD, Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystraße 67, 44139 Dortmund, Germany ()
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27
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Hwang M, Lee YJ, Lee M, Kang B, Lee YS, Hwang J, Woo SI, Hahn SW. Relationship Between the Loudness Dependence of the Auditory Evoked Potential and the Severity of Suicidal Ideation in Patients with Major Depressive Disorder. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2021; 19:323-333. [PMID: 33888661 PMCID: PMC8077063 DOI: 10.9758/cpn.2021.19.2.323] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/22/2020] [Accepted: 09/29/2020] [Indexed: 11/18/2022]
Abstract
Objective The loudness dependence of the auditory evoked potential (LDAEP) is a reliable indicator that is inversely related to central serotonergic activity, and recent studies have suggested an association between LDAEP and suicidal ideation. This study investigated differences in LDAEP between patients with major depressive disorder and high suicidality and those with major depressive disorder and low suicidality compared to healthy controls. Methods This study included 67 participants: 23 patients with major depressive disorder with high suicidality (9 males, mean age 29.3 ± 15.7 years, total score of SSI-BECK ≥ 15), 22 patients with major depressive disorder with low suicidality (9 males, mean age 42.2 ± 14.4 years, total score of SSI-BECK ≤ 14), and 22 healthy controls (11 males, mean age 31.6 ± 8.7 years). Participants completed the following assessments: Patient Health Questionnaire-9, Beck Depression Inventory-II, Beck Scale for Suicidal ideation, State Anxiety Scale of the State-Trait Anxiety Inventory, Beck Anxiety Inventory, and LDAEP (measured at electrode Cz). Results There were no sex-related differences among groups (p = 0.821). The high-suicidality group exhibited significantly higher LDAEP compared to the low-suicidality group (0.82 ± 0.79 vs. 0.26 ± 0.36, p = 0.014). No significant differences were found between the control and high-suicidality (p = 0.281) or the control and low-suicidality groups (p = 0.236). Conclusion LDAEP was applied to demonstrate the association between serotonergic activity and suicidal ideation and suicide risk in major depression and may be a candidate of biological marker for preventing suicide in this study.
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Affiliation(s)
- Mingyu Hwang
- Department of Psychiatry, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Yeon Jung Lee
- Department of Psychiatry, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Minji Lee
- Department of Psychiatry, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Byungjoo Kang
- Department of Psychiatry, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Yun Sung Lee
- Department of Medical Sciences, Graduate School of Soonchunhyang University, Asan, Korea
| | - Jaeuk Hwang
- Department of Psychiatry, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Sung-Il Woo
- Department of Psychiatry, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Sang-Woo Hahn
- Department of Psychiatry, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
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Filatova EV, Shadrina MI, Slominsky PA. Major Depression: One Brain, One Disease, One Set of Intertwined Processes. Cells 2021; 10:cells10061283. [PMID: 34064233 PMCID: PMC8224372 DOI: 10.3390/cells10061283] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 01/18/2023] Open
Abstract
Major depressive disorder (MDD) is a heterogeneous disease affecting one out of five individuals and is the leading cause of disability worldwide. Presently, MDD is considered a multifactorial disease with various causes such as genetic susceptibility, stress, and other pathological processes. Multiple studies allowed the formulation of several theories attempting to describe the development of MDD. However, none of these hypotheses are comprehensive because none of them can explain all cases, mechanisms, and symptoms of MDD. Nevertheless, all of these theories share some common pathways, which lead us to believe that these hypotheses depict several pieces of the same big puzzle. Therefore, in this review, we provide a brief description of these theories and their strengths and weaknesses in an attempt to highlight the common mechanisms and relationships of all major theories of depression and combine them together to present the current overall picture. The analysis of all hypotheses suggests that there is interdependence between all the brain structures and various substances involved in the pathogenesis of MDD, which could be not entirely universal, but can affect all of the brain regions, to one degree or another, depending on the triggering factor, which, in turn, could explain the different subtypes of MDD.
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Belete K, Kassew T, Demilew D, Amare Zeleke T. Prevalence and Correlates of Suicide Ideation and Attempt among Pregnant Women Attending Antenatal Care Services at Public Hospitals in Southern Ethiopia. Neuropsychiatr Dis Treat 2021; 17:1517-1529. [PMID: 34040377 PMCID: PMC8140917 DOI: 10.2147/ndt.s309702] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/23/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Suicide ideation and attempt are common among pregnant women, risk factors for completed suicide, and associated adverse maternal and fetal outcomes. It is under-recognized and has not been investigated well in low-income countries like Ethiopia. This study aimed to assess the prevalence and factors associated with suicide ideation and attempt among pregnant women attending antenatal care services at public hospitals in southern Ethiopia. METHODS A group of 762 pregnant women who were attending the antenatal service at public hospitals in Hawassa, southern Ethiopia, selected by a systematic random sampling technique, took part in an interview. A Composite International Diagnostic Interview (CIDI) was used to measure suicide ideation and attempt. Chi-square and binary logistic regression analyses were performed to identify the associated factors. An adjusted odds ratio with a 95% confidence interval was used for reporting the result with a p-value<0.05 statistical significance level. RESULTS The prevalence of suicide ideation and attempt among pregnant women was 11.8% and 2.7%, respectively. Unplanned pregnancy (AOR=2.01, 95% CI=1.04-3.88), poor social support (AOR=3.29, 95% CI=1.62-6.68), common mental disorders (AOR=2.77, 95% CI=1.50-5.09), and lifetime suicide ideation (AOR=4.63, 95% CI=2.63-8.16) were factors significantly associated with suicide ideation. Social support was the only correlated factor with suicide attempt among pregnant mothers. CONCLUSION The prevalence of suicide ideation and attempt among pregnant women was found to be high. Intervention strategies towards suicidal ideation and attempt should consider improving social support and antenatal related common mental disorders with a primary focus on women with unplanned pregnancy and prior history of suicide ideation.
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Affiliation(s)
- Kenean Belete
- Yirgalem Hospital Medical College, Yirgalem, Sidama, Ethiopia
| | - Tilahun Kassew
- Department of Psychiatry, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Demeke Demilew
- Department of Psychiatry, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Tadele Amare Zeleke
- Department of Psychiatry, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Trzeciak P, Herbet M. Role of the Intestinal Microbiome, Intestinal Barrier and Psychobiotics in Depression. Nutrients 2021; 13:927. [PMID: 33809367 PMCID: PMC8000572 DOI: 10.3390/nu13030927] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/07/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022] Open
Abstract
The intestinal microbiota plays an important role in the pathophysiology of depression. As determined, the microbiota influences the shaping and modulation of the functioning of the gut-brain axis. The intestinal microbiota has a significant impact on processes related to neurotransmitter synthesis, the myelination of neurons in the prefrontal cortex, and is also involved in the development of the amygdala and hippocampus. Intestinal bacteria are also a source of vitamins, the deficiency of which is believed to be related to the response to antidepressant therapy and may lead to exacerbation of depressive symptoms. Additionally, it is known that, in periods of excessive activation of stress reactions, the immune system also plays an important role, negatively affecting the tightness of the intestinal barrier and intestinal microflora. In this review, we have summarized the role of the gut microbiota, its metabolites, and diet in susceptibility to depression. We also describe abnormalities in the functioning of the intestinal barrier caused by increased activity of the immune system in response to stressors. Moreover, the presented study discusses the role of psychobiotics in the prevention and treatment of depression through their influence on the intestinal barrier, immune processes, and functioning of the nervous system.
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Affiliation(s)
| | - Mariola Herbet
- Chair and Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 8b Street, 20-090 Lublin, Poland;
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31
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Clinton SM, Shupe EA, Glover ME, Unroe KA, McCoy CR, Cohen JL, Kerman IA. Modeling heritability of temperamental differences, stress reactivity, and risk for anxiety and depression: Relevance to research domain criteria (RDoC). Eur J Neurosci 2021; 55:2076-2107. [PMID: 33629390 PMCID: PMC8382785 DOI: 10.1111/ejn.15158] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/29/2021] [Accepted: 02/20/2021] [Indexed: 01/04/2023]
Abstract
Animal models provide important tools to study biological and environmental factors that shape brain function and behavior. These models can be effectively leveraged by drawing on concepts from the National Institute of Mental Health Research Domain Criteria (RDoC) Initiative, which aims to delineate molecular pathways and neural circuits that underpin behavioral anomalies that transcend psychiatric conditions. To study factors that contribute to individual differences in emotionality and stress reactivity, our laboratory utilized Sprague-Dawley rats that were selectively bred for differences in novelty exploration. Selective breeding for low versus high locomotor response to novelty produced rat lines that differ in behavioral domains relevant to anxiety and depression, particularly the RDoC Negative Valence domains, including acute threat, potential threat, and loss. Bred Low Novelty Responder (LR) rats, relative to their High Responder (HR) counterparts, display high levels of behavioral inhibition, conditioned and unconditioned fear, avoidance, passive stress coping, anhedonia, and psychomotor retardation. The HR/LR traits are heritable, emerge in the first weeks of life, and appear to be driven by alterations in the developing amygdala and hippocampus. Epigenomic and transcriptomic profiling in the developing and adult HR/LR brain suggest that DNA methylation and microRNAs, as well as differences in monoaminergic transmission (dopamine and serotonin in particular), contribute to their distinct behavioral phenotypes. This work exemplifies ways that animal models such as the HR/LR rats can be effectively used to study neural and molecular factors driving emotional behavior, which may pave the way toward improved understanding the neurobiological mechanisms involved in emotional disorders.
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Affiliation(s)
- Sarah M Clinton
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Elizabeth A Shupe
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Matthew E Glover
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Keaton A Unroe
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Chelsea R McCoy
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Joshua L Cohen
- Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA
| | - Ilan A Kerman
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.,Behavioral Health Service Line, Veterans Affairs Pittsburgh Health System, Pittsburgh, PA, USA
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Ofori E, Onyameh EK, Gonela UM, Voshavar C, Bricker B, Swanson TL, Eshleman AJ, Schmachtenberg JL, Bloom SH, Janowsky AJ, Ablordeppey SY. New dual 5-HT1A and 5-HT7 receptor ligands derived from SYA16263. Eur J Med Chem 2021; 214:113243. [PMID: 33582388 DOI: 10.1016/j.ejmech.2021.113243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/23/2021] [Accepted: 01/25/2021] [Indexed: 12/15/2022]
Abstract
We have previously reported that dual 5-HT1A and 5-HT7 receptor ligands might find utility as treatment options for various CNS related conditions including cognitive and anxiolytic impairments. We have also more recently reported that SYA16263 has antipsychotic-like properties with an absence of catalepsy in animal models ascribed to its ability to recruit β-arrestin to the D2 receptor. However, SYA16263 also binds with very high affinity to 5-HT1AR (Ki = 1.1 nM) and a moderate affinity at 5-HT7R (Ki = 90 nM). Thus, it was of interest to exploit its pharmacophore elements in designing new dual receptor ligands. Using SYA16263 as the lead molecule, we have conducted a limited structure-affinity relationship (SAFIR) study by modifying various structural elements in the arylalkyl moiety, resulting in the identification of a new dual 5-HT1AR and 5-HT7R ligand, 6-chloro-2-methyl-2-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-inden-1-one (21), which unlike SYA16263, has a sub-nanomolar (5-HT1AR, Ki = 0.74 nM) and a low nanomolar (5-HT7R, Ki = 8.4 nM) affinity for these receptors. Interestingly, 21 is a full agonist at 5-HT1AR and antagonist at the 5-HT7R, functional characteristics which point to its potential as an antidepressant agent.
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Affiliation(s)
- Edward Ofori
- Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Edem K Onyameh
- Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Uma M Gonela
- Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Chandrashekhar Voshavar
- Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Barbara Bricker
- Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Tracy L Swanson
- Research Service, VA Portland Health Care System, And Department of Psychiatry, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Amy J Eshleman
- Research Service, VA Portland Health Care System, And Department of Psychiatry, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Jennifer L Schmachtenberg
- Research Service, VA Portland Health Care System, And Department of Psychiatry, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Shelley H Bloom
- Research Service, VA Portland Health Care System, And Department of Psychiatry, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Aaron J Janowsky
- Research Service, VA Portland Health Care System, And Department of Psychiatry, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Seth Y Ablordeppey
- Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL, 32307, USA.
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Pandey GN, Sharma A, Rizavi HS, Ren X. Dysregulation of Protein Kinase C in Adult Depression and Suicide: Evidence From Postmortem Brain Studies. Int J Neuropsychopharmacol 2021; 24:400-408. [PMID: 33515455 PMCID: PMC8130206 DOI: 10.1093/ijnp/pyab003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 01/06/2021] [Accepted: 01/27/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Several lines of evidence suggest the abnormalities of protein kinase C (PKC) signaling system in mood disorders and suicide based primarily on the studies of PKC and its isozymes in the platelets and postmortem brain of depressed and suicidal subjects. In this study, we examined the role of PKC isozymes in depression and suicide. METHODS We determined the protein and mRNA expression of various PKC isozymes in the prefrontal cortical region (Brodmann area 9) in 24 normal control subjects, 24 depressed suicide (DS) subjects, and 12 depressed nonsuicide (DNS) subjects. The levels of mRNA in the prefrontal cortex were determined by quantitative real-time reverse transcription PCR, and the protein expression was determined by western blotting. RESULTS We observed a significant decrease in mRNA expression of PKCα, PKCβI, PKCδ, and PKCε and decreased protein expression in either the membrane or the cytosol fraction of PKC isozymes PKCα, PKCβI, PKCβII, and PKCδ in DS and DNS subjects compared with normal control subjects. CONCLUSIONS The current study provides detailed evidence of specific dysregulation of certain PKC isozymes in the postmortem brain of DS and DNS subjects and further supports earlier evidence for the role of PKC in the platelets and brain of the adult and teenage depressed and suicidal population. This comprehensive study may lead to further knowledge of the involvement of PKC in the pathophysiology of depression and suicide.
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Affiliation(s)
- Ghanshyam N Pandey
- University of Illinois at Chicago, Department of Psychiatry, Chicago, IL, USA,Correspondence: Ghanshyam N. Pandey, PhD, University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL 60612, USA ()
| | - Anuradha Sharma
- University of Illinois at Chicago, Department of Psychiatry, Chicago, IL, USA
| | - Hooriyah S Rizavi
- University of Illinois at Chicago, Department of Psychiatry, Chicago, IL, USA
| | - Xinguo Ren
- University of Illinois at Chicago, Department of Psychiatry, Chicago, IL, USA
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Martin H, Bullich S, Guiard BP, Fioramonti X. The impact of insulin on the serotonergic system and consequences on diabetes-associated mood disorders. J Neuroendocrinol 2021; 33:e12928. [PMID: 33506507 DOI: 10.1111/jne.12928] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/20/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022]
Abstract
The idea that insulin could influence emotional behaviours has long been suggested. However, the underlying mechanisms have yet to be solved and there is no direct and clear-cut evidence demonstrating that such action involves brain serotonergic neurones. Indeed, initial arguments in favour of the association between insulin, serotonin and mood arise from clinical or animal studies showing that impaired insulin action in type 1 or type 2 diabetes causes anxiety- and depressive symptoms along with blunted plasma and brain serotonin levels. The present review synthesises the main mechanistic hypotheses that might explain the comorbidity between diabetes and depression. It also provides a state of knowledge of the direct and indirect experimental evidence that insulin modulates brain serotonergic neurones. Finally, it highlights the literature suggesting that antidiabetic drugs present antidepressant-like effects and, conversely, that serotonergic antidepressants impact glucose homeostasis. Overall, this review provides mechanistic insights into how insulin signalling alters serotonergic neurotransmission and related behaviours bringing new targets for therapeutic options.
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Affiliation(s)
- Hugo Martin
- NutriNeuro, UMR 1286 INRAE, Bordeaux INP, Bordeaux University, Bordeaux, France
| | - Sébastien Bullich
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, UPS, Université de Toulouse, Toulouse, France
| | - Bruno P Guiard
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, UPS, Université de Toulouse, Toulouse, France
| | - Xavier Fioramonti
- NutriNeuro, UMR 1286 INRAE, Bordeaux INP, Bordeaux University, Bordeaux, France
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Li C, McCloskey N, Phillips J, Simmons SJ, Kirby LG. CRF-5-HT interactions in the dorsal raphe nucleus and motivation for stress-induced opioid reinstatement. Psychopharmacology (Berl) 2021; 238:29-40. [PMID: 33231727 PMCID: PMC7796902 DOI: 10.1007/s00213-020-05652-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 08/20/2020] [Indexed: 01/17/2023]
Abstract
RATIONALE The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Our previous data show that stressors can inhibit 5-HT neuronal activity and release by stimulating the release of the stress neurohormone corticotropin-releasing factor (CRF) within the serotonergic dorsal raphe nucleus (DRN). The inhibitory effects of CRF on 5-HT DRN neurons are indirect, mediated by CRF-R1 receptors located on GABAergic afferents. OBJECTIVES We tested the hypothesis that DRN CRF-R1 receptors contribute to stress-induced reinstatement of morphine-conditioned place preference (CPP). We also examined the role of this circuitry in stress-induced negative affective state with 22-kHz distress ultrasonic vocalizations (USVs), which are naturally emitted by rats in response to environmental challenges such as pain, stress, and drug withdrawal. METHODS First, we tested if activation of CRF-R1 receptors in the DRN with the CRF-R1-preferring agonist ovine CRF (oCRF) would reinstate morphine CPP and then if blockade of CRF-R1 receptors in the DRN with the CRF-R1 antagonist NBI 35965 would attenuate swim stress-induced reinstatement of morphine CPP. Second, we tested if intra-DRN pretreatment with NBI 35965 would attenuate foot shock stress-induced 22-kHz USVs. RESULTS Intra-DRN injection of oCRF reinstated morphine CPP, while intra-DRN injection of NBI 35965 attenuated swim stress-induced reinstatement. Moreover, intra-DRN pretreatment with NBI 35965 significantly reduced 22-kHz distress calls induced by foot shock. CONCLUSIONS These data provide evidence that stress-induced negative affective state is mediated by DRN CRF-R1 receptors and may contribute to reinstatement of morphine CPP.
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MESH Headings
- Analgesics, Opioid/administration & dosage
- Analgesics, Opioid/pharmacology
- Animals
- Behavior, Animal/drug effects
- Conditioning, Psychological/drug effects
- Corticotropin-Releasing Hormone/administration & dosage
- Corticotropin-Releasing Hormone/agonists
- Corticotropin-Releasing Hormone/analogs & derivatives
- Corticotropin-Releasing Hormone/metabolism
- Dorsal Raphe Nucleus/drug effects
- Dorsal Raphe Nucleus/metabolism
- Extinction, Psychological/drug effects
- Male
- Morphine/administration & dosage
- Morphine/pharmacology
- Morphine Dependence/metabolism
- Motivation/drug effects
- Neurons/drug effects
- Neurons/metabolism
- Rats
- Rats, Sprague-Dawley
- Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors
- Reinforcement, Psychology
- Serotonin/metabolism
- Sheep
- Stress, Psychological/metabolism
- Stress, Psychological/psychology
- Substance Withdrawal Syndrome/metabolism
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Affiliation(s)
- Chen Li
- Center for Substance Abuse Research and Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St., Philadelphia, PA, 19140, USA
| | - Nicholas McCloskey
- Center for Substance Abuse Research and Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St., Philadelphia, PA, 19140, USA
| | - Jared Phillips
- Center for Substance Abuse Research and Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St., Philadelphia, PA, 19140, USA
| | - Steven J Simmons
- Department of Anesthesia and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Lynn G Kirby
- Center for Substance Abuse Research and Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St., Philadelphia, PA, 19140, USA.
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Kawa L, Arborelius UP, Hökfelt T, Risling M. Sex-Specific Differences in Rodents Following a Single Primary Blast Exposure: Focus on the Monoamine and Galanin Systems. Front Neurol 2020; 11:540144. [PMID: 33178100 PMCID: PMC7593658 DOI: 10.3389/fneur.2020.540144] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 08/25/2020] [Indexed: 01/16/2023] Open
Abstract
Most blast-induced traumatic brain injuries (bTBI) are mild in severity and culpable for the lingering and persistent neuropsychological complaints in affected individuals. There is evidence that the prevalence of symptoms post-exposure may be sex-specific. Our laboratory has focused on changes in the monoamine and the neuropeptide, galanin, systems in male rodents following primary bTBI. In this study, we aimed to replicate these findings in female rodents. Brainstem sections from the locus coeruleus (LC) and dorsal raphe nuclei (DRN) were processed for in situ hybridisation at 1 and 7 days post-bTBI. We investigated changes in the transcripts for tyrosine hydroxylase (TH), tryptophan hydroxylase two (TPH2) and galanin. Like in males, we found a transient increase in TH transcript levels bilaterally in the female LC. Changes in TPH2 mRNA were more pronounced and extensive in the DRN of females compared to males. Galanin mRNA was increased bilaterally in the LC and DRN, although this increase was not apparent until day 7 in the LC. Serum analysis revealed an increase in corticosterone, but only in exposed females. These changes occurred without any visible signs of white matter injury, cell death, or blood–brain barrier breakdown. Taken together, in the apparent absence of visible structural damage to the brain, the monoamine and galanin systems, two key players in emotional regulation, are activated deferentially in males and females following primary blast exposure. These similarities and differences should be considered when developing and evaluating diagnostic and therapeutic interventions for bTBI.
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Affiliation(s)
- Lizan Kawa
- Department of Neuroscience, Karolinska Institutet, Solna, Sweden
| | - Ulf P Arborelius
- Department of Neuroscience, Karolinska Institutet, Solna, Sweden
| | - Tomas Hökfelt
- Department of Neuroscience, Karolinska Institutet, Solna, Sweden
| | - Mårten Risling
- Department of Neuroscience, Karolinska Institutet, Solna, Sweden
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Ding L, Maloney SK, Wang M, Rodger J, Chen L, Blache D. Association between temperament related traits and single nucleotide polymorphisms in the serotonin and oxytocin systems in Merino sheep. GENES BRAIN AND BEHAVIOR 2020; 20:e12714. [PMID: 33161622 DOI: 10.1111/gbb.12714] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 11/04/2020] [Accepted: 11/06/2020] [Indexed: 01/26/2023]
Abstract
Animal temperament is defined as the consistent behavioral and physiological differences that are seen between individuals in response to the same stressor. Neurotransmitter systems, like serotonin and oxytocin in the central nervous system, underlie variation in behavioral traits in humans and other animals. Variations like single nucleotide polymorphisms (SNPs) in the genes for tryptophan 5-hydroxylase (TPH2), the serotonin transporter (SLC6A4), the serotonin receptor (HTR2A), and the oxytocin receptor (OXTR) are associated with behavioral phenotype in humans. Thus, the objective of this study was to identify SNPs in those genes and to test if those variations are associated with the temperament in Merino sheep. Using ewes from the University of Western Australia temperament flock, which has been selected on emotional reactivity for more than 20 generations, eight SNPs (rs107856757, rs107856818, rs107856856 and rs107857156 in TPH2, rs20917091 in SLC6A4, rs17196799 and rs17193181 in HTR2A, and rs17664565 in OXTR) were found to be distributed differently between calm and nervous sheep. These eight SNPs were then genotyped in 260 sheep from a flock that has never been selected on emotional reactivity, followed by the estimation of the behavioral traits of those 260 sheep using an arena test and an isolation box test. We found that several SNPs in TPH2 (rs107856757, rs107856818, rs107856856 and rs107857156) were in strong linkage disequilibrium, and all were associated with behavioral phenotype in the nonselected sheep. Similarly, rs17196799 in HTR2A was also associated with the behavioral phenotype.
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Affiliation(s)
- Luoyang Ding
- School of Agriculture and Environment, The University of Western Australia, Crawley, Western Australia, Australia.,College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu, China
| | - Shane K Maloney
- School of Human Sciences, The University of Western Australia, Crawley, Western Australia, Australia
| | - Mengzhi Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu, China
| | - Jennifer Rodger
- School of Biological Sciences, The University of Western Australia, Crawley, Western Australia, Australia
| | - Lianmin Chen
- Department of Genetics and Pediatrics, University of Groningen, Groningen, Netherlands
| | - Dominique Blache
- School of Agriculture and Environment, The University of Western Australia, Crawley, Western Australia, Australia
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Brito-da-Costa AM, Dias-da-Silva D, Gomes NGM, Dinis-Oliveira RJ, Madureira-Carvalho Á. Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N, N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact. Pharmaceuticals (Basel) 2020; 13:ph13110334. [PMID: 33114119 PMCID: PMC7690791 DOI: 10.3390/ph13110334] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/16/2020] [Accepted: 10/20/2020] [Indexed: 12/11/2022] Open
Abstract
Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. Herein, the toxicokinetics and toxicodynamics of the psychoactive DMT and harmala alkaloids harmine, harmaline and tetrahydroharmine, are comprehensively covered, particularly emphasizing the psychological, physiological, and toxic effects deriving from their concomitant intake. Potential therapeutic utility, particularly in mental and psychiatric disorders, and forensic aspects of DMT and ayahuasca are also reviewed and discussed. Following administration of ayahuasca, DMT is rapidly absorbed and distributed. Harmala alkaloids act as potent inhibitors of monoamine oxidase A (MAO-A), preventing extensive first-pass degradation of DMT into 3-indole-acetic acid (3-IAA), and enabling sufficient amounts of DMT to reach the brain. DMT has affinity for a variety of serotonergic and non-serotonergic receptors, though its psychotropic effects are mainly related with the activation of serotonin receptors type 2A (5-HT2A). Mildly to rarely severe psychedelic adverse effects are reported for ayahuasca or its alkaloids individually, but abuse does not lead to dependence or tolerance. For a long time, the evidence has pointed to potential psychotherapeutic benefits in the treatment of depression, anxiety, and substance abuse disorders; and although misuse of ayahuasca has been diverting attention away from such clinical potential, research onto its therapeutic effects has now strongly resurged.
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Affiliation(s)
- Andreia Machado Brito-da-Costa
- Department of Sciences, IINFACTS-Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal; (A.M.B.-d.-C.); (N.G.M.G.); (Á.M.-C.)
| | - Diana Dias-da-Silva
- Department of Sciences, IINFACTS-Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal; (A.M.B.-d.-C.); (N.G.M.G.); (Á.M.-C.)
- UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Correspondence: (D.D.-d.-S.); (R.J.D.-O.); Tel.: +351-224-157-216 (R.J.D.-O.)
| | - Nelson G. M. Gomes
- Department of Sciences, IINFACTS-Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal; (A.M.B.-d.-C.); (N.G.M.G.); (Á.M.-C.)
- LAQV-REQUIMTE, Laboratory of Pharmacognosy, Department of Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Ricardo Jorge Dinis-Oliveira
- Department of Sciences, IINFACTS-Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal; (A.M.B.-d.-C.); (N.G.M.G.); (Á.M.-C.)
- UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Correspondence: (D.D.-d.-S.); (R.J.D.-O.); Tel.: +351-224-157-216 (R.J.D.-O.)
| | - Áurea Madureira-Carvalho
- Department of Sciences, IINFACTS-Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal; (A.M.B.-d.-C.); (N.G.M.G.); (Á.M.-C.)
- LAQV-REQUIMTE, Laboratory of Pharmacognosy, Department of Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
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Midbrain circuits of novelty processing. Neurobiol Learn Mem 2020; 176:107323. [PMID: 33053429 DOI: 10.1016/j.nlm.2020.107323] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 09/22/2020] [Accepted: 10/02/2020] [Indexed: 12/22/2022]
Abstract
Novelty triggers an increase in orienting behavior that is critical to evaluate the potential salience of unknown events. As novelty becomes familiar upon repeated encounters, this increase in response rapidly habituates as a form of behavioral adaptation underlying goal-directed behaviors. Many neurodevelopmental, psychiatric and neurodegenerative disorders are associated with abnormal responses to novelty and/or familiarity, although the neuronal circuits and cellular/molecular mechanisms underlying these natural behaviors in the healthy brain are largely unknown, as is the maladaptive processes that occur to induce impairment of novelty signaling in diseased brains. In rodents, the development of cutting-edge tools that allow for measurements of real time activity dynamics in selectively identified neuronal ensembles by gene expression signatures is beginning to provide advances in understanding the neural bases of the novelty response. Accumulating evidence indicate that midbrain circuits, the majority of which linked to dopamine transmission, promote exploratory assessments and guide approach/avoidance behaviors to different types of novelty via specific projection sites. The present review article focuses on midbrain circuit analysis relevant to novelty processing and habituation with familiarity.
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Costa LHA, Santos BM, Branco LGS. Can selective serotonin reuptake inhibitors have a neuroprotective effect during COVID-19? Eur J Pharmacol 2020; 889:173629. [PMID: 33022271 PMCID: PMC7832208 DOI: 10.1016/j.ejphar.2020.173629] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 09/18/2020] [Accepted: 10/02/2020] [Indexed: 02/08/2023]
Abstract
The absence of a specific treatment for SARS-CoV-2 infection led to an intense global effort in order to find new therapeutic interventions and improve patient outcomes. One important feature of COVID-19 pathophysiology is the activation of immune cells, with consequent massive production and release of inflammatory mediators that may cause impairment of several organ functions, including the brain. In addition to its classical role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5-HT) has immunomodulatory properties, downregulating the inflammatory response by central and peripheral mechanisms. In this review, we describe the roles of 5-HT in the regulation of systemic inflammation and the potential benefits of the use of specific serotonin reuptake inhibitors as a coadjutant therapy to attenuate neurological complications of COVID-19.
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Affiliation(s)
- Luis H A Costa
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 14040-904, Brazil
| | - Bruna M Santos
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 14040-904, Brazil
| | - Luiz G S Branco
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 14040-904, Brazil.
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Serotonin hyperpolarizes the dorsal raphe nucleus neurons of mice by activating G protein–coupled inward rectifier potassium channels. Neuroreport 2020; 31:928-935. [DOI: 10.1097/wnr.0000000000001501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Sagiv E, Gvion Y. A multi factorial model of self-harm behaviors in Anorexia-nervosa and Bulimia-nervosa. Compr Psychiatry 2020; 96:152142. [PMID: 31726288 DOI: 10.1016/j.comppsych.2019.152142] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 09/02/2019] [Accepted: 10/21/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Co-existence of eating disorders and NSSI, suicide attempts and ideations is well established yet much is not known about the personality traits and behavioral tendencies that maintain this relationship. To this date no empirical work has been produced that offers a multifactorial view on the contributing variables to the occurrence of self-harm behaviors in EDs. METHOD Binge eating, depression, impulsivity, ruminations and loss aversion were assessed in a sample of 93 patients diagnosed with Anorexia-Nervosa and Bulimia-Nervosa and other EDs with a history of NSSI and suicide attempts. RESULTS Binge eating was found to be a predictor of depression, which in turn was found to be related to NSSI frequency, suicide attempts and suicide ideations. Ruminations were found to mediate a relationship between depression and suicide ideations. Trait impulsivity predicted suicide attempts, while the attentional construct of impulsivity was associated to suicide ideations as well as attempts. Higher loss aversion was positively associated with NSSI frequency and suicide ideations. CONCLUSION Our findings suggest that trait and state aspects of impulsivity are related to different self-harm behaviors in EDs. Exploring these differences is potentially of great value in understanding the process of transition from suicidal ideation to suicide attempt and the process of NSSI and may assist clinicians formulate better interventions for patients with EDs at risk. Ways in which individual findings in our model correspond with previous research and future implications are discussed.
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Affiliation(s)
- Eran Sagiv
- Bar Ilan University, Sheba tel hashomer medical center, Israel.
| | - Yari Gvion
- Bar Ilan University, Sheba tel hashomer medical center, Israel
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Huang WS, Chen GJ, Tsai TH, Cheng CY, Shiue CY, Ma KH, Yeh SHH. In vivo long-lasting alterations of central serotonin transporter activity and associated dopamine synthesis after acute repeated administration of methamphetamine. EJNMMI Res 2019; 9:92. [PMID: 31535286 PMCID: PMC6751231 DOI: 10.1186/s13550-019-0557-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 08/23/2019] [Indexed: 11/22/2022] Open
Abstract
Background Methamphetamine (METH)-associated alterations in the striatal dopamine (DA) system or dopamine transport (DAT) have been identified in clinical and preclinical studies with positron emission tomography (PET) imaging but have not been well correlated with in vivo serotonin transporter (SERT) availability due to the lack of appropriate imaging agents to assess SERTs. N,N-dimethyl-2-(2-amino-4-[18F]-fluorophenylthio) benzylamine (4-[18F]-ADAM) has been developed by our group and validated for its high affinity and selectivity for SERTs, allowing the in vivo examination of SERT density, location, and binding function. The aims of this study were to investigate the potential of SERT imaging using 4-[18F]-ADAM PET to estimate the long-lasting effects of METH-induced serotonergic neurotoxicity, and further determine whether a correlative relationship exists between SERT availability/activity and tyrosine hydroxylase (TH) activity in various brain regions due to the long-lasting consequences of METH treatment. Results Male rats received four administrations of METH (5 or 10 mg/kg, s.c.) or saline (1 ml/kg, s.c.) at 1-h intervals. At 30 days post-administration, in vivo SERT availability and activity were measured by 4-[18F]ADAM PET imaging. In contrast to the controls, the uptake of 4-[18F]ADAM in METH-treated mice was significantly reduced in a dose-dependent manner in the midbrain, followed by the hypothalamus, thalamus, striatum, hippocampus, and frontal cortex. The regional effects of METH on TH activity were assessed by quantitative immunohistochemistry and presented as integrated optical density (IOD). A significant decrease in TH immunostaining and IOD ratios was seen in the caudate, putamen, nucleus accumbens, substantia nigra pars compacta, and substantia nigra pars reticulata in the METH-treated rats compared to controls. Conclusion The present results suggested that the long-lasting response to METH decreased the uptake of 4-[18F]-ADAM and varied regionally along with TH immunoreactivity. In addition, 4-[18F]ADAM PET could be used to detect serotonergic neuron loss and to evaluate the severity of serotonergic neurotoxicity of METH.
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Affiliation(s)
- Wen-Sheng Huang
- Department of Nuclear Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, 11217, Taiwan, Republic of China.,Nuclear Medicine Department, Tri-Service General Hospital, Taipei, Taiwan
| | - Guann-Juh Chen
- Department of Neurological Surgery, National Defense Medical Center, Tri-Service General Hospital, No. 325, Sec. 2, Chenggong Rd., Neihu District, Taipei City, 11490, Taiwan, Republic of China.,Department of Neurological Surgery, Chiayi Branch, Taichung Veterans General Hospital, No. 600, Sec. 2, Shixian Rd., West District, Chiayi City, 60090, Taiwan, Republic of China
| | - Tung-Han Tsai
- Department of Neurological Surgery, National Defense Medical Center, Tri-Service General Hospital, No. 325, Sec. 2, Chenggong Rd., Neihu District, Taipei City, 11490, Taiwan, Republic of China
| | - Chen-Yi Cheng
- Nuclear Medicine Department, Tri-Service General Hospital, Taipei, Taiwan
| | - Chyng-Yann Shiue
- Department of Nuclear Medicine, National Taiwan University Hospital, No. 1, Changde St., Zhongzheng District, Taipei City, 10048, Taiwan, Republic of China
| | - Kuo-Hsing Ma
- Department of Anatomy and Biology, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Rd., Neihu District, Taipei City, 11490, Taiwan, Republic of China.
| | - Skye Hsin-Hsien Yeh
- Brain Research Center, National Yang-Ming University, No. 155, Sec. 2, Linong Street, Taipei City, 112, Taiwan, Republic of China.
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Expression, purification and stabilization of human serotonin transporter from E. coli. Protein Expr Purif 2019; 164:105479. [PMID: 31442583 DOI: 10.1016/j.pep.2019.105479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 07/31/2019] [Accepted: 08/15/2019] [Indexed: 11/21/2022]
Abstract
The serotonin transporter belongs to the family of sodium-chloride coupled neurotransmitter transporter and is related to depression in humans. It is therefore an important drug target to support treatment of depression. Recently, structures of human serotonin transporter in complex with inhibitor molecules have been published. However, the production of large protein amounts for crystallization experiments remains a bottleneck. Here we present the possibility to obtain purified serotonin transporter from E. coli. Fos-choline 12 solubilized target protein was obtained with a purity of >95% and a yield of 1.2 mg L-1 culture in autoinduction medium. CD spectroscopic analysis of protein stability allowed identifying CHS and POPX as stabilizing components, which increased hSERT thermostability by 7 °C. The kinetic dissociation constant KD of 2.8 μM (±0.05) for of the inhibitor Desipramine was determined with a ka of 10,848 M - 1 s-1 (±220) and a kd of 0.03 s-1 (±4.7 × 10-5).
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Jayamohananan H, Manoj Kumar MK, T P A. 5-HIAA as a Potential Biological Marker for Neurological and Psychiatric Disorders. Adv Pharm Bull 2019; 9:374-381. [PMID: 31592064 PMCID: PMC6773935 DOI: 10.15171/apb.2019.044] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 04/08/2019] [Accepted: 04/14/2019] [Indexed: 11/21/2022] Open
Abstract
Neurological and psychiatric disorders occur in about 6 percent of the global population
indicating a significant amount of people suffering from neurological disorder on a varying range
in day to day life. On an extensive view, there is a critical requirement for the development of
an alternative biomarker for these conditions. The thwart found in developing a biomarker is
the difficulty in identifying a serum biomarker as these are mostly limited to the central nervous
system (CNS). Serotonin being a neurotransmitter synthesized in the raphe nuclei of the brain
could serve as an alternative biomarker. Here, the limitation is that it’s quickly metabolized
by the mitochondrial enzyme MAO to 5-hydroxy indole acetic acid (5HIAA). This subsequent
metabolite can be used for the analysis of serotonin levels in brain by analysing its concentration
in the cerebrospinal fluid (CSF). Many theories suggest that the variations in serotonin level
could lead to the development of many neurological and psychiatric disorders like Alzheimer’s
disease (AD), schizophrenia, depression and so on. A decreased level is noticed in these patients
but this could either be due to decreased production or increased reuptake of serotonin from
the neuronal synapses. For instance, we know that a patient with depression shows a significant
reduction in the levels of 5HIAA, due to the location of the raphe nuclei within regions of
memory and cognition. Similarly, it does shows variation in AD and mild cognitive disorder.
Evolving of 5HIAA as a biomarker, could be more delicate and enhanced strategy for monitoring
these disorders.
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Affiliation(s)
- Hridya Jayamohananan
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, India
| | | | - Aneesh T P
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, India
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Morgese MG, Trabace L. Monoaminergic System Modulation in Depression and Alzheimer's Disease: A New Standpoint? Front Pharmacol 2019; 10:483. [PMID: 31156428 PMCID: PMC6533589 DOI: 10.3389/fphar.2019.00483] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 04/16/2019] [Indexed: 12/26/2022] Open
Abstract
The prevalence of depression has dramatically increased, and it has been estimated that over 300 million people suffer from depression all over the world. Depression is highly comorbid with many central and peripheral disorders. In this regard, depressive states have been associated with the development of neurological disorders such as Alzheimer's disease (AD). Accordingly, depression is a risk factor for AD and depressive symptomatology is common in pre-clinical AD, representing an early manifestation of this disease. Neuropsychiatric symptoms may represent prodromal symptoms of dementia deriving from neurobiological changes in specific cerebral regions; thus, the search for common biological substrates is becoming an imperative and intriguing field of research. Soluble forms of beta amyloid peptide (Aβ) have been implicated both in the development of early memory deficits and neuropsychiatric symptoms. Indeed, soluble Aβ species have been shown to induce a depressive-like phenotype in AD animal models. Alterations in monoamine content are a common feature of these neuropathologies. Interestingly, serotonergic system modulation has been implicated in alteration of Aβ production. In addition, noradrenaline is considered crucially involved in compensatory mechanisms, leading to increased Aβ degradation via several mechanisms, including microglia modulation. In further agreement, antidepressant drugs have also been shown to potentially modulate cognitive symptoms in AD and depression. Thus, the present review summarizes the main knowledge about biological and pathological substrates, such as monoamine and related molecules, commonly involved in AD and depression pathology, thus shading light on new therapeutic approaches.
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Affiliation(s)
- Maria Grazia Morgese
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Luigia Trabace
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
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Wadhawan A, Stiller JW, Potocki E, Okusaga O, Dagdag A, Lowry CA, Benros ME, Postolache TT. Traumatic Brain Injury and Suicidal Behavior: A Review. J Alzheimers Dis 2019; 68:1339-1370. [PMID: 30909230 DOI: 10.3233/jad-181055] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Abhishek Wadhawan
- Department of Psychiatry, Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, USA
- Saint Elizabeths Hospital, Psychiatry Residency Training Program, Washington, DC, USA
| | - John W. Stiller
- Department of Psychiatry, Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, USA
- Saint Elizabeths Hospital, Neurology Consultation Service, Washington, DC, USA
- Maryland State Athletic Commission, Baltimore, MD, USA
| | - Eileen Potocki
- VA Maryland Healthcare System, Baltimore VA Medical Center, Baltimore, MD, USA
| | - Olaoluwa Okusaga
- Department of Psychiatry, Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, USA
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA
- Michael E DeBakey VA Medical Center, Houston, TX, USA
| | - Aline Dagdag
- Department of Psychiatry, Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Psychiatry, University of Maryland Medical Center, Baltimore, MD, USA
| | - Christopher A. Lowry
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA
- Department of Physical Medicine and Rehabilitation and Center for Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO, USA
| | - Michael E. Benros
- Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
| | - Teodor T. Postolache
- Department of Psychiatry, Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, USA
- Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO, USA
- Mental Illness Research, Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 5, VA Capitol Health Care Network, Baltimore, MD, USA
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Reisinger SN, Kong E, Molz B, Humberg T, Sideromenos S, Cicvaric A, Steinkellner T, Yang J, Cabatic M, Monje FJ, Sitte HH, Nichols BJ, Pollak DD. Flotillin-1 interacts with the serotonin transporter and modulates chronic corticosterone response. GENES, BRAIN, AND BEHAVIOR 2019; 18:e12482. [PMID: 29667320 PMCID: PMC6392109 DOI: 10.1111/gbb.12482] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 04/05/2018] [Accepted: 04/12/2018] [Indexed: 01/08/2023]
Abstract
Aberrant serotonergic neurotransmission in the brain is considered at the core of the pathophysiological mechanisms involved in neuropsychiatric disorders. Gene by environment interactions contribute to the development of depression and involve modulation of the availability and functional activity of the serotonin transporter (SERT). Using behavioral and in vivo electrophysiological approaches together with biochemical, molecular-biological and molecular imaging tools we establish Flotillin-1 (Flot1) as a novel protein interacting with SERT and demonstrate its involvement in the response to chronic corticosterone (CORT) treatment. We show that genetic Flot1 depletion augments chronic CORT-induced behavioral despair and describe concomitant alterations in the expression of SERT, activity of serotonergic neurons and alterations of the glucocorticoid receptor transport machinery. Hence, we propose a role for Flot1 as modulatory factor for the depressogenic consequences of chronic CORT exposure and suggest Flotillin-1-dependent regulation of SERT expression and activity of serotonergic neurotransmission at the core of the molecular mechanisms involved.
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Affiliation(s)
- S. N. Reisinger
- Department of Neurophysiology and NeuropharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - E. Kong
- Department of Neurophysiology and NeuropharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - B. Molz
- Department of Neurophysiology and NeuropharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - T. Humberg
- Department of Neurophysiology and NeuropharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - S. Sideromenos
- Department of Neurophysiology and NeuropharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - A. Cicvaric
- Department of Neurophysiology and NeuropharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - T. Steinkellner
- Department of PharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - J.‐W. Yang
- Department of PharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - M. Cabatic
- Department of Neurophysiology and NeuropharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - F. J. Monje
- Department of Neurophysiology and NeuropharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - H. H. Sitte
- Department of PharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | | | - D. D. Pollak
- Department of Neurophysiology and NeuropharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
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Bubak AN, Watt MJ, Renner KJ, Luman AA, Costabile JD, Sanders EJ, Grace JL, Swallow JG. Sex differences in aggression: Differential roles of 5-HT2, neuropeptide F and tachykinin. PLoS One 2019; 14:e0203980. [PMID: 30695038 PMCID: PMC6350964 DOI: 10.1371/journal.pone.0203980] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 01/15/2019] [Indexed: 11/18/2022] Open
Abstract
Despite the conserved function of aggression across taxa in obtaining critical resources such as food and mates, serotonin's (5-HT) modulatory role on aggressive behavior appears to be largely inhibitory for vertebrates but stimulatory for invertebrates. However, critical gaps exist in our knowledge of invertebrates that need to be addressed before definitively stating opposing roles for 5-HT and aggression. Specifically, the role of 5-HT receptor subtypes are largely unknown, as is the potential interactive role of 5-HT with other neurochemical systems known to play a critical role in aggression. Similarly, the influence of these systems in driving sex differences in aggressive behavior of invertebrates is not well understood. Here, we investigated these questions by employing complementary approaches in a novel invertebrate model of aggression, the stalk-eyed fly. A combination of altered social conditions, pharmacological manipulation and 5-HT2 receptor knockdown by siRNA revealed an inhibitory role of this receptor subtype on aggression. Additionally, we provide evidence for 5-HT2's involvement in regulating neuropeptide F activity, a suspected inhibitor of aggression. However, this function appears to be stage-specific, altering only the initiation stage of aggressive conflicts. Alternatively, pharmacologically increasing systemic concentrations of 5-HT significantly elevated the expression of the neuropeptide tachykinin, which did not affect contest initiation but instead promoted escalation via production of high intensity aggressive behaviors. Notably, these effects were limited solely to males, with female aggression and neuropeptide expression remaining unaltered by any manipulation that affected 5-HT. Together, these results demonstrate a more nuanced role for 5-HT in modulating aggression in invertebrates, revealing an important interactive role with neuropeptides that is more reminiscent of vertebrates. The sex-differences described here also provide valuable insight into the evolutionary contexts of this complex behavior.
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Affiliation(s)
- Andrew N. Bubak
- Department of Neurology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Michael J. Watt
- Center for Brain and Behavior Research, Basic Biomedical Sciences, University of South Dakota, Vermillion, South Dakota, United States of America
| | - Kenneth J. Renner
- Biology Department, University of South Dakota, Vermillion, South Dakota, United States of America
| | - Abigail A. Luman
- Department of Integrative Biology, University of Colorado-Denver, Denver, United States of America
| | - Jamie D. Costabile
- Department of Integrative Biology, University of Colorado-Denver, Denver, United States of America
| | - Erin J. Sanders
- Department of Integrative Biology, University of Colorado-Denver, Denver, United States of America
| | - Jaime L. Grace
- Department of Biology, Bradley University, Peoria, Illinois, United States of America
| | - John G. Swallow
- Department of Integrative Biology, University of Colorado-Denver, Denver, United States of America
- * E-mail:
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Sebold M, Garbusow M, Jetzschmann P, Schad DJ, Nebe S, Schlagenhauf F, Heinz A, Rapp M, Romanczuk-Seiferth N. Reward and avoidance learning in the context of aversive environments and possible implications for depressive symptoms. Psychopharmacology (Berl) 2019; 236:2437-2449. [PMID: 31254091 PMCID: PMC6695365 DOI: 10.1007/s00213-019-05299-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 06/05/2019] [Indexed: 01/22/2023]
Abstract
BACKGROUND Aversive stimuli in the environment influence human actions. This includes valence-dependent influences on action selection, e.g., increased avoidance but decreased approach behavior. However, it is yet unclear how aversive stimuli interact with complex learning and decision-making in the reward and avoidance domain. Moreover, the underlying computational mechanisms of these decision-making biases are unknown. METHODS To elucidate these mechanisms, 54 healthy young male subjects performed a two-step sequential decision-making task, which allows to computationally model different aspects of learning, e.g., model-free, habitual, and model-based, goal-directed learning. We used a within-subject design, crossing task valence (reward vs. punishment learning) with emotional context (aversive vs. neutral background stimuli). We analyzed choice data, applied a computational model, and performed simulations. RESULTS Whereas model-based learning was not affected, aversive stimuli interacted with model-free learning in a way that depended on task valence. Thus, aversive stimuli increased model-free avoidance learning but decreased model-free reward learning. The computational model confirmed this effect: the parameter lambda that indicates the influence of reward prediction errors on decision values was increased in the punishment condition but decreased in the reward condition when aversive stimuli were present. Further, by using the inferred computational parameters to simulate choice data, our effects were captured. Exploratory analyses revealed that the observed biases were associated with subclinical depressive symptoms. CONCLUSION Our data show that aversive environmental stimuli affect complex learning and decision-making, which depends on task valence. Further, we provide a model of the underlying computations of this affective modulation. Finally, our finding of increased decision-making biases in subjects reporting subclinical depressive symptoms matches recent reports of amplified Pavlovian influences on action selection in depression and suggests a potential vulnerability factor for mood disorders. We discuss our findings in the light of the involvement of the neuromodulators serotonin and dopamine.
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Affiliation(s)
- Miriam Sebold
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
- Department for Social and Preventive Medicine, University of Potsdam, Potsdam, Germany.
| | - M Garbusow
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - P Jetzschmann
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - D J Schad
- Cognitive Science, University of Potsdam, Potsdam, Germany
| | - S Nebe
- Zurich Center for Neuroeconomics, Department of Economics, University of Zurich, Zurich, Switzerland
| | - F Schlagenhauf
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
- Max Planck Institute for Human Cognitive and Brain Sciences, 04303, Leipzig, Germany
| | - A Heinz
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - M Rapp
- Department for Social and Preventive Medicine, University of Potsdam, Potsdam, Germany
| | - N Romanczuk-Seiferth
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
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