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Demin KA, Kolesnikova TO, Galstyan DS, Krotova NA, Ilyin NP, Derzhavina KA, Seredinskaya M, Nerush M, Pushkareva SA, Masharsky A, de Abreu MS, Kalueff AV. The Utility of Prolonged Chronic Unpredictable Stress to Study the Effects of Chronic Fluoxetine, Eicosapentaenoic Acid, and Lipopolysaccharide on Anxiety-Like Behavior and Hippocampal Transcriptomic Responses in Male Rats. J Neurosci Res 2025; 103:e70025. [PMID: 39907099 DOI: 10.1002/jnr.70025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 12/05/2024] [Accepted: 01/16/2025] [Indexed: 02/06/2025]
Abstract
Chronic stress is a common trigger of multiple neuropsychiatric illnesses. Animal models are widely used to study stress-induced brain disorders and their interplay with neuroinflammation and other neuroimmune processes. Here, we apply the prolonged 12-week chronic unpredictable stress (PCUS) model to examine rat behavioral and hippocampal transcriptomic responses to stress and to chronic 4-week treatment with a classical antidepressant fluoxetine, an anti-inflammatory agent eicosapentaenoic acid (EPA), a pro-inflammatory agent lipopolysaccharide and their combinations. Overall, PCUS evoked anxiety-like behavioral phenotype in rats, corrected by chronic fluoxetine (alone or combined with other drugs), and EPA. PCUS also evoked pronounced transcriptomic responses in rat hippocampi, involving > 200 differentially expressed genes. While pharmacological manipulations did not affect hippocampal gene expression markedly, Gpr6, Drd2 and Adora2a were downregulated in stressed rats treated with fluoxetine, EPA and fluoxetine + EPA, suggesting their respective protein products (G protein-coupled receptor 6, dopamine D2 receptor and adenosine A2A receptor) as potential evolutionarily conserved targets under chronic stress. Overall, these findings support the validity of rat PCUS paradigm as a useful model to study stress-related anxiety pathogenesis, and call for further research probing how various conventional and novel drugs may (co)modulate behavioral and neurotranscriptomic biomarkers of chronic stress.
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Affiliation(s)
- Konstantin A Demin
- Almazov National Medical Research Centre, St. Petersburg, Russia
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Tatiana O Kolesnikova
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
- Neuroscience Program, Sirius University of Science and Technology, Sochi, Russia
| | - David S Galstyan
- Almazov National Medical Research Centre, St. Petersburg, Russia
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Natalia A Krotova
- Almazov National Medical Research Centre, St. Petersburg, Russia
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Nikita P Ilyin
- Almazov National Medical Research Centre, St. Petersburg, Russia
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | | | - Maria Seredinskaya
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Maria Nerush
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Sofia A Pushkareva
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Alexey Masharsky
- Core Facility Centre for Molecular and Cell Technologies, St. Petersburg State University, St. Petersburg, Russia
| | - Murilo S de Abreu
- Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
- Western Caspian University, Baku, Azerbaijan
| | - Allan V Kalueff
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
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Wang D, Wang J, Yan D, Wang M, Yang L, Demin KA, de Abreu MS, Kalueff AV. Minocycline reduces neurobehavioral deficits evoked by chronic unpredictable stress in adult zebrafish. Brain Res 2024; 1845:149209. [PMID: 39233136 DOI: 10.1016/j.brainres.2024.149209] [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: 06/18/2024] [Revised: 08/11/2024] [Accepted: 08/28/2024] [Indexed: 09/06/2024]
Abstract
Chronic stress-related brain disorders are widespread and debilitating, and often cause lasting neurobehavioral deficits. Minocycline, a common antibiotic and an established inhibitor of microglia, emerges as potential treatment of these disorders. The zebrafish (Danio rerio) is an important emerging model organism in translational neuroscience and stress research. Here, we evaluated the potential of minocycline to correct microglia-mediated behavioral, genomic and neuroimmune responses induced by chronic unpredictable stress (CUS) in adult zebrafish. We demonstrated that CUS evoked overt behavioral deficits in the novel tank, light-dark box and shoaling tests, paralleled by elevated stress hormones (CRH, ACTH and cortisol), and upregulated brain expression of the 'neurotoxic M1' microglia-specific biomarker gene (MHC-2) and pro-inflammatory cytokine genes (IL-1β, IL-6 and IFN-γ). CUS also elevated peripheral (whole-body) pro-inflammatory (IL-1β, IFN-γ) and lowered anti-inflammatory cytokines (IL-4 and IL-10), as well as reduced whole-brain serotonin, dopamine and norepinephrine levels, and increased brain dopamine and serotonin turnover. In contrast, minocycline attenuated most of these effects, also reducing CUS-elevated peripheral levels of IL-6 and IFN-γ. Collectively, this implicates microglia in zebrafish responses to chronic stress, and suggests glial pathways as potential evolutionarily conserved drug targets for treating stress-evoked neuropathogenesis. Our findings also support the growing translational value of zebrafish models for understanding complex molecular mechanisms of brain pathogenesis and its therapy.
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Affiliation(s)
- Dongmei Wang
- School of Pharmacy, Southwest University, Chongqing, China
| | - Jingtao Wang
- School of Pharmacy, Southwest University, Chongqing, China
| | - Dongni Yan
- School of Pharmacy, Southwest University, Chongqing, China
| | - Mengyao Wang
- School of Pharmacy, Southwest University, Chongqing, China
| | - Longen Yang
- School of Pharmacy, Southwest University, Chongqing, China; Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou, China; Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou, China
| | - Konstantin A Demin
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Murilo S de Abreu
- Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil; Western Caspian University, Baku, Azerbaijan; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
| | - Allan V Kalueff
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia; Institute of Experimental Medicine, Almazov National Medical Research Center, St. Petersburg, Russia; Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou, China; Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou, China; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
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Inozemtseva LS, Yatsenko KA, Glazova NY, Kamensky AA, Myasoedov NF, Levitskaya NG, Grivennikov IA, Dolotov OV. Antidepressant-like and antistress effects of the ACTH(4-10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress. Eur J Pharmacol 2024; 984:177068. [PMID: 39442746 DOI: 10.1016/j.ejphar.2024.177068] [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: 02/22/2024] [Revised: 10/19/2024] [Accepted: 10/20/2024] [Indexed: 10/25/2024]
Abstract
Current antidepressant therapy shows substantial limitations, and there is an urgent need for the development of new treatment strategies for depression. Stressful events and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis play an important role in the pathogenesis of depression. HPA axis activity is self-regulated by negative feedback at several levels including adrenocorticotropic hormone (ACTH)-mediated feedback. Here, we investigated whether noncorticotropic synthetic analogs of the ACTH(4-10) fragment, ACTH(4-7)-Pro-Gly-Pro (Semax) and Ac-Nle4-cyclo[Asp5-His6-D-Phe7-Arg8-Trp9-Lys10]ACTH(4-10)-NH2 (Melanotan II (MTII), a potent agonist of melanocortin receptors), have potential antidepressant activity in a chronic unpredictable stress (CUS) rat model of depression. Stressed and control male adult Sprague-Dawley rats received daily intraperitoneal injections of saline or a low dose (60 nmol/kg of body weight (BW)) of Semax or MTII. Rats were monitored for BW and hedonic status, as measured in the sucrose preference test. We found that chronic treatment with Semax and MTII reversed or substantially attenuated CUS-induced anhedonia, BW gain suppression, adrenal hypertrophy and a decrease in the hippocampal levels of BDNF. In the forced swim test, no effects of the CUS procedure or peptides on the duration of rat immobility were detected. Our findings show that in the CUS paradigm, systemically administered ACTH(4-10) analogs Semax and MTII exert antidepressant-like effects on anhedonia and hippocampal BDNF levels, and attenuate markers of chronic stress load, at least in male rats. The results support the argument that ACTH(4-10) analogs and other noncorticotropic melanocortins may have promising therapeutic potential for the treatment and prevention of depression and other stress-related pathologies.
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Affiliation(s)
| | | | - Natalya Yu Glazova
- National Research Center "Kurchatov Institute", Moscow, Russia; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Andrey A Kamensky
- Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
| | | | - Natalia G Levitskaya
- National Research Center "Kurchatov Institute", Moscow, Russia; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
| | | | - Oleg V Dolotov
- National Research Center "Kurchatov Institute", Moscow, Russia; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
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Zhang M, Wu L, Zhang S, Li Y, Chen J. Non-coding RNA alterations in occlusal disharmony-induced anxiety-like behaviour. J Oral Rehabil 2024; 51:2248-2260. [PMID: 39049786 DOI: 10.1111/joor.13816] [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: 06/03/2023] [Revised: 07/10/2024] [Accepted: 07/17/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND Occlusal disharmony (OD) may induce anxiety-like behaviours; however, the underlying mechanism remains unclear. Herein, we explored the expression profiles of non-coding RNAs (ncRNAs), along with their biological function and regulatory network, in anxiety-like behaviour induced by OD. MATERIALS AND METHODS Occlusal disharmony was produced by anterior crossbite of C57BL/6 mice. Behavioural tests, corticosterone (CORT) and serotonin (5-HT) levels were used to measure anxiety. In addition, RNA sequencing was used to screen all differentially expressed (DE) ncRNAs. Moreover, the RNA-binding proteins interacting with ncRNAs were predicted by the ENCORI database and confirmed using western blots. RESULTS The significant differences in behavioural tests and CORT suggested the successful induction of anxiety-like behaviour by OD. In OD mice, ncRNAs were significantly dysregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that the DE ncRNAs were enriched in anxiety-related pathways. CircRNA10039 was upregulated, and PTBP1 was predicted to interact with circRNA10039. In addition, KEGG pathway analysis showed that PTBP1 may be associated with messenger RNA biogenesis and spliceosomes. CONCLUSION OD induced by anterior crossbite can lead to the anxiety-like behaviours. During this process, ncRNA also changes. CircRNA10039 and PTBP1 may play a role in OD-induced anxiety-like behaviours.
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Affiliation(s)
- Mi Zhang
- Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Wu
- School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Sihui Zhang
- School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Yuxuan Li
- School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Jiang Chen
- School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
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Gencturk S, Unal G. Rodent tests of depression and anxiety: Construct validity and translational relevance. COGNITIVE, AFFECTIVE & BEHAVIORAL NEUROSCIENCE 2024; 24:191-224. [PMID: 38413466 PMCID: PMC11039509 DOI: 10.3758/s13415-024-01171-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/03/2024] [Indexed: 02/29/2024]
Abstract
Behavioral testing constitutes the primary method to measure the emotional states of nonhuman animals in preclinical research. Emerging as the characteristic tool of the behaviorist school of psychology, behavioral testing of animals, particularly rodents, is employed to understand the complex cognitive and affective symptoms of neuropsychiatric disorders. Following the symptom-based diagnosis model of the DSM, rodent models and tests of depression and anxiety focus on behavioral patterns that resemble the superficial symptoms of these disorders. While these practices provided researchers with a platform to screen novel antidepressant and anxiolytic drug candidates, their construct validity-involving relevant underlying mechanisms-has been questioned. In this review, we present the laboratory procedures used to assess depressive- and anxiety-like behaviors in rats and mice. These include constructs that rely on stress-triggered responses, such as behavioral despair, and those that emerge with nonaversive training, such as cognitive bias. We describe the specific behavioral tests that are used to assess these constructs and discuss the criticisms on their theoretical background. We review specific concerns about the construct validity and translational relevance of individual behavioral tests, outline the limitations of the traditional, symptom-based interpretation, and introduce novel, ethologically relevant frameworks that emphasize simple behavioral patterns. Finally, we explore behavioral monitoring and morphological analysis methods that can be integrated into behavioral testing and discuss how they can enhance the construct validity of these tests.
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Affiliation(s)
- Sinem Gencturk
- Behavioral Neuroscience Laboratory, Department of Psychology, Boğaziçi University, 34342, Istanbul, Turkey
| | - Gunes Unal
- Behavioral Neuroscience Laboratory, Department of Psychology, Boğaziçi University, 34342, Istanbul, Turkey.
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O'Donnell MG, Stumpp L, Gallaher MJ, Powers RW. Pre-pregnancy stress induces maternal vascular dysfunction during pregnancy and postpartum. Reprod Sci 2023; 30:3197-3211. [PMID: 37219786 PMCID: PMC10204668 DOI: 10.1007/s43032-023-01248-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 04/21/2023] [Indexed: 05/24/2023]
Abstract
An estimated 20% of women suffer from a stress-related mood disorder including depression and anxiety during and after pregnancy, making these disorders among the most common complications of pregnancy. These stress-related disorders are associated with adverse pregnancy outcomes including gestational hypertension and preeclampsia, which are associated with poor cardiometabolic health postpartum. Despite these associations, the direct impact of stress and related disorders on maternal vascular health, and contributing mechanisms, remain understudied. The aim of this study was to investigate the effect of pre-pregnancy stress on maternal vascular outcomes in a BALB/c mouse model of chronic unpredictable stress. Maternal blood pressure and ex-vivo vascular function were investigated during pregnancy and postpartum. Offspring characteristics were assessed at the end of pregnancy and postpartum. Main findings show that pre-pregnancy stress exposure increased blood pressure during mid and late pregnancy and impaired ex vivo vascular function at the end of pregnancy. These effects persisted into the postpartum period, suggesting a long-term effect of stress on maternal vascular health, which appear to be partially attributable to disruptions in nitric oxide (NO) pathway signaling. These data suggest exposure to stress and related disorders, even prior to pregnancy, can contribute to vascular complications during pregnancy and postpartum.
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Affiliation(s)
- Mary Gemmel O'Donnell
- Magee-Womens Research Institute, Pittsburgh, PA, 15213, USA.
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
- Department of Biology, Thiel College, Greenville, PA, 16125, USA.
| | - Lauren Stumpp
- Magee-Womens Research Institute, Pittsburgh, PA, 15213, USA
| | | | - Robert W Powers
- Magee-Womens Research Institute, Pittsburgh, PA, 15213, USA
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
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Gallas-Lopes M, Bastos LM, Benvenutti R, Panzenhagen AC, Piato A, Herrmann AP. Systematic review and meta-analysis of 10 years of unpredictable chronic stress in zebrafish. Lab Anim (NY) 2023; 52:229-246. [PMID: 37709998 DOI: 10.1038/s41684-023-01239-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 08/04/2023] [Indexed: 09/16/2023]
Abstract
The zebrafish (Danio rerio) is a model animal that is being increasingly used in neuroscience research. A decade ago, the first study on unpredictable chronic stress (UCS) in zebrafish was published, inspired by protocols established for rodents in the early 1980s. Since then, several studies have been published by different groups, in some cases with conflicting results. Here we conducted a systematic review to identify studies evaluating the effects of UCS in zebrafish and meta-analytically synthetized the data of neurobehavioral outcomes and relevant biomarkers. Literature searches were performed in three databases (PubMed, Scopus and Web of Science) with a two-step screening process based on inclusion/exclusion criteria. The included studies underwent extraction of qualitative and quantitative data, as well as risk-of-bias assessment. Outcomes of included studies (n = 38) were grouped into anxiety/fear-related behavior, locomotor function, social behavior or cortisol level domains. UCS increased anxiety/fear-related behavior and cortisol levels while decreasing locomotor function, but a significant summary effect was not observed for social behavior. Despite including a substantial number of studies, the high heterogeneity and the methodological and reporting problems evidenced in the risk-of-bias analysis made it difficult to assess the internal validity of most studies and the overall validity of the model. Our review thus evidences the need to conduct well-designed experiments to better evaluate the effects of UCS on diverse behavioral patterns displayed by zebrafish.
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Affiliation(s)
- Matheus Gallas-Lopes
- Brazilian Reproducibility Initiative in Preclinical Systematic Review and Meta-Analysis (BRISA) Collaboration, Rio de Janeiro, Brazil
- Laboratório de Neurobiologia e Psicofarmacologia Experimental (PsychoLab), Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Laboratório de Psicofarmacologia e Comportamento (LAPCOM), Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Leonardo M Bastos
- Laboratório de Neurobiologia e Psicofarmacologia Experimental (PsychoLab), Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Laboratório de Psicofarmacologia e Comportamento (LAPCOM), Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Radharani Benvenutti
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Alana C Panzenhagen
- Brazilian Reproducibility Initiative in Preclinical Systematic Review and Meta-Analysis (BRISA) Collaboration, Rio de Janeiro, Brazil
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Angelo Piato
- Laboratório de Psicofarmacologia e Comportamento (LAPCOM), Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Ana P Herrmann
- Brazilian Reproducibility Initiative in Preclinical Systematic Review and Meta-Analysis (BRISA) Collaboration, Rio de Janeiro, Brazil.
- Laboratório de Neurobiologia e Psicofarmacologia Experimental (PsychoLab), Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
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Campeau S, McNulty C, Stanley JT, Gerber AN, Sasse SK, Dowell RD. Determination of steady-state transcriptome modifications associated with repeated homotypic stress in the rat rostral posterior hypothalamic region. Front Neurosci 2023; 17:1173699. [PMID: 37360161 PMCID: PMC10288150 DOI: 10.3389/fnins.2023.1173699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 05/18/2023] [Indexed: 06/28/2023] Open
Abstract
Chronic stress is epidemiologically correlated with physical and psychiatric disorders. Whereas many animal models of chronic stress induce symptoms of psychopathology, repeated homotypic stressors to moderate intensity stimuli typically reduce stress-related responses with fewer, if any, pathological symptoms. Recent results indicate that the rostral posterior hypothalamic (rPH) region is a significant component of the brain circuitry underlying response reductions (habituation) associated with repeated homotypic stress. To test whether posterior hypothalamic transcriptional regulation associates with the neuroendocrine modifications induced by repeated homotypic stress, RNA-seq was performed in the rPH dissected from adult male rats that experienced either no stress, 1, 3, or 7 stressful loud noise exposures. Plasma samples displayed reliable increases of corticosterone in all stressed groups, with the smallest increase in the group exposed to 7 loud noises, indicating significant habituation compared to the other stressed groups. While few or no differentially expressed genes were detected 24-h after one or three loud noise exposures, relatively large numbers of transcripts were differentially expressed between the group exposed to 7 loud noises when compared to the control or 3-stress groups, respectively, which correlated with the corticosterone response habituation observed. Gene ontology analyses indicated multiple significant functional terms related to neuron differentiation, neural membrane potential, pre- and post-synaptic elements, chemical synaptic transmission, vesicles, axon guidance and projection, glutamatergic and GABAergic neurotransmission. Some of the differentially expressed genes (Myt1l, Zmat4, Dlx6, Csrnp3) encode transcription factors that were independently predicted by transcription factor enrichment analysis to target other differentially regulated genes in this study. A similar experiment employing in situ hybridization histochemical analysis in additional animals validated the direction of change of the 5 transcripts investigated (Camk4, Gabrb2, Gad1, Grin2a and Slc32a) with a high level of temporal and regional specificity for the rPH. In aggregate, the results suggest that distinct patterns of gene regulation are obtained in response to a repeated homotypic stress regimen; they also point to a significant reorganization of the rPH region that may critically contribute to the phenotypic modifications associated with repeated homotypic stress habituation.
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Affiliation(s)
- Serge Campeau
- Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, United States
| | - Connor McNulty
- Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, United States
| | - Jacob T. Stanley
- Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, United States
- BioFrontiers Institute, University of Colorado, Boulder, CO, United States
| | - Anthony N. Gerber
- Department of Medicine, National Jewish Health, Denver, CO, United States
- Department of Medicine, University of Colorado, Aurora, CO, United States
| | - Sarah K. Sasse
- Department of Medicine, National Jewish Health, Denver, CO, United States
| | - Robin D. Dowell
- Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, United States
- BioFrontiers Institute, University of Colorado, Boulder, CO, United States
- Department of Computer Science, University of Colorado, Boulder, CO, United States
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Kalinichenko LS, Smaga I, Filip M, Lenz B, Kornhuber J, Müller CP. Sex-specific effects of different types of prenatal stress on foetal testosterone levels and NMDA expression in mice. Behav Brain Res 2023; 439:114225. [PMID: 36435218 DOI: 10.1016/j.bbr.2022.114225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 11/24/2022]
Abstract
Prenatal stress is a critical life event often resulting in mental illnesses in the offspring. The critical developmental processes, which might trigger a cascade of molecular events resulting in mental disorders in adulthood, are still to be elucidated. Here we proposed that sex hormones, particularly testosterone, might determine the "developmental programming" of long-term consequences of prenatal stress in foetuses of both sexes. We observed that severe prenatal stress in the model of repeated corticosterone injections enhanced brain levels of corticosterone and testosterone in male foetuses. The expression of GluN1 and GluN2A, but not GluN2B NMDA receptor subunits were significantly reduced in the brain of stressed male foetuses. However, female foetuses were protected against stress effects on the brain corticosterone and testosterone levels. More moderate types of stress, such as repeated restraint stress and chronic unpredictable stress, did not induce an increase in brain corticosterone in dams and testosterone concentrations in foetuses of both sexes. Moreover, chronic unpredictable stress reduced brain testosterone concentration in male foetuses. Altogether, changes in brain testosterone level might be one of the crucial mechanisms determining the development of long-term consequences of severe prenatal stress in male, but not in female foetuses. Targeting this mechanism might allow to develop principally new prediction and therapeutic approaches for prenatal stress-associated psychiatric disorders.
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Affiliation(s)
- Liubov S Kalinichenko
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany.
| | - Irena Smaga
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Smętna 12, Kraków 31-343, Poland
| | - Malgorzata Filip
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Smętna 12, Kraków 31-343, Poland
| | - Bernd Lenz
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, J5, Mannheim 68159, Germany
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Christian P Müller
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany; Centre for Drug Research, Universiti Sains Malaysia, Minden, Penang 11800, Malaysia
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10
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Martins-Macedo J, Mateus-Pinheiro A, Alves C, Veloso F, Gomes ED, Ribeiro I, Correia JS, Silveira-Rosa T, Alves ND, Rodrigues AJ, Bessa JM, Sousa N, Oliveira JF, Patrício P, Pinto L. StressMatic: A Novel Automated System to Induce Depressive- and Anxiety-like Phenotype in Rats. Cells 2023; 12:cells12030381. [PMID: 36766724 PMCID: PMC9913774 DOI: 10.3390/cells12030381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/09/2023] [Accepted: 01/17/2023] [Indexed: 01/22/2023] Open
Abstract
Major depressive disorder (MDD) is a multidimensional psychiatric disorder that is estimated to affect around 350 million people worldwide. Generating valid and effective animal models of depression is critical and has been challenging for neuroscience researchers. For preclinical studies, models based on stress exposure, such as unpredictable chronic mild stress (uCMS), are amongst the most reliable and used, despite presenting concerns related to the standardization of protocols and time consumption for operators. To overcome these issues, we developed an automated system to expose rodents to a standard uCMS protocol. Here, we compared manual (uCMS) and automated (auCMS) stress-exposure protocols. The data shows that the impact of the uCMS exposure by both methods was similar in terms of behavioral (cognition, mood, and anxiety) and physiological (cell proliferation and endocrine variations) measurements. Given the advantages of time and standardization, this automated method represents a step forward in this field of preclinical research.
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Affiliation(s)
- Joana Martins-Macedo
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
- Bn’ML—Behavioral & Molecular Lab, University of Minho, 4710-057 Braga, Portugal
| | - António Mateus-Pinheiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
- Bn’ML—Behavioral & Molecular Lab, University of Minho, 4710-057 Braga, Portugal
| | - Cátia Alves
- Bn’ML—Behavioral & Molecular Lab, University of Minho, 4710-057 Braga, Portugal
- Department of Marketing and International Business, University of Vienna, Oskar Morgenstern-Platz 1, 1090 Vienna, Austria
| | - Fernando Veloso
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
- 2Ai—School of Technology, IPCA, 4750-810 Barcelos, Portugal
- LASI—Associate Laboratory of Intelligent Systems, 4800-058 Guimarães, Portugal
- Department of Mechanical Engineering, School of Engineering, University of Minho, 4800-058 Guimarães, Portugal
| | - Eduardo D. Gomes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
| | - Inês Ribeiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
| | - Joana S. Correia
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
- Bn’ML—Behavioral & Molecular Lab, University of Minho, 4710-057 Braga, Portugal
| | - Tiago Silveira-Rosa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
| | - Nuno D. Alves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
| | - Ana J. Rodrigues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
| | - João M. Bessa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
- Bn’ML—Behavioral & Molecular Lab, University of Minho, 4710-057 Braga, Portugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
- Bn’ML—Behavioral & Molecular Lab, University of Minho, 4710-057 Braga, Portugal
| | - João F. Oliveira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
- 2Ai—School of Technology, IPCA, 4750-810 Barcelos, Portugal
| | - Patrícia Patrício
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
- Bn’ML—Behavioral & Molecular Lab, University of Minho, 4710-057 Braga, Portugal
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal
- Bn’ML—Behavioral & Molecular Lab, University of Minho, 4710-057 Braga, Portugal
- Correspondence: ; Tel.: +351-253-604-929
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11
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Demin KA, Krotova NA, Ilyin NP, Galstyan DS, Kolesnikova TO, Strekalova T, de Abreu MS, Petersen EV, Zabegalov KN, Kalueff AV. Evolutionarily conserved gene expression patterns for affective disorders revealed using cross-species brain transcriptomic analyses in humans, rats and zebrafish. Sci Rep 2022; 12:20836. [PMID: 36460699 PMCID: PMC9718822 DOI: 10.1038/s41598-022-22688-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 10/18/2022] [Indexed: 12/03/2022] Open
Abstract
Widespread, debilitating and often treatment-resistant, depression and other stress-related neuropsychiatric disorders represent an urgent unmet biomedical and societal problem. Although animal models of these disorders are commonly used to study stress pathogenesis, they are often difficult to translate across species into valuable and meaningful clinically relevant data. To address this problem, here we utilized several cross-species/cross-taxon approaches to identify potential evolutionarily conserved differentially expressed genes and their sets. We also assessed enrichment of these genes for transcription factors DNA-binding sites down- and up- stream from their genetic sequences. For this, we compared our own RNA-seq brain transcriptomic data obtained from chronically stressed rats and zebrafish with publicly available human transcriptomic data for patients with major depression and their respective healthy control groups. Utilizing these data from the three species, we next analyzed their differential gene expression, gene set enrichment and protein-protein interaction networks, combined with validated tools for data pooling. This approach allowed us to identify several key brain proteins (GRIA1, DLG1, CDH1, THRB, PLCG2, NGEF, IKZF1 and FEZF2) as promising, evolutionarily conserved and shared affective 'hub' protein targets, as well as to propose a novel gene set that may be used to further study affective pathogenesis. Overall, these approaches may advance cross-species brain transcriptomic analyses, and call for further cross-species studies into putative shared molecular mechanisms of affective pathogenesis.
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Affiliation(s)
- Konstantin A Demin
- Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia.
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.
| | - Nataliya A Krotova
- Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Nikita P Ilyin
- Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
- Neurobiology Program, Sirius University of Science and Technology, Sochi, Russia
| | - David S Galstyan
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
- Laboratory of Preclinical Bioscreening, Granov Russian Research Center of Radiology and Surgical Technologies, Ministry of Healthcare of Russian Federation, Pesochny, Russia
| | | | | | | | | | | | - Allan V Kalueff
- Laboratory of Preclinical Bioscreening, Granov Russian Research Center of Radiology and Surgical Technologies, Ministry of Healthcare of Russian Federation, Pesochny, Russia.
- Institute of Neurosciences and Medicine, Novosibirsk, Russia.
- Ural Federal University, Ekaterinburg, Russia.
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12
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Verma H, Shivavedi N, Tej GNVC, Kumar M, Nayak PK. Prophylactic administration of rosmarinic acid ameliorates depression-associated cardiac abnormalities in Wistar rats: Evidence of serotonergic, oxidative, and inflammatory pathways. J Biochem Mol Toxicol 2022; 36:e23160. [PMID: 35838106 DOI: 10.1002/jbt.23160] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 05/05/2022] [Accepted: 07/01/2022] [Indexed: 12/16/2022]
Abstract
Psychiatric disorders and associated cardiac comorbidities have increased the risk of mortality worldwide. Researchers reported that depression increases the possibility of future cardiac abnormalities by approximately 30%. Therefore, there is an unmet need to develop therapeutic interventions to treat depression and associated cardiac abnormalities. The present study was conducted to evaluate the prophylactic effect of rosmarinic acid (RA) against chronic unpredictable stress (CUS)-induced depression associated cardiac abnormalities in Wistar rats. The CUS paradigm, which comprised several stressors, was employed for 40 days to induce depressive-like behavior and associated cardiac abnormalities in rats. Along with CUS, RA at a dose of 25 and 50 mg/kg was administered orally to two groups of animals for 40 days. Behavioral tests (forced swim test and sucrose consumption test) and molecular biomarkers (corticosterone and serotonin) were performed. Electrocardiography was performed before CUS (Day 0), Day 20, and Day 40 to study electrocardiogram parameters. Furthermore, changes in body weight, organ weight, tissue lipid peroxidation, glutathione, catalase, cTn-I, MMP-2, and proinflammatory cytokines (TNF-α and IL-6) were estimated. Our results showed that RA treatment caused a reduction in immobility period, adrenal hyperplasia, corticosterone level, tissue lipid peroxidation, cTn-I, MMP-2, proinflammatory cytokines, and QRS complex duration, while an increase in sucrose consumption, brain serotonin level, T-wave width, glutathione, and catalase activity as compared with the CUS-control group. The results of our study proved that RA administration ameliorates CUS-induced depression-associated cardiac abnormalities in rats via serotonergic, oxidative, and inflammatory pathways.
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Affiliation(s)
- Himanshu Verma
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (IIT), Banaras Hindu University (BHU), Varanasi, Uttar Pradesh, India
| | - Naveen Shivavedi
- Shri Ram Group Of Institutions, Faculty of Pharmacy, Jabalpur, Madhya Pradesh, India
| | - Gullanki N V C Tej
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (IIT), Banaras Hindu University (BHU), Varanasi, Uttar Pradesh, India
| | - Mukesh Kumar
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (IIT), Banaras Hindu University (BHU), Varanasi, Uttar Pradesh, India
| | - Prasanta K Nayak
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (IIT), Banaras Hindu University (BHU), Varanasi, Uttar Pradesh, India
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13
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Aleksic M, Brkic Z, Petrovic Z, Francija E, Lukic I, Adzic M. Sex‐specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive‐like behavior in mice. J Neurosci Res 2022; 100:1239-1253. [DOI: 10.1002/jnr.25032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 01/17/2022] [Accepted: 01/29/2022] [Indexed: 11/09/2022]
Affiliation(s)
- Minja Aleksic
- Department of Molecular Biology and Endocrinology, “VINČA” Institute of Nuclear Sciences ‐ National Institute of thе Republic of Serbia University of Belgrade Belgrade Serbia
| | - Zeljka Brkic
- Department of Molecular Biology and Endocrinology, “VINČA” Institute of Nuclear Sciences ‐ National Institute of thе Republic of Serbia University of Belgrade Belgrade Serbia
| | - Zorica Petrovic
- Dominick P. Purpura Department of Neuroscience Albert Einstein College of Medicine Bronx New York USA
| | - Ester Francija
- Department of Molecular Biology and Endocrinology, “VINČA” Institute of Nuclear Sciences ‐ National Institute of thе Republic of Serbia University of Belgrade Belgrade Serbia
| | - Iva Lukic
- Department of Molecular Biology and Endocrinology, “VINČA” Institute of Nuclear Sciences ‐ National Institute of thе Republic of Serbia University of Belgrade Belgrade Serbia
| | - Miroslav Adzic
- Department of Molecular Biology and Endocrinology, “VINČA” Institute of Nuclear Sciences ‐ National Institute of thе Republic of Serbia University of Belgrade Belgrade Serbia
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14
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Rhaponticum uniflorum and Serratula centauroides Extracts Attenuate Emotional Injury in Acute and Chronic Emotional Stress. Pharmaceuticals (Basel) 2021; 14:ph14111186. [PMID: 34832968 PMCID: PMC8621925 DOI: 10.3390/ph14111186] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/15/2021] [Accepted: 11/17/2021] [Indexed: 11/16/2022] Open
Abstract
In modern life, the use of plant stress-protectors has taken on particular significance due to the wide distribution of neurosis-like and neurotic diseases caused by neuroendocrine-immune system imbalance. Special attention has been paid to the plants containing ecdysteroids, i.e., hormone-like bioactive substances with high adaptogenic activity. The article deals with the study of bioactivity of two plant extracts as Rhaponticum uniflorum (L.) DC. and Serratula centauroides L. with a high content of ecdysteroids and phenolic compounds. The models of acute and chronic emotional stress in white rats were used to estimate the stress-protective activity of R. uniflorum and S. centauroides extracts. Both extracts showed the stress-protective effect via inhibiting the development of signs induced by single and long-term effects of stress factors. In acute stress, the development of Selye's triad signs was less pronounced against the background of the plant remedies introduction. In chronic stress, the extracts prevented the development of anxiety-depressive syndrome. Besides, R. uniflorum and S. centauroides extracts banned the development of stress-induced injuries in the brain cortex and had a neuroprotective effect on ischemia against chronic stress. The stress-protective effects of both plant extracts were based on a decrease of hyperactivation of the central stress-promoting systems (sympathoadrenal, hypothalamic-pituitary-adrenal) due to their GABA-mimetic effects. Peripheral mechanisms were connected with the inhibition of free radical oxidation processes and with an increase in the endogenous antioxidant system activity. Thus, R. uniflorum and S. centauroides extracts have a high potential to increase non-specific body resistance against acute and chronic emotional stress effects.
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15
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Xiong TW, Liu B, Wu Q, Xu YY, Liu P, Wang Y, Liu J, Shi JS. Beneficial effects of Dendrobium nobile Lindl. Alkaloids (DNLA) on anxiety and depression induced by chronic unpredictable stress in rats. Brain Res 2021; 1771:147647. [PMID: 34481787 DOI: 10.1016/j.brainres.2021.147647] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/26/2021] [Accepted: 08/31/2021] [Indexed: 11/25/2022]
Abstract
Dendrobium nobile Lindl. alkaloid (DNLA) is effective against animal models of Alzheimer's disease. This study further examined its effect on anxiety and depression produced by chronic unpredictable stress (CUS). Rats were subjected to CUS for 42 days, followed by DNLA treatment (20 mg/kg/day, po) for 28 days. The behavioral tests, histopathology, neurotransmitters and RNA-Seq were examined. DNLA attenuated body weight loss and CUS-induced anxiety/depressive-like behaviors, as evidenced by the elevated-plus-maze test, open-field test and sucrose preference. DNLA alleviated neuronal damage and loss and increased Nissl bodies in the hippocampus CA2 region and cortex. DNLA decreased CUS-elevated 5-hydroxytryptamine, dopamine and monoamine oxidase and catechol-O-methyltransferase activities in the brain. DNLA attenuated HPA activation by decreasing adrenocorticotropic hormones and the expression of corticotropin-releasing hormone receptor-1, and increased the expression of glucocorticoid receptor in the brain. RNA-Seq revealed distinct gene expression patterns among groups. Gene ontology revealed the cell projection assembly, postsynapse and centrosome as top biological processes, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment showed the cAMP, cGMP-PKG, glutamatergic synapse and circadian as major pathways for DNLA effects. Using DESeq2, CUS modulated 1700 differentially expressed genes (DEGs), which were prevented or attenuated by DNLA. CUS-induced DEGs were highly correlated with the Gene Expression Omnibus (GEO) database for anxiety and depression and were ameliorated by DNLA. Taken together, DNLA attenuated anxiety/depression-like behavior and neuronal damage induced by CUS in rats. The mechanisms could be related to regulation of the monoamine neurotransmitters and the HPA axis, and modulation of gene expression in the hippocampus.
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Affiliation(s)
- Ting-Wang Xiong
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, China; Zunyi Medical and Pharmaceutical College, Zunyi, China.
| | - Bo Liu
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Qin Wu
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Yun-Yan Xu
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Ping Liu
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, China; Department of Clinical Pharmacy, Zunyi Medical University, Zunyi, China.
| | - Yan Wang
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Jie Liu
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Jing-Shan Shi
- Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, China.
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16
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Chakraborty P, Chattarji S, Jeanneteau F. A salience hypothesis of stress in PTSD. Eur J Neurosci 2021; 54:8029-8051. [PMID: 34766390 DOI: 10.1111/ejn.15526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 09/13/2021] [Accepted: 10/30/2021] [Indexed: 11/30/2022]
Abstract
Attention to key features of contexts and things is a necessary tool for all organisms. Detecting these salient features of cues, or simply, salience, can also be affected by exposure to traumatic stress, as has been widely reported in individuals suffering from post-traumatic stress disorder (PTSD). Interestingly, similar observations have been robustly replicated across many animal models of stress as well. By using evidence from such rodent stress paradigms, in the present review, we explore PTSD through the lens of salience processing. In this context, we propose that interaction between the neurotrophin brain-derived neurotrophic factor (BDNF) and glucocorticoids determines the long lasting cellular and behavioural consequences of stress salience. We also describe the dual effect of glucocorticoid therapy in the amelioration of PTSD symptoms. Finally, by integrating in vivo observations at multiple scales of plasticity, we propose a unifying hypothesis that pivots on a crucial role of glucocorticoid signalling in dynamically orchestrating stress salience.
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Affiliation(s)
- Prabahan Chakraborty
- Institut de Genomique Fonctionnelle, University of Montpellier, Inserm, CNRS, Montpellier, 34090, France.,Tata Institute of Fundamental Research, National Centre for Biological Sciences, Bellary Road, Bangalore, 560065, India
| | - Sumantra Chattarji
- Tata Institute of Fundamental Research, National Centre for Biological Sciences, Bellary Road, Bangalore, 560065, India.,Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India.,Centre for Discovery Brain Sciences, Deanery of Biomedical Sciences, University of Edinburgh, Edinburgh, UK
| | - Freddy Jeanneteau
- Institut de Genomique Fonctionnelle, University of Montpellier, Inserm, CNRS, Montpellier, 34090, France
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17
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Colla ARS, Pazini FL, Lieberknecht V, Camargo A, Rodrigues ALS. Ursolic acid abrogates depressive-like behavior and hippocampal pro-apoptotic imbalance induced by chronic unpredictable stress. Metab Brain Dis 2021; 36:437-446. [PMID: 33394285 DOI: 10.1007/s11011-020-00658-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 12/14/2020] [Indexed: 01/01/2023]
Abstract
Emerging evidence has shown that ursolic acid exerts antidepressant-like effects, however, its ability to elicit an antidepressant-like response in rodents subjected to stress model that mimics behavioral and neurochemical alterations found in depression remains to be determined. Thus, this study investigated the possible antidepressant-like effect of ursolic acid in mice subjected to chronic unpredictable stress (CUS) for 14 days, and whether this effect could be associated with the modulation of serum corticosterone levels and hippocampal Bcl-2/Bax mRNA expression. Our results indicated that CUS induced a depressive-like behavior, as demonstrated by an increase in the immobility time and latency to first grooming in the tail suspension test and splash test, respectively. Conversely, the repeated administration of ursolic acid (0.1 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.) in the last 7 days of CUS completely prevented CUS-induced behavioral alterations, suggesting an antidepressant-like effect. Additionally, CUS significantly increased the mRNA expression of Bax (pro-apoptosis marker), but not Bcl-2 (anti-apoptosis marker) in the hippocampus. Moreover, reduced hippocampal mRNA expression of Bcl-2/Bax ratio was detected in CUS-exposed mice. Ursolic acid, but not fluoxetine, prevented CUS-induced increase in the expression of Bax, but both ursolic acid and fluoxetine prevented CUS-induced reduction on Bcl-2/Bax ratio. Furthermore, neither CUS nor treatments with ursolic acid or fluoxetine altered serum corticosterone levels. Our study unveils the ability of ursolic acid to prevent the depressive-like behavior induced by stress and the modulation of Bcl-2/Bax expression could be associated with this response.
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Affiliation(s)
- André R S Colla
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, 88040-900, SC, Brazil
| | - Francis L Pazini
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, 88040-900, SC, Brazil
| | - Vicente Lieberknecht
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, 88040-900, SC, Brazil
| | - Anderson Camargo
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, 88040-900, SC, Brazil
| | - Ana Lúcia S Rodrigues
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, 88040-900, SC, Brazil.
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18
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Understanding complex dynamics of behavioral, neurochemical and transcriptomic changes induced by prolonged chronic unpredictable stress in zebrafish. Sci Rep 2020; 10:19981. [PMID: 33203921 PMCID: PMC7673038 DOI: 10.1038/s41598-020-75855-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 10/12/2020] [Indexed: 12/11/2022] Open
Abstract
Stress-related neuropsychiatric disorders are widespread, debilitating and often treatment-resistant illnesses that represent an urgent unmet biomedical problem. Animal models of these disorders are widely used to study stress pathogenesis. A more recent and historically less utilized model organism, the zebrafish (Danio rerio), is a valuable tool in stress neuroscience research. Utilizing the 5-week chronic unpredictable stress (CUS) model, here we examined brain transcriptomic profiles and complex dynamic behavioral stress responses, as well as neurochemical alterations in adult zebrafish and their correction by chronic antidepressant, fluoxetine, treatment. Overall, CUS induced complex neurochemical and behavioral alterations in zebrafish, including stable anxiety-like behaviors and serotonin metabolism deficits. Chronic fluoxetine (0.1 mg/L for 11 days) rescued most of the observed behavioral and neurochemical responses. Finally, whole-genome brain transcriptomic analyses revealed altered expression of various CNS genes (partially rescued by chronic fluoxetine), including inflammation-, ubiquitin- and arrestin-related genes. Collectively, this supports zebrafish as a valuable translational tool to study stress-related pathogenesis, whose anxiety and serotonergic deficits parallel rodent and clinical studies, and genomic analyses implicate neuroinflammation, structural neuronal remodeling and arrestin/ubiquitin pathways in both stress pathogenesis and its potential therapy.
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19
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Boyko M, Kutz R, Grinshpun J, Zvenigorodsky V, Gruenbaum BF, Gruenbaum SE, Frenkel A, Brotfain E, Israel Melamed, Frank D, Zeldetz V, Zlotnik A. The effect of depressive-like behavior and antidepressant therapy on social behavior and hierarchy in rats. Behav Brain Res 2019; 370:111953. [PMID: 31108115 PMCID: PMC6863054 DOI: 10.1016/j.bbr.2019.111953] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 05/15/2019] [Accepted: 05/16/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Depression is common and results in a significant morbidity and economic burden. Depression is associated with pervasive impairments in social functioning, and antidepressant treatments are highly variable in improving these impairments. The objectives of this study were to test the effects of depression on social organization and behavior in a rodent model of depression, and to study the effectiveness of antidepressant medication in improving both symptoms of depression and the social function of depressed animals. METHODS One hundred-twenty male Sprague-Dawley rats were randomly and equally divided between the control group and depression group. After induction of depression by 5 weeks of chronic unpredictable stress, rats received either antidepressant treatment or placebo. In parallel with the initiation of drug therapy, 20 social groups of six rats were subjected to the complex diving-for-food situation to evaluate their social functioning. Four behavioral tests evaluated symptoms of depression and anxiety at 3 different time points. RESULTS We found that 1) depressed rats were significantly more active and aggressive in all parameters of social organization test compared with the control and antidepressant treatment groups, 2) depressed rats that received antidepressant treatment exhibited social behaviors like the control group, and 3) depression in the experimental groups was not accompanied by symptoms of anxiety. CONCLUSIONS These results suggest that depression can significantly alter the social behavior and hierarchy in the social group in rats. Investigations of complex social group dynamics offer novel opportunities for translational studies of mood and psychiatric disorders.
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Affiliation(s)
- Matthew Boyko
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva, Israel.
| | - Ruslan Kutz
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva, Israel
| | - Julia Grinshpun
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva, Israel
| | - Vladislav Zvenigorodsky
- Department of Radiology, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva, Israel
| | - Benjamin F Gruenbaum
- Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, 06525, USA
| | - Shaun E Gruenbaum
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Amit Frenkel
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva, Israel
| | - Evgeni Brotfain
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva, Israel
| | - Israel Melamed
- Department of Neurosurgery, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva, Israel
| | - Dmitry Frank
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva, Israel
| | - Vladimir Zeldetz
- Department of Emergent Medicine, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva, Israel
| | - Alexander Zlotnik
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva, Israel
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20
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Hypothalamic-pituitary-adrenal axis responsivity to an acute novel stress in female rats subjected to the chronic mild stress paradigm. Brain Res 2019; 1723:146402. [PMID: 31446015 DOI: 10.1016/j.brainres.2019.146402] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 08/20/2019] [Accepted: 08/21/2019] [Indexed: 12/29/2022]
Abstract
The chronic mild stress (CMS) paradigm is the most frequently investigated animal model for major depression. The hypothalamic-pituitary-adrenal (HPA) axis participates in the generation of depressive symptomatology. We examined whether the depression-like state induced by CMS is associated with immediate changes in HPA axis activation in response to a novel acute stress and whether this response could be modified by hormonal status. Adult female Wistar rats were ovariectomized and received estrogen or vehicle pellets. After 2 weeks, rats were subjected to CMS (or control) conditions for 2.5 or 4.5 weeks. Rats were subsequently subjected to restraint stress for 1 h, and plasma corticosterone (CT) levels were determined before (2:00 p.m.) and after acute stress induction (3:00 and 4:00 p.m.). CT levels and FOS expression were measured in the medial parvocellular subdivision of the PVN (PaMP), central (CeA) and medial amygdala (MeA) and ventral subiculum of the hippocampus (vSub). Plasma CT levels in animals treated with 6.5 weeks of estrogen were elevated before and 1 h after restraint stress induction. Results indicate that the estrogen chronicity and CMS exposure impacted CT secretion. Neuronal PaMP, CeA, MeA and vSub activity decreased after 4.5 weeks of CMS in all groups. No differences were detected between CMS and non-CMS groups. These data suggest that the HPA central hyporesponsiveness observed in the experimental groups subjected to a longer protocol period was independent to CMS paradigm and estrogen treatment restored partially its activity. These data suggest that additional stressors could be responsible for the observed alterations of the HPA axis.
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Filho PWLL, Chaves Filho AJM, Vieira CFX, Oliveira TDQ, Soares MVR, Jucá PM, Quevedo J, Barichello T, Macedo D, das Chagas Medeiros F. Peritoneal endometriosis induces time-related depressive- and anxiety-like alterations in female rats: involvement of hippocampal pro-oxidative and BDNF alterations. Metab Brain Dis 2019; 34:909-925. [PMID: 30798429 DOI: 10.1007/s11011-019-00397-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 02/06/2019] [Indexed: 12/12/2022]
Abstract
Endometriosis is a gynecological condition affecting 10% of women in reproductive age. High rates of depression and anxiety are observed in these patients. The mechanisms underlying endometriosis-induced behavioral alterations are still elusive. Animal models provide a useful tool to study the temporal sequence and biological pathways involved in this disease and comorbid states. Here, we sought to characterize time-related behavioral alterations in rats submitted to endometriosis model (EM) induced by peritoneal auto-transplantation of uterine tissues weekly for three weeks. Corticosterone stress reactivity, oxidative stress markers - reduced glutathione (GSH), lipid peroxidation, activity of superoxide dismutase (SOD) and myeloperoxidase (MPO) - and brain-derived-neurotrophic factor (BDNF) levels in the hippocampus were also evaluated. We observed a progressive increase in anxiety-like behavior from 14th to 21st days post-EM. Despair-like behavior was observed from the 14th day post-EM on, while anhedonia and apathetic-like behaviors accompanied by increased corticosterone stress response were detected on 21 days post-EM. Increased pain sensitivity was observed from the 7th day post-EM and was accompanied by increased endometrioma weight. The pro-oxidative alterations, decreased GSH and increased SOD activity were observed on 21 days post-EM, except for lipid peroxidation that was altered from the 14th day. Decreased BDNF also occurred on the 21st day. Therefore, this study demonstrates that EM is related to several features of clinical depression and proposes the contribution of hippocampal oxidative state and neurotrophic support for the emergence of these changes. Our results support the use of this model as a useful tool to test new strategies for endometriosis-related neuropsychiatric symptoms.
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Affiliation(s)
- Paulo Wagner Linhares Lima Filho
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Rua Cel. Nunes de Melo 1000. CEP, Fortaleza, Ceará, 60430-270, Brazil
- Surgery Department, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Adriano José Maia Chaves Filho
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Rua Cel. Nunes de Melo 1000. CEP, Fortaleza, Ceará, 60430-270, Brazil
| | - Charliene Freire Xavier Vieira
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Rua Cel. Nunes de Melo 1000. CEP, Fortaleza, Ceará, 60430-270, Brazil
| | - Tatiana de Queiroz Oliveira
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Rua Cel. Nunes de Melo 1000. CEP, Fortaleza, Ceará, 60430-270, Brazil
| | - Michelle Verde Ramo Soares
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Rua Cel. Nunes de Melo 1000. CEP, Fortaleza, Ceará, 60430-270, Brazil
| | - Paloma Marinho Jucá
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Rua Cel. Nunes de Melo 1000. CEP, Fortaleza, Ceará, 60430-270, Brazil
| | - Joao Quevedo
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Laboratory of Neurosciences, Graduate Program in Health Sciences, University of Southern Santa Catarina - UNESC, Criciúma, SC, Brazil
| | - Tatiana Barichello
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Laboratory of Neurosciences, Graduate Program in Health Sciences, University of Southern Santa Catarina - UNESC, Criciúma, SC, Brazil
| | - Danielle Macedo
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Rua Cel. Nunes de Melo 1000. CEP, Fortaleza, Ceará, 60430-270, Brazil.
- National Institute for Translational Medicine (INCT-TM, CNPq), Ribeirão Preto, Brazil.
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22
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Milanesi LH, Rossato DR, Dias VT, Kronbauer M, D’avila LF, Somacal S, Duarte T, Duarte MMF, Emanuelli T, Burger ME. Mediterranean X Western based diets: Opposite influences on opioid reinstatement. Toxicol Lett 2019; 308:7-16. [DOI: 10.1016/j.toxlet.2019.03.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 02/11/2019] [Accepted: 03/17/2019] [Indexed: 01/06/2023]
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Chaby LE, Karavidha K, Lisieski MJ, Perrine SA, Liberzon I. Cognitive Flexibility Training Improves Extinction Retention Memory and Enhances Cortical Dopamine With and Without Traumatic Stress Exposure. Front Behav Neurosci 2019; 13:24. [PMID: 30881293 PMCID: PMC6406056 DOI: 10.3389/fnbeh.2019.00024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Accepted: 01/30/2019] [Indexed: 11/13/2022] Open
Abstract
Stress exposure can cause lasting changes in cognition, but certain individual traits, such as cognitive flexibility, have been shown to reduce the degree, duration, or severity of cognitive changes following stress. Both stress and cognitive flexibility training affect decision making by modulating monoamine signaling. Here, we test the role cognitive flexibility training, and high vs. low cognitive flexibility at the individual level, in attenuating stress-induced changes in memory and monoamine levels using the single prolonged stress (SPS) rodent model of traumatic stress in male Sprague-Dawley rats. Exposure to SPS can heighten fear responses to conditioned cues (i.e., freezing) after a fear association has been extinguished, referred to as a deficit in extinction retention. This deficit is thought to reflect an impairment in context processing that is characteristic of posttraumatic stress disorder (PTSD). During a cognitive flexibility training we assessed individual variability in cognitive skills and conditioned rats to discriminately use cues in their environment. We found that cognitive flexibility training, alone or followed by SPS exposure, accelerated extinction learning and decreased fear responses over time during extinction retention testing, compared with rats not given cognitive flexibility training. These findings suggest that cognitive flexibility training may improve context processing in individuals with and without traumatic stress exposure. Individual performance during the reversal phase of the cognitive flexibility training predicted subsequent context processing; individuals with high reversal performance exhibited a faster decrease in freezing responses during extinction retention testing. Thus, high reversal performance predicted enhanced retention of extinction learning over time and suggests that cognitive flexibility training may be a strategy to promote context processing. In a brain region vital for maintaining cognitive flexibility and fear suppression, the prelimbic cortex (PLC), cognitive flexibility training also lastingly enhanced dopamine (DA) and norepinephrine (NE) levels, in animals with and without traumatic stress exposure. In contrast, cognitive flexibility training prior to traumatic stress exposure decreased levels of DA and its metabolites in the striatum, a region mediating reflexive decision making. Overall, our results suggest that cognitive flexibility training can provide lasting benefits by enhancing extinction retention, a hallmark cognitive effect of trauma, and prelimbic DA, which can maintain flexibility across changing contexts.
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Affiliation(s)
- Lauren E Chaby
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States.,Research Service, John D. Dingell VA Medical Center, Detroit, MI, United States
| | - Klevis Karavidha
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States
| | - Michael J Lisieski
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States
| | - Shane A Perrine
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States.,Research Service, John D. Dingell VA Medical Center, Detroit, MI, United States
| | - Israel Liberzon
- Department of Psychiatry, VA Medical Center, Ann Arbor, MI, United States.,Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States
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24
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Lima CNDC, da Silva FER, Chaves Filho AJM, Queiroz AIDG, Okamura AMNC, Fries GR, Quevedo J, de Sousa FCF, Vasconcelos SMM, de Lucena DF, Fonteles MMDF, Macedo DS. High Exploratory Phenotype Rats Exposed to Environmental Stressors Present Memory Deficits Accompanied by Immune-Inflammatory/Oxidative Alterations: Relevance to the Relationship Between Temperament and Mood Disorders. Front Psychiatry 2019; 10:547. [PMID: 31428001 PMCID: PMC6689823 DOI: 10.3389/fpsyt.2019.00547] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 07/15/2019] [Indexed: 12/11/2022] Open
Abstract
Low-exploratory (LE) and high-exploratory (HE) rodents mimic human depressive and hyperthymic temperaments, respectively. Mood disorders (MD) may be developed by the exposure of these temperaments to environmental stress (ES). Psychiatric symptoms severity in MD patients is related to the magnitude of memory impairment. Thus, we aimed at studying the consequences of the exposure of LE and HE male Wistar rats, during periadolescence, to a combination of ES, namely, paradoxical sleep deprivation (PSD) and unpredictable stress (US), on anxiety-related behavior in the plus maze test, working (WM) and declarative memory (DM) performance. We also evaluated hippocampal immune-inflammatory/oxidative, as consequences of ES, and prevention of ES-induced alterations by the mood-stabilizing drugs, lithium and valproate. Medium exploratory (ME) control rats were used for comparisons with HE- and LE-control rats. We observed that HE-controls presented increased anxiolytic behavior that was significantly increased by ES exposure, whereas LE-controls presented increased anxiety-like behavior relative to ME-controls. Lithium and valproate prevented anxiolytic alterations in HE+ES rats. HE+ES- and LE+ES-rats presented WM and DM deficits. Valproate and lithium prevented WM deficits in LE-PSD+US rats. Lithium prevented DM impairment in HE+ES-rats. Hippocampal levels of reduced glutathione (GSH) increased four-fold in HE+ES-rats, being prevented by valproate and lithium. All groups of LE+ES-rats presented increased levels of GSH in relation to controls. Increments in lipid peroxidation in LE+ES- and HE+ES-rats were prevented by valproate in HE+ES-rats and by both drugs in LE+ES-rats. Nitrite levels were increased in HE+ES- and LE+ES-rats (five-fold increase), which was prevented by both drugs in LE+ES-rats. HE+ES-rats presented a two-fold increase in the inducible nitric oxide synthase (iNOS) expression that was prevented by lithium. HE+ES-rats showed increased hippocampal and plasma levels of interleukin (IL)-1β and IL-4. Indoleamine 2, 3-dioxygenase 1 (IDO1) was increased in HE+ES- and LE+ES-rats, while tryptophan 2,3-dioxygenase (TDO2) was increased only in HE+ES-rats. Altogether, our results showed that LE- and HE-rats exposed to ES present distinct anxiety-related behavior and similar memory deficits. Furthermore, HE+ES-rats presented more brain and plasma inflammatory alterations that were partially prevented by the mood-stabilizing drugs. These alterations in HE+ES-rats may possibly be related to the development of mood symptoms.
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Affiliation(s)
- Camila Nayane de Carvalho Lima
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara, Fortaleza, Brazil.,Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
| | - Francisco Eliclécio Rodrigues da Silva
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara, Fortaleza, Brazil
| | - Adriano José Maia Chaves Filho
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara, Fortaleza, Brazil
| | - Ana Isabelle de Gois Queiroz
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara, Fortaleza, Brazil
| | - Adriana Mary Nunes Costa Okamura
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara, Fortaleza, Brazil
| | - Gabriel Rodrigo Fries
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
| | - João Quevedo
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
| | - Francisca Cléa F de Sousa
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara, Fortaleza, Brazil
| | - Silvania Maria Mendes Vasconcelos
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara, Fortaleza, Brazil
| | - David F de Lucena
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara, Fortaleza, Brazil
| | - Marta Maria de França Fonteles
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara, Fortaleza, Brazil
| | - Danielle S Macedo
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara, Fortaleza, Brazil.,National Institute for Translational Medicine (INCT-TM, CNPq), Neurosciences and Behavior Department, Faculdade de Medicina de Ribeirão Preto (FMRP), Ribeirão Preto, Brazil
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25
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Burstein O, Doron R. The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice. J Vis Exp 2018. [PMID: 30417885 DOI: 10.3791/58184] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Depression is a highly prevalent and debilitating condition, only partially addressed by current pharmacotherapies. The lack of response to treatment by many patients prompts the need to develop new therapeutic alternatives and to better understand the etiology of the disorder. Pre-clinical models with translational merits are rudimentary for this task. Here we present a protocol for the unpredictable chronic mild stress (UCMS) method in mice. In this protocol, adolescent mice are chronically exposed to interchanging unpredictable mild stressors. Resembling the pathogenesis of depression in humans, stress exposure during the sensitive period of mice adolescence instigates a depressive-like phenotype evident in adulthood. UCMS can be used for screenings of antidepressants on the variety of depressive-like behaviors and neuromolecular indices. Among the more prominent tests to assess depressive-like behavior in rodents is the sucrose preference test (SPT), which reflects anhedonia (core symptom of depression). The SPT will also be presented in this protocol. The ability of UCMS to induce anhedonia, instigate long-term behavioral deficits and enable reversal of these deficits via chronic (but not acute) treatment with antidepressants strengthens the protocol's validity compared to other animal protocols for inducing depressive-like behaviors.
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Affiliation(s)
- Or Burstein
- School of Behavioral Science, The Academic College Tel-Aviv-Yaffo
| | - Ravid Doron
- School of Behavioral Science, The Academic College Tel-Aviv-Yaffo; Department of Education and Psychology, Open University;
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26
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Van Laeken N, Pauwelyn G, Dockx R, Descamps B, Brans B, Peremans K, Baeken C, Goethals I, Vanhove C, De Vos F. Regional alterations of cerebral [18F]FDG metabolism in the chronic unpredictable mild stress- and the repeated corticosterone depression model in rats. J Neural Transm (Vienna) 2018; 125:1381-1393. [DOI: 10.1007/s00702-018-1899-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 06/25/2018] [Indexed: 10/28/2022]
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Abstract
Positive emotions have been shown to induce resilience to stress in humans, as well as increase cognitive abilities (learning, memory, and problem solving) and improve overall health. In rats, frequency modulated 50-kHz ultrasonic vocalizations (hedonic 50 kHz) reflect a positive affective state and are best elicited by rough-and-tumble play. A well-established rat chronic unpredictable stress paradigm was used to produce a robust and long-lasting decrease in positive affect, increase in negative affect, and learned helplessness in Sprague-Dawley rats. Rough-and-tumble play (3 min every 3 days) reversed stress-induced effects of chronic unpredictable stress in the Porsolt forced swim test, novelty-induced hypophagia, sucrose preference, and ultrasonic vocalization assays compared with a light touch control group. These data demonstrate that positive affect induces resilience to stress effects in rats, and that rough-and-tumble play can be used to explore the biological basis of resilience that may lead to the development of new therapeutics for stress-related disorders.
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28
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Peng WF, Fan F, Li X, Zhang QQ, Ding J, Wang X. Different behavioral and pathological changes between epilepsy-associated depression and primary depression models. Epilepsy Behav 2018; 83:212-218. [PMID: 29678455 DOI: 10.1016/j.yebeh.2017.12.038] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 12/29/2017] [Accepted: 12/30/2017] [Indexed: 10/17/2022]
Abstract
PURPOSE Comorbid depression is common in patients with epilepsy. However, the epilepsy-associated depression is generally atypical and has not been fully recognized by neurologists. This study aimed to compare the behavioral and pathological changes between the chronic lithium chloride-pilocarpine rat epilepsy model (Licl-pilocarpine model) and the Chronic Unpredictable Mild Stress rat depression model (CUMS model), to evaluate for differences between epilepsy-associated depression and primary depression. METHODS The Licl-pilocarpine model and the CUMS model were established respectively and simultaneously. Spontaneous seizures were recorded by video monitoring. Forced swim test (FST) and sucrose consumption test (SCT) were performed to test depressive behaviors. Immobility time (IMT) and climbing time (CMT) in FST, sucrose preference rate (SPR) in SCT, and weight gain rate (WGR) were adopted to represent severity of depressive behaviors in rats. Immunofluorescent staining was conducted to measure expressions of neuronal specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), and cluster of differentiation molecule 11b (CD11b) in the hippocampus of Licl-pilocarpine model, CUMS model, and Control group. RESULTS Significantly, more prolonged IMT was observed in both the Licl-pilocarpine model (p<0.05) and the CUMS model (p<0.01) than Control group. But decreased WGR was only seen in the CUMS model. The percentage of rats with CMT greater than 100s was significantly higher in the Licl-pilocarpine model than the CUMS model (p<0.05). Increased CMT was observed in the Licl-pilocarpine model with mild depression subgroup (EMD, IMT≤100s) even compared with the Control group. Neuronal loss was both found in the Licl-pilocarpine model and the CUMS model when comparing with the Control group (p<0.05). However, the number of GFAP and CD11b staining cells was both greater in the Licl-pilocarpine model than the CUMS model and the Control group (p<0.05). CONCLUSION There were some different depressive behavioral and hippocampal pathological changes between the Licl-pilocarpine and the CUMS models except for some common features. Gliosis and microglial activation might be more involved in the pathophysiology of epilepsy-associated depression than primary depression.
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Affiliation(s)
- Wei-Feng Peng
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Fan Fan
- Department of Emergency, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Xin Li
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Qian-Qian Zhang
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Jing Ding
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Xin Wang
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China; The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China.
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29
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Lam VYY, Raineki C, Takeuchi LE, Ellis L, Woodward TS, Weinberg J. Chronic Stress Alters Behavior in the Forced Swim Test and Underlying Neural Activity in Animals Exposed to Alcohol Prenatally: Sex- and Time-Dependent Effects. Front Behav Neurosci 2018; 12:42. [PMID: 29593510 PMCID: PMC5855032 DOI: 10.3389/fnbeh.2018.00042] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 02/23/2018] [Indexed: 12/21/2022] Open
Abstract
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) stress response has been suggested to play a role in vulnerability to stress-related disorders, such as depression. Prenatal alcohol exposure (PAE) may result in HPA dysregulation, which in turn may predispose individuals to the effects of stress exposure throughout life, and increase their risk of developing depression compared to unexposed individuals. We examined the immediate and delayed effects of chronic unpredictable stress (CUS) in adulthood on behavior of PAE animals in the forced swim test (FST) and the neurocircuitry underlying behavioral, emotional, and stress regulation. Adult male and female offspring from PAE and control conditions were tested for 2 days in the FST, with testing initiated either 1 day (CUS-1; immediate) or 14 days (CUS-14; delayed) post-CUS. Following testing, c-fos mRNA expression of the medial prefrontal cortex (mPFC), amygdala, hippocampal formation, and the paraventricular nucleus of the hypothalamus was assessed. Our results indicate that PAE and CUS interact to differentially alter FST behaviors and neural activation of several brain areas in males and females, and effects may depend on whether testing is immediate or delayed post-CUS. PAE males showed decreased time immobile (Day 1 of FST) following immediate testing, while PAE females showed increased time immobile (Day 2 of FST) following delayed testing compared to their respective control counterparts. Moreover, in males, PAE decreased c-fos mRNA expression in the lateral and central nuclei of the amygdala in the non-CUS condition, and increased c-fos mRNA expression in the CA1 in the CUS-14 condition. By contrast in females, c-fos mRNA expression in the Cg1 was decreased in PAE animals (independent of CUS) and decreased in all mPFC subregions in CUS-14 animals (independent of prenatal treatment). Constrained principal component analysis, used to identify neural and behavioral networks, revealed that PAE altered the activation of these networks and modulated the effects of CUS on these networks in a sex- and time-dependent manner. This dysregulation of the neurocircuitry underlying behavioral, emotional and stress regulation, may ultimately contribute to an increased vulnerability to psychopathologies, such as depression, that are often observed following PAE.
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Affiliation(s)
- Vivian Y Y Lam
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Charlis Raineki
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Lily E Takeuchi
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Linda Ellis
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Todd S Woodward
- Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.,BC Mental Health and Addictions Research Institute, Vancouver, BC, Canada
| | - Joanne Weinberg
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
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Role of Cyclooxygenase Inhibitors in Diminution of Dissimilar Stress-induced Depressive Behavior and Memory Impairment in Rats. Neuroscience 2018; 370:121-129. [DOI: 10.1016/j.neuroscience.2017.11.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 08/04/2017] [Accepted: 11/06/2017] [Indexed: 01/14/2023]
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31
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Vaz RP, Cardoso A, Serrão P, Pereira PA, Madeira MD. Chronic stress leads to long-lasting deficits in olfactory-guided behaviors, and to neuroplastic changes in the nucleus of the lateral olfactory tract. Horm Behav 2018; 98:130-144. [PMID: 29277699 DOI: 10.1016/j.yhbeh.2017.12.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 11/27/2017] [Accepted: 12/20/2017] [Indexed: 10/18/2022]
Abstract
A recent study reported that the integrity of the nucleus of the lateral olfactory tract (nLOT) is required for normal olfaction and for the display of odor-driven behaviors that are critical for species survival and reproduction. In addition to being bi-directionally connected with a key element of the neural circuitry that mediates stress response, the basolateral nucleus of the amygdala, the nLOT is a potential target for glucocorticoids as its cells express glucocorticoid receptors. Herein, we have addressed this hypothesis by exploring, first, if chronic variable stress (CVS) disrupts odor detection and discrimination, and innate olfactory-driven behaviors, namely predator avoidance, sexual behavior and aggression in male rats. Next, we examined if CVS alters the nLOT structure and if such changes can be ascribed to stress-induced effects on the activity of the main output neurons, which are glutamatergic, and/or of local GABAergic interneurons. Finally, we analyzed if the stress-induced changes are transient or, conversely, persist after cessation of CVS exposure. Our data demonstrate that CVS leads to severe olfactory deficits with inability to detect and discriminate between odors and to innately avoid predator odors. No effects of CVS on sexual and aggressive behaviors were observed. Results also showed that CVS leads to somatic hypertrophy of pyramidal glutamatergic neurons, which likely results from neuronal disinhibition consequent to the loss of inhibitory inputs mediated by GABAergic interneurons. Most of the CVS-induced effects persist beyond a 4-week stress-free period, suggesting long-lasting effects of chronic stress on the structure and function of the olfactory system.
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Affiliation(s)
- Ricardo P Vaz
- Unit of Anatomy - Department of Biomedicine, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; Otorhinolaryngology Department, Centro Hospitalar S. João, EPE, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal.
| | - Armando Cardoso
- Unit of Anatomy - Department of Biomedicine, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal.
| | - Paula Serrão
- Unit of Pharmacology and Therapeutics - Department of Biomedicine, Faculty of Medicine, University of Porto, Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
| | - Pedro A Pereira
- Unit of Anatomy - Department of Biomedicine, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal.
| | - M Dulce Madeira
- Unit of Anatomy - Department of Biomedicine, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal.
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Zhao M, Garland T, Chappell MA, Andrew JR, Harris BN, Saltzman W. Effects of a physical and energetic challenge on male California mice ( Peromyscus californicus): modulation by reproductive condition. J Exp Biol 2018; 221:jeb168559. [PMID: 29170256 PMCID: PMC5818025 DOI: 10.1242/jeb.168559] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 11/14/2017] [Indexed: 12/13/2022]
Abstract
Reproduction strongly influences metabolism, morphology and behavior in female mammals. In species in which males provide parental care, reproduction might have similar effects on fathers. We examined effects of an environmental challenge on metabolically important physiological, morphological and behavioral measures, and determined whether these effects differed between reproductive and non-reproductive males in the biparental California mouse (Peromyscus californicus). Males were paired with an ovary-intact female, an ovariectomized female treated with estrogen and progesterone to induce estrus, or an untreated ovariectomized female. Within each group, half of the animals were housed under standard laboratory conditions and half in cages requiring them to climb wire towers to obtain food and water; these latter animals were also fasted for 24 h every third day. We predicted that few differences would be observed between fathers and non-reproductive males under standard conditions, but that fathers would be in poorer condition than non-reproductive males under challenging conditions. Body and fat mass showed a housing condition×reproductive group interaction: the challenge condition increased body and fat mass in both groups of non-reproductive males, but breeding males were unaffected. Males housed under the physical and energetic challenge had higher blood lipid content, lower maximal aerobic capacity and related traits (hematocrit and relative triceps surae mass), increased pain sensitivity and increased number of fecal boli excreted during tail-suspension tests (a measure of anxiety), compared with controls. Thus, our physical and energetic challenge paradigm altered metabolism, morphology and behavior, but these effects were largely unaffected by reproductive condition.
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Affiliation(s)
- Meng Zhao
- Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA 92521, USA
| | - Theodore Garland
- Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA 92521, USA
| | - Mark A Chappell
- Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA 92521, USA
| | - Jacob R Andrew
- Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA 92521, USA
| | - Breanna N Harris
- Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA
| | - Wendy Saltzman
- Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA 92521, USA
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Zhong X, Li G, Qiu F, Huang Z. Paeoniflorin Ameliorates Chronic Stress-Induced Depression-Like Behaviors and Neuronal Damages in Rats via Activation of the ERK-CREB Pathway. Front Psychiatry 2018; 9:772. [PMID: 30692946 PMCID: PMC6339947 DOI: 10.3389/fpsyt.2018.00772] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Accepted: 12/24/2018] [Indexed: 12/23/2022] Open
Abstract
Neuronal damage is related to the onset and treatment of depressive disorders. Antidepressant-like effects have been elicited by paeoniflorin on animal models. The aim of this study is to demonstrate whether the neuroprotective effect of paeoniflorin on rats suffered from chronic unpredictable mild stress (CUMS) was regulated by the ERK-CREB signaling pathway. Results showed that paeoniflorin not only ameliorated depressive-like behavior with low locomotor activity and prolonged immobility duration in our forced swimming test but also reduced sucrose consumption. Paeoniflorin treatment decreased the degree of neuronal damage in the hippocampus of the model rats. Conversely, it markedly increased the mRNA levels of ERK1, ERK2, and CREB and the levels of ERK, p-ERK, CREB, and p-CREB protein expression in the hippocampus. Blockade of the ERK-CREB axis with the ERK-specific inhibitor U0126 repressed the neuroprotective and antidepressant-like effects of paeoniflorin on rats in the setting of chronic-mild-stress and abolished the recoveries of p-ERK mediated by paeoniflorin treatment. Thus, paeoniflorin possibly exerted a neuroprotective effect modulated by the ERK-CREB signaling pathway on CUMS-induced hippocampal damage in rats.
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Affiliation(s)
- Xiaoming Zhong
- Department of Chinese Medical Resources, College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Guanze Li
- Department of Chinese Medical Resources, College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Fengmei Qiu
- Pharmacy Teaching Experiment Centre, College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhen Huang
- Department of Chinese Medical Resources, College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
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Barbosa FM, Cabral D, Kabadayan F, Bondan EF, de Fátima Monteiro Martins M, Kirsten TB, Bonamin LV, Queiroz-Hazarbassanov N, Martha Bernardi M, Saraceni CHC. Depressive behavior induced by unpredictable chronic mild stress increases dentin hypersensitivity in rats. Arch Oral Biol 2017; 80:164-174. [DOI: 10.1016/j.archoralbio.2017.04.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 04/02/2017] [Accepted: 04/07/2017] [Indexed: 12/15/2022]
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Chronic social instability increases anxiety-like behavior and ethanol preference in male Long Evans rats. Physiol Behav 2017; 173:179-187. [DOI: 10.1016/j.physbeh.2017.02.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 02/09/2017] [Accepted: 02/10/2017] [Indexed: 01/28/2023]
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Tang X, Li J, Jiang T, Han SH, Yao DY. Experimental occlusal disharmony - A promoting factor for anxiety in rats under chronic psychological stress. Prog Neuropsychopharmacol Biol Psychiatry 2017; 75:165-175. [PMID: 28185964 DOI: 10.1016/j.pnpbp.2017.02.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 12/14/2016] [Accepted: 02/03/2017] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND PURPOSE Clinically, patients under chronic psychological stress (PS) appear to be more susceptible to occlusal disharmony (OD) compared with those without PS. OD was proved to introduce anxiety-like stress. Therefore, the purpose of the study was to investigate whether OD would affect psychological stress-induced anxiety and its underlying mechanisms. METHODS Chronic PS was induced by a communication box, and OD was produced by bonding a 0.3mm-thick crown on the right maxillary first molar of male Sprague-Dawley rats. Sixty-seven rats were randomly divided into 8 groups: (A) chronic PS plus OD group (n=6); (B) chronic PS plus sham OD group (n=6); (C) chronic PS only group (n=6); (D) OD group (n=6); (E) sham OD group (n=6); (F) control group (n=6); (G) naive group (n=6); (H) foot-shock group (n=25). Open-field test (OFT) and elevated plus maze test (EPM) were conducted on the 7th, 21th, 35th day to measure the anxiety level of each group except naive and foot-shock group. In addition, corticosterone (CORT) level in serum, 5-hydroxytryptamine (5-HT) and 5-HT2A receptor (5-HT2AR) expressions in prefrontal cortex (PFC), hippocampal CA1 and dentate gyrus (DG) areas were measured on the 35th day to elucidate the mechanism(s) by which the exacerbation occurred. RESULTS The significant differences in OFT and EPM tests on day 21 or day 35 between groups (p<0.01) indicated the successful establishment of animal model of PS or OD. And there was a significant increase in CORT concentration in serum (p<0.01), 5-HT expressions in PFC, hippocampal DG areas and 5-HT2AR expressions in PFC, hippocampal CA1 areas (p<0.05) in group A, B, C, D compared with group F. Similar results were also found in group A, B, C, D when compared with group G (p<0.05) except 5-HT expression in DG area in group C and D (p>0.05), together with a gradual decrease in values of all the parameters mentioned above from group A to group G. CONCLUSION The significant changes in exploratory behaviors, serum CORT concentration, 5-HT and 5-HT2AR expressions induced by OD in rats with or without chronic PS, and more obvious alterations in rats with chronic PS, may indicate that OD may be a promoting factor for anxiety through both peripheral and central pathways via the hypothalamus-pituitary-adrenal (HPA) axis and 5-HT system.
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Affiliation(s)
- Xuan Tang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, People's Republic of China
| | - Jian Li
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, People's Republic of China.
| | - Ting Jiang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, People's Republic of China.
| | - Shu-Hui Han
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, People's Republic of China
| | - Dong-Yuan Yao
- Jiangxi Mental Hospital and School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi, People's Republic of China
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Aikins DE, Strader JA, Kohler RJ, Bihani N, Perrine SA. Differences in hippocampal serotonergic activity in a mouse single prolonged stress paradigm impact discriminant fear acquisition and retention. Neurosci Lett 2016; 639:162-166. [PMID: 28025114 DOI: 10.1016/j.neulet.2016.12.056] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 12/22/2016] [Accepted: 12/22/2016] [Indexed: 11/25/2022]
Abstract
A mouse model of traumatic stress provided insight into a mechanism of individual differences in conditioned fear responding. Hippocampal serotonergic activity (metabolic turnover) was associated with increased behavioral freezing during fear acquisition in a portion of trauma-exposed subjects. These subjects later displayed enhanced fear to the neutral cue during retention. An inability to discriminate fear responses may underlie dysfunctional fear memories in a sub-population of individuals with Posttraumatic Stress Disorder, with contributions from the hippocampal serotonin system.
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Affiliation(s)
- Deane E Aikins
- Research & Development Service, John D. Dingell VA Medical Center, 4646 John R St., Detroit, MI 48201, United States; Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Drive, Detroit, MI 48201, United States
| | - John A Strader
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Drive, Detroit, MI 48201, United States
| | - Robert J Kohler
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Drive, Detroit, MI 48201, United States
| | - Nina Bihani
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Drive, Detroit, MI 48201, United States
| | - Shane A Perrine
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Drive, Detroit, MI 48201, United States.
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Long-lasting monoaminergic and behavioral dysfunctions in a mice model of socio-environmental stress during adolescence. Behav Brain Res 2016; 317:132-140. [PMID: 27641324 DOI: 10.1016/j.bbr.2016.09.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 09/06/2016] [Accepted: 09/11/2016] [Indexed: 11/22/2022]
Abstract
Adolescence is one of the critical periods of development and has great importance to health for an individual as an adult. Stressors or traumatic events during this period are associated with several psychiatric disorders as related to anxiety or depression and cognitive impairments, but whether negative experiences continue to hinder individuals as they age is not as well understood. We determined how stress during adolescence affects behavior and neurochemistry in adulthood. Using an unpredictable paradigm (2 stressors per day for 10days) in Balb/c mice, behavioral, hormonal, and neurochemical changes were identified 20days after the cessation of treatment. Adolescent stress increased motor activity, emotional arousal and vigilance, together with a reduction in anxiety, and also affected recognition memory. Furthermore, decreased serotonergic activity on hippocampus, hypothalamus and cortex, decreased noradrenergic activity on hippocampus and hypothalamus, and increased the turnover of dopamine in cortex. These data suggest behavioral phenotypes associated with emotional arousal, but not depression, emerge after cessation of stress and remain in adulthood. Social-environmental stress can induce marked and long-lasting changes in HPA resulting from monoaminergic neurotransmission, mainly 5-HT activity.
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Nedel WL, Nora DG, Salluh JIF, Lisboa T, Póvoa P. Corticosteroids for severe influenza pneumonia: A critical appraisal. World J Crit Care Med 2016; 5:89-95. [PMID: 26855898 PMCID: PMC4733461 DOI: 10.5492/wjccm.v5.i1.89] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 11/24/2015] [Accepted: 01/11/2016] [Indexed: 02/06/2023] Open
Abstract
Influenza pneumonia is associated with high number of severe cases requiring hospital and intensive care unit (ICU) admissions with high mortality. Systemic steroids are proposed as a valid therapeutic option even though its effects are still controversial. Heterogeneity of published data regarding study design, population demographics, severity of illness, dosing, type and timing of corticosteroids administered constitute an important limitation for drawing robust conclusions. However, it is reasonable to admit that, as it was not found any advantage of corticosteroid therapy in so diverse conditions, such beneficial effects do not exist at all. Its administration is likely to increase overall mortality and such trend is consistent regardless of the quality as well as the sample size of studies. Moreover it was shown that corticosteroids might be associated with higher incidence of hospital-acquired pneumonia and longer duration of mechanical ventilation and ICU stay. Finally, it is reasonable to conclude that corticosteroids failed to demonstrate any beneficial effects in the treatment of patients with severe influenza infection. Thus its current use in severe influenza pneumonia should be restricted to very selected cases and in the setting of clinical trials.
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Perrine SA, Eagle AL, George SA, Mulo K, Kohler RJ, Gerard J, Harutyunyan A, Hool SM, Susick LL, Schneider BL, Ghoddoussi F, Galloway MP, Liberzon I, Conti AC. Severe, multimodal stress exposure induces PTSD-like characteristics in a mouse model of single prolonged stress. Behav Brain Res 2016; 303:228-37. [PMID: 26821287 DOI: 10.1016/j.bbr.2016.01.056] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 01/20/2016] [Accepted: 01/22/2016] [Indexed: 12/26/2022]
Abstract
Appropriate animal models of posttraumatic stress disorder (PTSD) are needed because human studies remain limited in their ability to probe the underlying neurobiology of PTSD. Although the single prolonged stress (SPS) model is an established rat model of PTSD, the development of a similarly-validated mouse model emphasizes the benefits and cross-species utility of rodent PTSD models and offers unique methodological advantages to that of the rat. Therefore, the aims of this study were to develop and describe a SPS model for mice and to provide data that support current mechanisms relevant to PTSD. The mouse single prolonged stress (mSPS) paradigm, involves exposing C57Bl/6 mice to a series of severe, multimodal stressors, including 2h restraint, 10 min group forced swim, exposure to soiled rat bedding scent, and exposure to ether until unconsciousness. Following a 7-day undisturbed period, mice were tested for cue-induced fear behavior, effects of paroxetine on cue-induced fear behavior, extinction retention of a previously extinguished fear memory, dexamethasone suppression of corticosterone (CORT) response, dorsal hippocampal glucocorticoid receptor protein and mRNA expression, and prefrontal cortex glutamate levels. Exposure to mSPS enhanced cue-induced fear, which was attenuated by oral paroxetine treatment. mSPS also disrupted extinction retention, enhanced suppression of stress-induced CORT response, increased mRNA expression of dorsal hippocampal glucocorticoid receptors and decreased prefrontal cortex glutamate levels. These data suggest that the mSPS model is a translationally-relevant model for future PTSD research with strong face, construct, and predictive validity. In summary, mSPS models characteristics relevant to PTSD and this severe, multimodal stress modifies fear learning in mice that coincides with changes in the hypothalamo-pituitary-adrenal (HPA) axis, brain glucocorticoid systems, and glutamatergic signaling in the prefrontal cortex.
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Affiliation(s)
- Shane A Perrine
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
| | - Andrew L Eagle
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Sophie A George
- Department of Psychiatry, Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kostika Mulo
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Robert J Kohler
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Justin Gerard
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Arman Harutyunyan
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Steven M Hool
- Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA,; Wayne State University School of Medicine, Detroit, MI, USA
| | - Laura L Susick
- Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA,; Wayne State University School of Medicine, Detroit, MI, USA
| | - Brandy L Schneider
- Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA,; Wayne State University School of Medicine, Detroit, MI, USA
| | - Farhad Ghoddoussi
- Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Matthew P Galloway
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA; Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Israel Liberzon
- Department of Psychiatry, Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, USA,; Department of Psychiatry, VA Medical Center, Ann Arbor, MI, USA
| | - Alana C Conti
- Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA,; Wayne State University School of Medicine, Detroit, MI, USA
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Bhatt S, Shukla P, Raval J, Goswami S. Role of Aspirin and Dexamethasone against Experimentally Induced Depression in Rats. Basic Clin Pharmacol Toxicol 2016; 119:10-8. [DOI: 10.1111/bcpt.12539] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 11/20/2015] [Indexed: 12/28/2022]
Affiliation(s)
| | | | - Jibril Raval
- L. J. Institute of Pharmacy; L.J. Campus; Ahmedabad India
| | - Sunita Goswami
- Department of Pharmacology; L. M. College of Pharmacy; Navrangpura Ahmedabad India
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MANSKE SARAHL, VIJAYARAGHAVAN SURABHI, TUTHILL ALYSSA, BRUTUS OLIVIER, YANG JIE, GUPTA SHIKHA, JUDEX STEFAN. Extending Rest between Unloading Cycles Does Not Enhance Bone’s Long-Term Recovery. Med Sci Sports Exerc 2015; 47:2191-200. [DOI: 10.1249/mss.0000000000000636] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Riaz MS, Bohlen MO, Gunter BW, Quentin H, Stockmeier CA, Paul IA. Attenuation of social interaction-associated ultrasonic vocalizations and spatial working memory performance in rats exposed to chronic unpredictable stress. Physiol Behav 2015; 152:128-134. [PMID: 26367455 DOI: 10.1016/j.physbeh.2015.09.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 08/25/2015] [Accepted: 09/03/2015] [Indexed: 10/23/2022]
Abstract
Exposure to unpredictable chronic mild stress (CUS) is a commonly used protocol in rats that is reported to evoke antidepressant-reversible behaviors such as loss of preference for a sweetened water solution which is taken as an analog of the anhedonia seen in major depression. However, the induction of anhedonic-like behavior by chronic mild stress, gauged by an animal's preference for sucrose solution, is not fully reproducible and consistent across laboratories. In this study, we compared a widely used behavioral marker of anhedonia - the sucrose preference test, with another phenotypic marker of emotional valence, social interaction-associated ultrasonic vocalizations as well as a marker of an anxiety-like phenotype, novelty-suppressed feeding, and cognitive performance in the eight arm radial maze task in adult male Sprague-Dawley rats. Chronic four-week exposure to unpredictable mild stressors resulted in 1) attenuation of social interaction-associated ultrasonic vocalizations 2) attenuation of spatial memory performance on the radial arm maze 3) attenuation of body weight gain and 4) increased latency to feed in a novelty-suppressed feeding task. However, chronic exposure to CUS did not result in any significant change in sucrose preference at one-week and three-week intervals. Our results argue for the utility of ultrasonic vocalizations in a social interaction context as a comparable alternative or adjunct to the sucrose preference test in determining the efficacy of CUS to generate an anhedonic-like phenotypic state.
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Affiliation(s)
- Muhammad S Riaz
- Graduate Program in Neuroscience, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
| | - Martin O Bohlen
- Graduate Program in Neuroscience, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
| | - Barak W Gunter
- Graduate Program in Neuroscience, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
| | - Henry Quentin
- Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
| | - Craig A Stockmeier
- Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
| | - Ian A Paul
- Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
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Exposure to sub-chronic unpredictable stress accounts for antidepressant-like effects in hamsters treated with BDNF and CNQX. Brain Res Bull 2015; 118:65-77. [DOI: 10.1016/j.brainresbull.2015.09.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 09/17/2015] [Accepted: 09/21/2015] [Indexed: 11/21/2022]
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Pereira-Figueiredo I, Carro J, Muñoz LJ, Sancho C, Castellano O, Gómez-Nieto R, López DE. Sex Differences in the Effects of Sertraline and Stressors in Rats Previously Exposed to Restraint Stress. ACTA ACUST UNITED AC 2015. [DOI: 10.4236/jbise.2015.87038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Gupta D, Radhakrishnan M, Kurhe Y, Thangaraj D, Prabhakar V, Kanade P. Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression. Acta Pharmacol Sin 2014; 35:1493-503. [PMID: 25418380 DOI: 10.1038/aps.2014.89] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2014] [Accepted: 07/28/2014] [Indexed: 12/19/2022]
Abstract
AIM To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression. METHODS 5-HT3 receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.5-2 mg/kg, ip). In chronic depression model, mice were exposed to a 4-week chronic unpredictable stress (CUS) protocol, and treated with 6z (0.5-2 mg·kg(-1)·d(-1), po) or a positive drug fluoxetine (10 mg·kg(-1)·d(-1), po) in the last 2 weeks, followed by behavioral and biochemical assessments. RESULTS The 5-HT3 receptor antagonism of 6z (pA2=7.4) in guinea pig ileum was more potent than that of a standard 5-HT3 receptor antagonist ondansetron (pA2=6.9). In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration reversed CUS-induced depressive-like behavior, as evidenced by increased immobility duration in the forced swim test and sucrose preference in the sucrose preference test. Furthermore, chronic administration of 6z prevented CUS-induced brain oxidative stress, with significant reduction of pro-oxidant markers and elevation of antioxidant enzyme activity. Moreover, chronic administration of 6z attenuated CUS-induced hypothalamic-pituitary-adrenal axis hyperactivity, as shown by reduced plasma corticosterone levels. Similar results were observed in the fluoxetine-treated group. CONCLUSION 6z is a novel 5-HT3 receptor antagonist with potential antidepressant-like activities, which may be related to modulating hypothalamic-pituitary-adrenal axis and attenuating brain oxidative damage.
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Chronic light deprivation inhibits appetitive associative learning induced by ethanol and its respective c-Fos and pCREB expression. Int J Neuropsychopharmacol 2014; 17:1815-30. [PMID: 24905237 DOI: 10.1017/s1461145714000480] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
To address the role of mixed anxiety/mood disorder on appetitive associative learning, we verify whether previous chronic light deprivation changes ethanol-induced conditioned place preference and its respective expression of c-Fos and pCREB, markers of neuronal activity and plasticity. The experimental group was maintained in light deprivation for 24 h for a period of 4 wk. Subsequently, it was adapted to a standard light-dark cycle for 1 wk. As a control, some mice were maintained in standard cycle for a period of 4 wk (Naïve group). Then, all animals were submitted to behavioral tests to assess emotionality: elevated plus maze; open field; and forced swim. After that, they were submitted to ethanol-induced conditioned place preference. Ninety minutes after the place preference test, they were perfused, and their brains processed for c-Fos and pCREB immunohistochemistry. Light deprivation induced anxiety-like trait (elevated plus maze), despair (forced swim), and hyperlocomotion (open field), common features seen in other animal models of depression. Ethanol-induced conditioned place preference was accompanied by increases on c-Fos and pCREB in the hippocampus, prefrontal cortex and striatum. Interestingly, mice previously submitted to light deprivation did not develop either acquisition and/or expression of ethanol-induced conditioned place preference or increases in c-Fos and pCREB. Therefore, chronic light deprivation mimics several behavioral aspects of other animal models of depression. Furthermore, it could be useful to study the neurochemical mechanisms involved in the dual diagnosis. However, given its likely deleterious effects on appetitive associative memory, it should be used with caution to investigate the cognitive aspects related to the dual diagnosis.
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Senuma M, Mori C, Ogawa T, Kuwagata M. Prenatal sodium arsenite affects early development of serotonergic neurons in the fetal rat brain. Int J Dev Neurosci 2014; 38:204-12. [PMID: 25291237 DOI: 10.1016/j.ijdevneu.2014.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Revised: 09/26/2014] [Accepted: 09/26/2014] [Indexed: 10/24/2022] Open
Abstract
Prenatal arsenite exposure has been associated with developmental disorders in children, including reduced IQ and language abnormalities. Animal experiments have also shown that exposure to arsenite during development induced developmental neurotoxicity after birth. However, the evidence is not enough, and the mechanism is poorly understood, especially on the exposure during early brain development. This study assessed effects of sodium (meta) arsenite shortly after exposure on early developing fetal rat brains. Pregnant rats were administered 50 mg/L arsenite in their drinking water or 20 mg/kg arsenite orally using a gastric tube, on gestational days (GD) 9-15. Fetal brains were examined on GD16. Pregnant rats administered 20 mg/kg arsenite showed reductions in maternal body weight gain and food consumption during treatment, but not with 50 mg/L arsenite. Arsenite did not affect fetal development, as determined by body weight, mortality and brain size. Arsenite also did not induce excessive cell death or affect neural cell division in any region of the fetal neuroepithelium. Thyrosine hydroxylase immunohistochemistry revealed no difference in the distribution of catecholaminergic neurons between fetuses of arsenite treated and control rats. However, reductions in the number of serotonin positive cells in the fetal median and dorsal raphe nuclei were observed following maternal treatment with 20mg/kg arsenite. Image analysis showed that the serotonin positive areas decreased in all fetal mid- and hind-brain areas without altering distribution patterns. Maternal stress induced by arsenite toxicity did not alter fetal development. These results suggest that arsenite-induced neurodevelopmental toxicity involves defects in the early development of the serotonin nervous system.
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Affiliation(s)
- Mika Senuma
- Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
| | - Chisato Mori
- Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City 260-8670, Japan.
| | - Tetsuo Ogawa
- Department of Biology, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
| | - Makiko Kuwagata
- Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
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Behavioural and transcriptional effects of escitalopram in the chronic escape deficit model of depression. Behav Brain Res 2014; 272:121-30. [DOI: 10.1016/j.bbr.2014.06.040] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 06/17/2014] [Accepted: 06/23/2014] [Indexed: 02/02/2023]
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50
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Luo XM, Yuan SN, Guan XT, Xie X, Shao F, Wang WW. Juvenile stress affects anxiety-like behavior and limbic monoamines in adult rats. Physiol Behav 2014; 135:7-16. [DOI: 10.1016/j.physbeh.2014.05.035] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 04/25/2014] [Accepted: 05/28/2014] [Indexed: 01/07/2023]
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