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Dixon R, Malave L, Thompson R, Wu S, Li Y, Sadik N, Anacker C. Sex-specific and Developmental Effects of Early Life Adversity on Stress Reactivity are Rescued by Postnatal Knockdown of 5-HT 1A Autoreceptors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.22.576344. [PMID: 38328253 PMCID: PMC10849559 DOI: 10.1101/2024.01.22.576344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Early Life Adversity (ELA) predisposes to stress hypersensitivity in adulthood, but neurobiological mechanisms that protect from the enduring effects of ELA are poorly understood. Serotonin 1A (5HT 1A ) autoreceptors in the raphé nuclei regulate adult stress vulnerability, but whether 5HT 1A could be targeted to prevent ELA effects on susceptibility to future stressors is unknown. Here, we exposed mice with postnatal knockdown of 5HT 1A autoreceptors to the limited bedding and nesting model of ELA from postnatal day (P)3-10 and tested behavioral, neuroendocrine, neurogenic, and neuroinflammatory responses to an acute swim stress in male and female mice in adolescence (P35) and in adulthood (P56). In females, ELA decreased raphé 5HT neuron activity in adulthood and increased passive coping with the acute swim stress, corticosterone levels, neuronal activity, and corticotropin-releasing factor (CRF) levels in the paraventricular nucleus (PVN) of the hypothalamus. ELA also reduced neurogenesis in the ventral dentate gyrus (vDG) of the hippocampus, an important mediator of individual differences in stress susceptibility, and increased microglia activation in the PVN and vDG. These effects of ELA were specific to females and manifested predominantly in adulthood, but not earlier on in adolescence. Postnatal knockdown of 5HT 1A autoreceptors prevented these effects of ELA on 5HT neuron activity, stress reactivity, neurogenesis, and neuroinflammation in adult female mice. Our findings demonstrate that ELA induces long-lasting and sex-specific impairments in the serotonin system, stress reactivity, and vDG function, and identify 5HT 1A autoreceptors as potential targets to prevent these enduring effects of ELA.
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Chen MA, LeRoy AS, Majd M, Chen JY, Brown RL, Christian LM, Fagundes CP. Immune and Epigenetic Pathways Linking Childhood Adversity and Health Across the Lifespan. Front Psychol 2021; 12:788351. [PMID: 34899540 PMCID: PMC8662704 DOI: 10.3389/fpsyg.2021.788351] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 11/04/2021] [Indexed: 12/17/2022] Open
Abstract
Childhood adversity is associated with a host of mental and physical health problems across the lifespan. Individuals who have experienced childhood adversity (e.g., child abuse and neglect, family conflict, poor parent/child relationships, low socioeconomic status or extreme poverty) are at a greater risk for morbidity and premature mortality than those not exposed to childhood adversity. Several mechanisms likely contribute to the relationship between childhood adversity and health across the lifespan (e.g., health behaviors, cardiovascular reactivity). In this paper, we review a large body of research within the field of psychoneuroimmunology, demonstrating the relationship between early life stress and alterations of the immune system. We first review the literature demonstrating that childhood adversity is associated with immune dysregulation across different indices, including proinflammatory cytokine production (and its impact on telomere length), illness and infection susceptibility, latent herpesvirus reactivation, and immune response to a tumor. We then summarize the growing literature on how childhood adversity may alter epigenetic processes. Finally, we propose future directions related to this work that have basic and applied implications.
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Affiliation(s)
- Michelle A Chen
- Department of Psychological Sciences, Rice University, Houston, TX, United States
| | - Angie S LeRoy
- Department of Psychological Sciences, Rice University, Houston, TX, United States
| | - Marzieh Majd
- Department of Psychological Sciences, Rice University, Houston, TX, United States
| | - Jonathan Y Chen
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Ryan L Brown
- Department of Psychological Sciences, Rice University, Houston, TX, United States
| | - Lisa M Christian
- Department of Psychiatry & Behavioral Health and the Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Christopher P Fagundes
- Department of Psychological Sciences, Rice University, Houston, TX, United States.,Department of Behavioral Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Department of Psychiatry & Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States
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3
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Pape K, Cowell W, Sejbaek CS, Andersson NW, Svanes C, Kolstad HA, Liu X, Hougaard KS, Wright RJ, Schlünssen V. Adverse childhood experiences and asthma: trajectories in a national cohort. Thorax 2021; 76:547-553. [PMID: 33766987 PMCID: PMC8223631 DOI: 10.1136/thoraxjnl-2020-214528] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/10/2021] [Accepted: 03/03/2021] [Indexed: 12/14/2022]
Abstract
Objective Research has linked early adverse childhood experiences (ACEs) with asthma development; however, existing studies have generally relied on parent report of exposure and outcome. We aimed to examine the association of early life ACEs with empirically determined trajectories of childhood asthma risk, using independent register information on both exposures and outcome. Methods Based on nationwide registries, we established a study cohort of 466 556 children born in Denmark (1997–2004). We obtained information on ACEs during the first 2 years of life (bereavement, parental chronic somatic and/or mental illness) and childhood asthma diagnosis or medication use from birth through age 10 years from the Danish National Patient and Prescription Registries, respectively. We identified asthma phenotypes using group-based trajectory modelling. We then used multinomial logistic regression to examine the association between early ACEs and asthma phenotypes. Results We identified four asthma phenotypes: non-asthmatic, early-onset transient, early-onset persistent and late-onset asthma. Girls with early-onset transient asthma (OR 1.13, 95% CI 1.04 to 1.24), early-onset persistent asthma (1.27, 95% CI 1.08 to 1.48) or late-onset asthma (OR 1.28, 95% CI 1.11 to 1.48) vs no asthma were more likely to have early life ACE exposure compared with girls without ACE exposure. Results were similar for boys who also had experienced early life ACEs with ORs of 1.16 (95% CI 1.08 to 1.25), 1.34 (95% CI 1.20 to 1.51) and 1.11 (95% CI 0.98 to 1.25), respectively. Conclusion In a nationwide-population study, we identified three childhood onset asthma phenotypes and found that ACEs early in life were associated with increased odds for each of these asthma phenotypes among both girls and boys.
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Affiliation(s)
- Kathrine Pape
- National Research Centre for the Working Environment, Kobenhavn, Denmark .,Department of Public Health, Environment, Occupation and Health, Danish Ramazzini Centre, Aarhus Universitet, Aarhus, Denmark
| | - Whitney Cowell
- Departments of Pediatrics & Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | | | - Niklas Worm Andersson
- Department of Public Health, Environment, Occupation and Health, Danish Ramazzini Centre, Aarhus Universitet, Aarhus, Denmark.,Department of Epidemiology Research, Statens Serum Institut, Kobenhavn, Denmark.,Department of Clinical Pharmacology, Bispeberg and Frederiksberg Hospitals, Copenhagen, Denmark
| | - Cecilie Svanes
- Center for International Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Hordaland, Norway.,Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway
| | - Henrik Albert Kolstad
- Department of Clinical Medicine, Occupational Medicine, Aarhus University, Aarhus, Denmark
| | - Xiaoqin Liu
- NCRR-The National Centre for Register-based Research, Aarhus University, Aarhus, Denmark
| | - Karin Sørig Hougaard
- National Research Centre for the Working Environment, Kobenhavn, Denmark.,Institute of Public Health, University of Copenhagen, Kobenhavn, Denmark
| | - Rosalind J Wright
- Departments of Pediatrics & Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Vivi Schlünssen
- National Research Centre for the Working Environment, Kobenhavn, Denmark.,Department of Public Health, Environment, Occupation and Health, Danish Ramazzini Centre, Aarhus Universitet, Aarhus, Denmark
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Martinez-Muniz GA, Wood SK. Sex Differences in the Inflammatory Consequences of Stress: Implications for Pharmacotherapy. J Pharmacol Exp Ther 2020; 375:161-174. [PMID: 32759370 PMCID: PMC7569308 DOI: 10.1124/jpet.120.266205] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/28/2020] [Indexed: 12/21/2022] Open
Abstract
Women are at significantly greater risk of developing stress-related disorders such as depression. The increased risk begins during puberty and continues throughout life until menopause, suggesting a role for ovarian hormones in this increased susceptibility. Importantly, inflammation has been gaining momentum in its role in the pathogenesis of depression. Herein, clinical and preclinical studies have been reviewed to better understand how sex differences within the immune system may contribute to exaggerated risk of depression in females. First, studies that investigate the ability of psychologic stress episodes to engage the inflammatory systems both in the brain and periphery are reviewed with a special focus on sex-specific effects. Moreover, studies are discussed that identify whether imbalanced inflammatory milieu contributes to the development of depression in males versus females and whether these effects are regulated by estradiol. Importantly, we propose a locus coeruleus-norepinephrine-cytokine circuit as a conduit through which stress could increase stress susceptibly in females. Finally, the anti-inflammatory capacity of traditional and nontraditional antidepressants is investigated, with the goal of providing a better understanding of pharmacotherapeutics to enhance strategies to personalize antidepressant treatments between the sexes. The studies reviewed herein strongly support the need for further studies to elucidate whether females are especially sensitive to anti-inflammatory compounds as adjuvants to traditional therapies. SIGNIFICANCE STATEMENT: Women have hve an increased risk of developing stress-related disorders such as depression. In this review, literature from clinical and preclinical studies are integrated to define sex differences in stress-induced inflammatory responses as a potential source for the etiology of sex differences in depressive disorders. Moreover, the anti-inflammatory capacity of traditional and nontraditional antidepressants is reviewed to inform on potential pharmacotherapeutic strategies to personalize antidepressant therapy in a sex-dependent manner.
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Affiliation(s)
- Gustavo A Martinez-Muniz
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina and Dorn Veterans Administration Medical Center, Columbia, South Carolina
| | - Susan K Wood
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina and Dorn Veterans Administration Medical Center, Columbia, South Carolina
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Kokkosis AG, Tsirka SE. Neuroimmune Mechanisms and Sex/Gender-Dependent Effects in the Pathophysiology of Mental Disorders. J Pharmacol Exp Ther 2020; 375:175-192. [PMID: 32661057 PMCID: PMC7569311 DOI: 10.1124/jpet.120.266163] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 07/09/2020] [Indexed: 12/12/2022] Open
Abstract
Innate and adaptive immune mechanisms have emerged as critical regulators of CNS homeostasis and mental health. A plethora of immunologic factors have been reported to interact with emotion- and behavior-related neuronal circuits, modulating susceptibility and resilience to mental disorders. However, it remains unclear whether immune dysregulation is a cardinal causal factor or an outcome of the pathologies associated with mental disorders. Emerging variations in immune regulatory pathways based on sex differences provide an additional framework for discussion in these psychiatric disorders. In this review, we present the current literature pertaining to the effects that disrupted immune pathways have in mental disorder pathophysiology, including immune dysregulation in CNS and periphery, microglial activation, and disturbances of the blood-brain barrier. In addition, we present the suggested origins of such immune dysregulation and discuss the gender and sex influence of the neuroimmune substrates that contribute to mental disorders. The findings challenge the conventional view of these disorders and open the window to a diverse spectrum of innovative therapeutic targets that focus on the immune-specific pathophenotypes in neuronal circuits and behavior. SIGNIFICANCE STATEMENT: The involvement of gender-dependent inflammatory mechanisms on the development of mental pathologies is gaining momentum. This review addresses these novel factors and presents the accumulating evidence introducing microglia and proinflammatory elements as critical components and potential targets for the treatment of mental disorders.
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Affiliation(s)
- Alexandros G Kokkosis
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York
| | - Stella E Tsirka
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York
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Feldman CH, Malspeis S, Leatherwood C, Kubzansky L, Costenbader KH, Roberts AL. Association of Childhood Abuse with Incident Systemic Lupus Erythematosus in Adulthood in a Longitudinal Cohort of Women. J Rheumatol 2019; 46:1589-1596. [PMID: 31092723 DOI: 10.3899/jrheum.190009] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/24/2019] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Exposure to severe stressors may alter immune function and augment inflammation and cytokine release, increasing risk of autoimmune disease. We examined whether childhood abuse was associated with a heightened risk of incident systemic lupus erythematosus (SLE). METHODS Data were drawn from the Nurses' Health Study II, a cohort of US female nurses enrolled in 1989, followed with biennial questionnaires. We measured childhood physical and emotional abuse with the Physical and Emotional Abuse Subscale of the Childhood Trauma Questionnaire and sexual abuse with the Sexual Maltreatment Scale of the Parent-Child Conflict Tactics Scale, both administered in 2001. We identified incident SLE (≥ 4 American College of Rheumatology 1997 classification criteria) through 2015. We used multivariable Cox regression models to evaluate the association between childhood abuse and SLE, accounting for potential confounders (e.g., parental education, occupation, home ownership) and mediators [e.g., depression, posttraumatic stress disorder (PTSD)]. RESULTS Among 67,516 women, there were 94 cases of incident SLE. In adjusted models, exposure to the highest versus lowest physical and emotional abuse was associated with 2.57 times greater risk of SLE (95% CI 1.30-5.12). We found that 17% (p < 0.0001) of SLE risk associated with abuse could be explained by depression and 23% (p < 0.0001) by PTSD. We did not observe a statistically significant association with sexual abuse (HR 0.84, 95% CI 0.40-1.77, highest vs lowest exposure). CONCLUSION We observed significantly increased risk of SLE among women who had experienced childhood physical and emotional abuse compared with women who had not. Exposure to childhood adversity may contribute to development of SLE.
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Affiliation(s)
- Candace H Feldman
- From the Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and the Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. .,C.H. Feldman, MD, ScD, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; S. Malspeis, MS, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; C. Leatherwood, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; L. Kubzansky, PhD, Harvard T.H. Chan School of Public Health; K.H. Costenbader, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; A.L. Roberts, PhD, Harvard T.H. Chan School of Public Health.
| | - Susan Malspeis
- From the Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and the Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,C.H. Feldman, MD, ScD, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; S. Malspeis, MS, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; C. Leatherwood, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; L. Kubzansky, PhD, Harvard T.H. Chan School of Public Health; K.H. Costenbader, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; A.L. Roberts, PhD, Harvard T.H. Chan School of Public Health
| | - Cianna Leatherwood
- From the Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and the Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,C.H. Feldman, MD, ScD, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; S. Malspeis, MS, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; C. Leatherwood, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; L. Kubzansky, PhD, Harvard T.H. Chan School of Public Health; K.H. Costenbader, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; A.L. Roberts, PhD, Harvard T.H. Chan School of Public Health
| | - Laura Kubzansky
- From the Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and the Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,C.H. Feldman, MD, ScD, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; S. Malspeis, MS, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; C. Leatherwood, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; L. Kubzansky, PhD, Harvard T.H. Chan School of Public Health; K.H. Costenbader, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; A.L. Roberts, PhD, Harvard T.H. Chan School of Public Health
| | - Karen H Costenbader
- From the Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and the Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,C.H. Feldman, MD, ScD, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; S. Malspeis, MS, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; C. Leatherwood, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; L. Kubzansky, PhD, Harvard T.H. Chan School of Public Health; K.H. Costenbader, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; A.L. Roberts, PhD, Harvard T.H. Chan School of Public Health
| | - Andrea L Roberts
- From the Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and the Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,C.H. Feldman, MD, ScD, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; S. Malspeis, MS, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; C. Leatherwood, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; L. Kubzansky, PhD, Harvard T.H. Chan School of Public Health; K.H. Costenbader, MD, MPH, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; A.L. Roberts, PhD, Harvard T.H. Chan School of Public Health
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Lima Giacobbo B, Doorduin J, Klein HC, Dierckx RAJO, Bromberg E, de Vries EFJ. Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation. Mol Neurobiol 2019; 56:3295-3312. [PMID: 30117106 PMCID: PMC6476855 DOI: 10.1007/s12035-018-1283-6] [Citation(s) in RCA: 491] [Impact Index Per Article: 81.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 07/24/2018] [Indexed: 12/26/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the healthy and diseased brain. As a result, there is a large body of evidence that associates BDNF with neuronal maintenance, neuronal survival, plasticity, and neurotransmitter regulation. Patients with psychiatric and neurodegenerative disorders often have reduced BDNF concentrations in their blood and brain. A current hypothesis suggests that these abnormal BDNF levels might be due to the chronic inflammatory state of the brain in certain disorders, as neuroinflammation is known to affect several BDNF-related signaling pathways. Activation of glia cells can induce an increase in the levels of pro- and antiinflammatory cytokines and reactive oxygen species, which can lead to the modulation of neuronal function and neurotoxicity observed in several brain pathologies. Understanding how neuroinflammation is involved in disorders of the brain, especially in the disease onset and progression, can be crucial for the development of new strategies of treatment. Despite the increasing evidence for the involvement of BDNF and neuroinflammation in brain disorders, there is scarce evidence that addresses the interaction between the neurotrophin and neuroinflammation in psychiatric and neurodegenerative diseases. This review focuses on the effect of acute and chronic inflammation on BDNF levels in the most common psychiatric and neurodegenerative disorders and aims to shed some light on the possible biological mechanisms that may influence this effect. In addition, this review will address the effect of behavior and pharmacological interventions on BDNF levels in these disorders.
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Affiliation(s)
- Bruno Lima Giacobbo
- Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Ipiranga Av. 6681, Porto Alegre, 90619-900, Brazil
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 31.001, 9713 GZ, Groningen, The Netherlands
| | - Janine Doorduin
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 31.001, 9713 GZ, Groningen, The Netherlands
| | - Hans C Klein
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 31.001, 9713 GZ, Groningen, The Netherlands
| | - Rudi A J O Dierckx
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 31.001, 9713 GZ, Groningen, The Netherlands
| | - Elke Bromberg
- Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Ipiranga Av. 6681, Porto Alegre, 90619-900, Brazil
| | - Erik F J de Vries
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 31.001, 9713 GZ, Groningen, The Netherlands.
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8
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Finnell JE, Wood SK. Putative Inflammatory Sensitive Mechanisms Underlying Risk or Resilience to Social Stress. Front Behav Neurosci 2018; 12:240. [PMID: 30416436 PMCID: PMC6212591 DOI: 10.3389/fnbeh.2018.00240] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/25/2018] [Indexed: 12/30/2022] Open
Abstract
It has been well recognized that exposure to stress can lead to the onset of psychosocial disorders such as depression. While there are a number of antidepressant therapies currently available and despite producing immediate neurochemical alterations, they require weeks of continuous use in order to exhibit antidepressant efficacy. Moreover, up to 30% of patients do not respond to typical antidepressants, suggesting that our understanding of the pathophysiology underlying stress-induced depression is still limited. In recent years inflammation has become a major focus in the study of depression as several clinical and preclinical studies have demonstrated that peripheral and central inflammatory mediators, including interleukin (IL)-1β, are elevated in depressed patients. Moreover, it has been suggested that inflammation and particularly neuroinflammation may be a direct and immediate link in the emergence of stress-induced depression due to the broad neural and glial effects that are elicited by proinflammatory cytokines. Importantly, individual differences in inflammatory reactivity may further explain why certain individuals exhibit differing susceptibility to the consequences of stress. In this review article, we discuss sources of individual differences such as age, sex and coping mechanisms that are likely sources of distinct changes in stress-induced neuroimmune factors and highlight putative sources of exaggerated neuroinflammation in susceptible individuals. Furthermore, we review the current literature of specific neural and glial mechanisms that are regulated by stress and inflammation including mitochondrial function, oxidative stress and mechanisms of glutamate excitotoxicity. Taken together, the impetus for this review is to move towards a better understanding of mechanisms regulated by inflammatory cytokines and chemokines that are capable of contributing to the emergence of depressive-like behaviors in susceptible individuals.
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Affiliation(s)
- Julie E Finnell
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Susan K Wood
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States.,WJB Dorn Veterans Administration Medical Center, Columbia, SC, United States
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9
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Caspani G, Corbet Burcher G, Garralda ME, Cooper M, Pierce CM, Als LC, Nadel S. Inflammation and psychopathology in children following PICU admission: an exploratory study. EVIDENCE-BASED MENTAL HEALTH 2018; 21:139-144. [PMID: 30301824 PMCID: PMC6241628 DOI: 10.1136/ebmental-2018-300027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/21/2018] [Accepted: 08/13/2018] [Indexed: 12/27/2022]
Abstract
Background Survivors of critical illness in childhood commonly display subsequent psychiatric symptoms including emotional and behavioural difficulties, and manifestations of post-traumatic stress disorder (PTSD). Anomalies in inflammatory profiles are an established finding in these childhood psychiatric conditions. Objective This exploratory study aimed to investigate whether abnormal peripheral blood inflammatory markers measured during paediatric intensive care unit (PICU) admission were associated with psychiatric symptoms after discharge. Methods We performed a prospective observational cohort study on 71 children with septic illness, meningoencephalitis and other critical disorders admitted to two PICUs between 2007 and 2010. 3–6 months following discharge, subjects were assessed for global psychiatric risk (ie, presence of emotional and behavioural difficulties on the parental Strengths and Difficulties Questionnaire (SDQ)), and for PTSD risk using the child-rated Impact of Events Scale (IES-8). Inflammatory and related biological markers were transcribed from PICU admission notes (white cell count, lymphocytes, neutrophils, C reactive protein (CRP), platelets, fibrinogen and lactate). Findings Global psychiatric risk at follow-up was associated with abnormal lymphocyte count during admission (χ2=6.757, p=0.014, n=48). In children with sepsis, partial correlation analyses controlling for age and gender highlighted associations between (i) SDQ scores and low lymphocyte count (r=−0.712; p=0.009, n=14), and (ii) IES-8 score and high CRP levels (r=0.823; p=0.006, n=11). These associations remained after correction for multiple comparisons. Conclusion These results support the hypothesis that acute inflammation may play a role in determining the development of psychopathology following PICU admission. Clinical implications If the findings are replicated, they may help to better highlight which children are at risk of post-PICU psychopathology and appropriately target follow-up.
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Affiliation(s)
- Giorgia Caspani
- Department of Surgery and Cancer, Imperial College London, London, UK
| | | | | | - Mehrengise Cooper
- Department of Paediatric Intensive Care, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Christine M Pierce
- Department of Paediatric Intensive Care, Great Ormond Street Hospital, London, UK
| | - Lorraine C Als
- Centre for Psychiatry, Imperial College London, London, UK
| | - Simon Nadel
- Department of Paediatric Intensive Care, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK
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10
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Aguilar-Raab C, Jarczok MN, Warth M, Stoffel M, Winter F, Tieck M, Berg J, Negi LT, Harrison T, Pace TWW, Ditzen B. Enhancing Social Interaction in Depression (SIDE study): protocol of a randomised controlled trial on the effects of a Cognitively Based Compassion Training (CBCT) for couples. BMJ Open 2018; 8:e020448. [PMID: 30287601 PMCID: PMC6173246 DOI: 10.1136/bmjopen-2017-020448] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Positive social interactions (PSIs) and stable relationships can exert substantial benefits on health. However, patients suffering from depression benefit less from these health-promoting effects. Moreover, relationship quality and even partners' health has been found to be negatively affected by depressive symptomatology, which may result in overall impairments in social functioning of a romantic couple. Psychobiological research indicates that these impairments may be accompanied by a maladaptive regulation of the patient's neuroendocrine response to external stressors. Concerning the improvement of social functioning, first studies showed promising results of "Cognitively Based Compassion Training (CBCT®)". However, randomised trials are still scarce. Previous programmes did not involve participation of the patient's romantic partner. Therefore, the present study aims to investigate whether a CBCT® programme adapted for couples (CBCT®-fC) can improve depressive symptoms, distress, social interaction skills and the neurobiological regulation of stress. METHODS AND ANALYSIS Couples with the female partner suffering from depression will be invited to participate in a pre-to-post intervention assessment on two consecutive days, respectively, involving a standardised PSI task, eye-tracking, ECG recordings, saliva-sampling, blood-sampling and questionnaire data. After baseline assessment, participating couples will be randomised to either a 10 week CBCT®-fC or to a treatment as usual control condition. The primary endpoint is the reduction of depressive symptoms measured by the Hamilton Depression Rating Scale. Secondary outcomes encompass self-rated depression (Beck Depression Inventory), attention towards the partners face during PSI (eye tracking), stress-related biomarkers (cortisol, α-amylase, interleukin (IL)-1ß/IL-6, heart rate variability), methylation of oxytocin-receptor-genes and serotonin-transporter-genes and self-ratings of psychological constructs such as relationship quality and empathy. ETHICS AND DISSEMINATION Ethical approval has been obtained by the Ethics Committee of the Medical Faculty Heidelberg. Results will be presented in international, peer-reviewed journals and on conferences in the field of clinical psychology and psychiatry. TRIAL REGISTRATION NUMBER NCT03080025.
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Affiliation(s)
- Corina Aguilar-Raab
- Institute of Medical Psychology, Center for Psychosocial Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Marc N Jarczok
- Institute of Medical Psychology, Center for Psychosocial Medicine, University Hospital Heidelberg, Heidelberg, Germany
- Department of Psychosomatic Medicine and Psychotherapy, University Clinic Ulm, Ulm, Germany
| | - Marco Warth
- Institute of Medical Psychology, Center for Psychosocial Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Martin Stoffel
- Institute of Medical Psychology, Center for Psychosocial Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Friederike Winter
- Institute of Medical Psychology, Center for Psychosocial Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Maria Tieck
- Institute of Medical Psychology, Center for Psychosocial Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Judith Berg
- Institute of Medical Psychology, Center for Psychosocial Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Lobsang Tenzin Negi
- Department of Religion, Emory-Tibet Partnership, Center for Contemplative Science and Compassion-Based Ethics, Emory College, Emory University, Atlanta, Georgia, USA
| | - Tim Harrison
- Emory-Tibet Partnership, Center for Contemplative Science and Compassion-Based Ethics, CBCT® Teacher Training, Emory University, Atlanta, Georgia, USA
| | - Thaddeus W W Pace
- College of Nursing, University of Arizona, Tucson, Arizona, USA
- Department of Psychiatry, College of Medicine, University of Arizona, Tucson, Arizona, USA
- Department of Psychology, College of Science, University of Arizona, Tucson, Arizona, USA
| | - Beate Ditzen
- Institute of Medical Psychology, Center for Psychosocial Medicine, University Hospital Heidelberg, Heidelberg, Germany
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11
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Langgartner D, Foertsch S, Füchsl AM, Reber SO. Light and water are not simple conditions: fine tuning of animal housing in male C57BL/6 mice. Stress 2017; 20:10-18. [PMID: 27788633 DOI: 10.1080/10253890.2016.1254186] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
While animal housing conditions are highly controlled and standardized between different laboratories, there are still many subtle differences that unavoidably influence the host organisms and, consequently, interlaboratory reproducibility. Here, we investigated the physiological and immunological consequences between two light/dark cycle (LDC) lengths (14-h/10-h vs. 12-h/12-h LDC) and two commonly used forms of drinking water (acidified drinking water (AW) versus normal tap water (NW)) in single-housed (SH) mice. Our results indicate that SH mice bred under a 12-h/12-h LDC and NW at the supplier's facility showed increased basal morning plasma corticosterone (CORT) levels even 4 weeks after arrival at our animal facility employing a 14-h/10-h LDC and AW. This effect was even more pronounced two weeks after arrival and had abated after 8 weeks. In agreement, increased plasma adrenocorticotropic hormone (ACTH), adrenal in vitro ACTH sensitivity, as well as relative and absolute adrenal weight normalized during this 8-week exposure to the novel and unfamiliar 14-h/10-h LDC and AW. Employment of a 12-h/12-h LDC in our facility completely abrogated the CORT-elevating effects of the 14-h/10-h LDC, despite these animals drinking AW. When both the water and light conditions were matched to those at the supplier's facility, we observed a further reduction in adrenal weight, increased thymus weight, and decreased pro-inflammatory cytokine secretion of isolated and anti-CD3/28-stimulated mesenteric lymph node cells. In summary, our results indicate that prolonged alteration of both the light phase and drinking water represent severe and long-lasting stressors for laboratory rodents. These findings are of general interest for all scientists obtaining their experimental animals from conventional suppliers.
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Affiliation(s)
- Dominik Langgartner
- a Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy , University Ulm , Ulm , Germany
| | - Sandra Foertsch
- a Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy , University Ulm , Ulm , Germany
| | - Andrea M Füchsl
- a Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy , University Ulm , Ulm , Germany
| | - Stefan O Reber
- a Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy , University Ulm , Ulm , Germany
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12
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Mutlu H, Bilgiç V, Erten S, Aras Ş, Tayfur M. Evaluation of the Relationship between Childhood Traumas and Adulthood Obesity Development. Ecol Food Nutr 2016; 55:390-401. [PMID: 27399037 DOI: 10.1080/03670244.2016.1198791] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
This study aimed to delineate the relationship between childhood traumas and adulthood obesity. A total of 314 individuals (157 obese and 157 nonobese) were recruited in the study. After obtaining anthropometric and sociodemographic variables, the Childhood Trauma Questionnaire (CTQ) was administered to the participants. Overall scores of CTQ were determined to be 42.6 ± 10.5 (higher trauma) in obese group and 37.2 ± 6.6 (lower trauma) in nonobese group (P < 0.001). Frequency rates of childhood traumatic experience were found to be 68.8% for obese people and 38.8% for nonobese people. In conclusion, an increased risk for adulthood obesity development was significantly associated with childhood traumatic experience.
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Affiliation(s)
- Hayrettin Mutlu
- a Fatih University Hospital , Center for Nutrition and Dietetics , Istanbul , Turkey
| | - Vedat Bilgiç
- b Department of Psychiatry , Fatih University Medical School , Istanbul , Turkey
| | - Sebahattin Erten
- c Department of Internal Medicine , Fatih University Hospital , Istanbul , Turkey
| | - Şükrü Aras
- d Department of Nutrition and Dietetics , Şifa University , Izmir , Turkey
| | - Muhittin Tayfur
- e Department of Nutrition and Dietetics , Başkent University , Ankara , Turkey
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Abstract
Early life trauma (ELT) comprises an array of disturbingly common distressing experiences between conception and the beginning of adulthood with numerous and significant potential long-term, even transgenerational, health consequences of great public health concern, including depression, cardiovascular disease, and other psychiatric and medical disorders, and neurobiological, psychological, and behavioral effects which are sufficiently robust to confound many types of biomedical research. The impact of ELT on a woman's health trajectory appears to vary with the specific characteristics of the ELT (e.g., type, number of different types, severity, and timing), the individual (e.g., age, genetics, epigenetics, personality, and cognitive factors), and the individual's environment (e.g., level of social support and ongoing stressors) and to be mediated to a significant extent by persistent changes in a number of biological systems, dysregulation of those governing the stress response chief among them. Growing knowledge of the risk factors and pathophysiological mechanisms by which ELT confers diathesis to various poor health outcomes and the unique treatment-response profiles of women with ELT will lead to much needed improvements in prevention, diagnostic, and therapeutic efforts, including more effective psychotherapy and pharmacotherapy approaches, hopefully making strides toward improvements in the lives of women everywhere and ending countless cycles of intergenerational trauma-associated pathology. This article attempts to broadly summarize the current state of knowledge about the long-term sequelae of ELT for women's health.
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14
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Derry HM, Padin AC, Kuo JL, Hughes S, Kiecolt-Glaser JK. Sex Differences in Depression: Does Inflammation Play a Role? Curr Psychiatry Rep 2015; 17:78. [PMID: 26272539 PMCID: PMC4869519 DOI: 10.1007/s11920-015-0618-5] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Women become depressed more frequently than men, a consistent pattern across cultures. Inflammation plays a key role in initiating depression among a subset of individuals, and depression also has inflammatory consequences. Notably, women experience higher levels of inflammation and greater autoimmune disease risk compared to men. In the current review, we explore the bidirectional relationship between inflammation and depression and describe how this link may be particularly relevant for women. Compared to men, women may be more vulnerable to inflammation-induced mood and behavior changes. For example, transient elevations in inflammation prompt greater feelings of loneliness and social disconnection for women than for men, which can contribute to the onset of depression. Women also appear to be disproportionately affected by several factors that elevate inflammation, including prior depression, somatic symptomatology, interpersonal stressors, childhood adversity, obesity, and physical inactivity. Relationship distress and obesity, both of which elevate depression risk, are also more strongly tied to inflammation for women than for men. Taken together, these findings suggest that women's susceptibility to inflammation and its mood effects may contribute to sex differences in depression. Depression continues to be a leading cause of disability worldwide, with women experiencing greater risk than men. Due to the depression-inflammation connection, these patterns may promote additional health risks for women. Considering the impact of inflammation on women's mental health may foster a better understanding of sex differences in depression, as well as the selection of effective depression treatments.
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Affiliation(s)
- Heather M. Derry
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA
,Department of Psychology, The Ohio State University, Columbus, OH, USA
| | - Avelina C. Padin
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA
,Department of Psychology, The Ohio State University, Columbus, OH, USA
| | - Jennifer L. Kuo
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA
,Department of Psychology, The Ohio State University, Columbus, OH, USA
| | - Spenser Hughes
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA
,Department of Psychology, The Ohio State University, Columbus, OH, USA
| | - Janice K. Kiecolt-Glaser
- Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA
,Department of Psychology, The Ohio State University, Columbus, OH, USA
,Department of Psychiatry and Behavioral Health, The Ohio State University College of Medicine, Columbus, OH, USA
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15
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Fagundes C, LeRoy A, Karuga M. Behavioral Symptoms after Breast Cancer Treatment: A Biobehavioral Approach. J Pers Med 2015; 5:280-95. [PMID: 26247972 PMCID: PMC4600148 DOI: 10.3390/jpm5030280] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 07/17/2015] [Accepted: 07/23/2015] [Indexed: 01/18/2023] Open
Abstract
Being diagnosed and treated for breast cancer is emotionally and physically challenging. Breast cancer is the most commonly diagnosed cancer and the second leading cause of death for women in the United States. Accordingly, women with a breast cancer history are the largest group of female cancer survivors. Psychological stress substantially augments adverse autonomic, endocrine, and immune discharge, including enhanced production of proinflammatory cytokines. Importantly, inflammation is a key biological mechanism underlying the symptom cluster of pain, depression, fatigue, and sleep disturbances; there is also good evidence that inflammation contributes to breast cancer recurrence. Stress may exert direct effects on psychological and physiological risk processes. In this review, we take a biobehavioral approach to understanding predictors and mechanisms underlying somatic symptoms in breast cancer survivors.
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Affiliation(s)
- Christopher Fagundes
- Department of Psychology, Rice University, Houston, TX 77005, USA.
- Department of Symptoms Research, MD Anderson Cancer Center, Houston, TX 77030, USA.
- Department of Psychiatry, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Angie LeRoy
- Department of Psychology, University of Houston, Houston, TX 77004, USA.
| | - Maryanne Karuga
- Department of Science, Technology, Engineering, and Mathematics, Dillard University, New Orleans, LA 70122, USA.
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16
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Abstract
In response to social-evaluative threat induced in the laboratory, lower (compared to higher) subjective social class of a participant predicts greater increases in the inflammatory cytokine interleukin-6 (IL-6). In spite of the interpersonal nature of social-evaluation, little work has explored whether characteristics of the evaluator shape physiological responses in this context. In the current study, in a sample of 190 college students (male=66), we explored whether one's subjective social class interacts with the perceived social class of an evaluator to predict changes in Oral Mucosal Transudate (OMT) IL-6 in response to the Trier Social Stress Test (TSST). Participants were randomly assigned to be the speaker or the evaluator. Extending past work, we found that while speakers low in subjective social class consistently respond with strong increases in IL-6 regardless of their perception of their evaluator's social class, speakers high in subjective social class responded with greater increases in IL-6 when their evaluator was perceived as high social class compared to when they were perceived as low social class. This finding highlights the importance of perceptions of the evaluator in informing inflammatory responses to a social-evaluative task.
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17
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Lukic I, Mitic M, Djordjevic J, Tatalovic N, Bozovic N, Soldatovic I, Mihaljevic M, Pavlovic Z, Radojcic MB, Maric NP, Adzic M. Lymphocyte levels of redox-sensitive transcription factors and antioxidative enzymes as indicators of pro-oxidative state in depressive patients. Neuropsychobiology 2015; 70:1-9. [PMID: 25170744 DOI: 10.1159/000362841] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 04/13/2014] [Indexed: 11/19/2022]
Abstract
BACKGROUND Oxidative stress is reliably observed in major depressive disorder (MDD). However, molecular data on the principal cellular redox-sensitive transcriptional factors and the levels of their downstream-regulated antioxidant enzymes in MDD are scarce. METHODS In the peripheral blood mononuclear cells (PBMC) of subjects with a current episode of MDD (n = 30) and healthy controls (n = 35), we investigated alterations in the levels of redox-sensing nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein, its inhibitor Keap1, and nuclear factor-κB (NF-κB), along with their cognate downstream effectors, the antioxidant enzymes (AOEs): manganese and copper zinc superoxide dismutase (MnSOD and CuZnSOD, respectively), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR). RESULTS MDD subjects exhibited higher levels of Nrf2 and its regulator Keap1, as well as NF-κB in the cytoplasm of PBMC compared to controls. This state was further reflected by increased levels of MnSOD, CuZnSOD and CAT proteins and by the lack of correlation between MnSOD and CAT, which could indicate impaired oxidative detoxification capacity in MDD patients. Moreover, increased levels of MnSOD, CuZnSOD and CAT in MDD patients positively correlated with levels of Nrf2, while increased levels of SODs were also positively related to NF-κB. There were no differences regarding the levels of GPx and GLR proteins, but the ratio of GLR/GPx was reduced, suggesting diminished capacity of GPx in antioxidative defence in PBMC of MDD subjects. CONCLUSION These data provide evidence that MDD is characterized by up-regulation of redox-sensitive transcriptional factors (Nrf2 and NF-κB) and AOEs (MnSOD, CuZnSOD and CAT), indicating pro-oxidative state in the PBMC of MDD patients.
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Affiliation(s)
- Iva Lukic
- Laboratory of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, Belgrade, Serbia
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18
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Cattaneo A, Macchi F, Plazzotta G, Veronica B, Bocchio-Chiavetto L, Riva MA, Pariante CM. Inflammation and neuronal plasticity: a link between childhood trauma and depression pathogenesis. Front Cell Neurosci 2015; 9:40. [PMID: 25873859 PMCID: PMC4379909 DOI: 10.3389/fncel.2015.00040] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 01/27/2015] [Indexed: 12/13/2022] Open
Abstract
During the past two decades, there has been increasing interest in understanding and characterizing the role of inflammation in major depressive disorder (MDD). Indeed, several are the evidences linking alterations in the inflammatory system to Major Depression, including the presence of elevated levels of pro-inflammatory cytokines, together with other mediators of inflammation. However, it is still not clear whether inflammation represents a cause or whether other factors related to depression result in these immunological effects. Regardless, exposure to early life stressful events, which represent a vulnerability factor for the development of psychiatric disorders, act through the modulation of inflammatory responses, but also of neuroplastic mechanisms over the entire life span. Indeed, early life stressful events can cause, possibly through epigenetic changes that persist over time, up to adulthood. Such alterations may concur to increase the vulnerability to develop psychopathologies. In this review we will discuss the role of inflammation and neuronal plasticity as relevant processes underlying depression development. Moreover, we will discuss the role of epigenetics in inducing alterations in inflammation-immune systems as well as dysfunction in neuronal plasticity, thus contributing to the long-lasting negative effects of stressful life events early in life and the consequent enhanced risk for depression. Finally we will provide an overview on the potential role of inflammatory system to aid diagnosis, predict treatment response, enhance treatment matching, and prevent the onset or relapse of Major Depression.
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Affiliation(s)
- Annamaria Cattaneo
- Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King's College London London, UK ; IRCCS Centro S Giovanni di Dio, Fatebenefratelli Brescia, Italy
| | - Flavia Macchi
- Department of Pharmacological and Biomolecular Sciences, University of Milan Milan, Italy
| | - Giona Plazzotta
- IRCCS Centro S Giovanni di Dio, Fatebenefratelli Brescia, Italy
| | - Begni Veronica
- Department of Pharmacological and Biomolecular Sciences, University of Milan Milan, Italy
| | - Luisella Bocchio-Chiavetto
- IRCCS Centro S Giovanni di Dio, Fatebenefratelli Brescia, Italy ; Faculty of Psychology, eCampus University Novedrate (Como), Italy
| | - Marco Andrea Riva
- Department of Pharmacological and Biomolecular Sciences, University of Milan Milan, Italy
| | - Carmine Maria Pariante
- Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King's College London London, UK
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Seligman F, Nemeroff CB. The interface of depression and cardiovascular disease: therapeutic implications. Ann N Y Acad Sci 2015; 1345:25-35. [PMID: 25809518 DOI: 10.1111/nyas.12738] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Patients with major depression are at an increased risk for developing cardiovascular disease, respond more poorly to treatment, and exhibit worse outcomes, including increased morbidity and mortality. This article reviews the relationship between depression and heart disease, with an emphasis on epidemiology, biological substrates that likely underlie this relationship, and implications for treatment.
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Affiliation(s)
- Fred Seligman
- Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida
| | - Charles B Nemeroff
- Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida
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Stewart AM, Nguyen M, Poudel MK, Warnick JE, Echevarria DJ, Beaton EA, Song C, Kalueff AV. The failure of anxiolytic therapies in early clinical trials: what needs to be done. Expert Opin Investig Drugs 2015; 24:543-56. [PMID: 25727478 DOI: 10.1517/13543784.2015.1019063] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Anxiety spectrum disorders (ASDs) are highly prevalent psychiatric illnesses that affect millions of people worldwide. Strongly associated with stress, common ASDs include generalized anxiety disorder, panic, social anxiety, phobias and drug-abuse-related anxiety. In addition to ASDs, several other prevalent psychiatric illnesses represent trauma/stressor-related disorders, such as post-traumatic stress disorder and acute stress disorder. Anxiolytic drugs, commonly prescribed to treat ASDs and trauma/stressor-related disorders, form a highly heterogenous group, modulating multiple neurotransmitters and physiological mechanisms. However, overt individual differences in efficacy and the potential for serious side-effects (including addiction and drug interaction) indicate a need for further drug development. Yet, over the past 50 years, there has been relatively little progress in the development of novel anxiolytic medications, especially when promising candidate drugs often fail in early clinical trials. AREAS COVERED Herein, the authors present recommendations of the Task Force on Anxiolytic Drugs of the International Stress and Behavior Society on how to improve anxiolytic drug discovery. These recommendations cover a wide spectrum of aspects, ranging from methodological improvements to conceptual insights and innovation. EXPERT OPINION In order to improve the success of anxiolytic drugs in early clinical trials, the goals of preclinical trials may need to be adjusted from a clinical perspective and better synchronized with those of clinical studies. Indeed, it is important to realize that the strategic goals and approaches must be similar if we want to have a smoother transition between phases.
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Affiliation(s)
- Adam Michael Stewart
- ZENEREI Institute , 309 Palmer Court, Slidell, LA , USA +1 240 328 2275 ; +1 240 328 2275 ;
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Farzi A, Reichmann F, Holzer P. The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour. Acta Physiol (Oxf) 2015; 213:603-27. [PMID: 25545642 DOI: 10.1111/apha.12445] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 11/10/2014] [Accepted: 12/21/2014] [Indexed: 12/18/2022]
Abstract
Neuropeptide Y (NPY), one of the most abundant peptides in the nervous system, exerts its effects via five receptor types, termed Y1, Y2, Y4, Y5 and Y6. NPY's pleiotropic functions comprise the regulation of brain activity, mood, stress coping, ingestion, digestion, metabolism, vascular and immune function. Nerve-derived NPY directly affects immune cells while NPY also acts as a paracrine and autocrine immune mediator, because immune cells themselves are capable of producing and releasing NPY. NPY is able to induce immune activation or suppression, depending on a myriad of factors such as the Y receptors activated and cell types involved. There is an intricate relationship between psychological stress, mood disorders and the immune system. While stress represents a risk factor for the development of mood disorders, it exhibits diverse actions on the immune system as well. Conversely, inflammation is regarded as an internal stressor and is increasingly recognized to contribute to the pathogenesis of mood and metabolic disorders. Intriguingly, the cerebral NPY system has been found to protect against distinct disturbances in response to immune challenge, attenuating the sickness response and preventing the development of depression. Thus, NPY plays an important homeostatic role in balancing disturbances of physiological systems caused by peripheral immune challenge. This implication is particularly evident in the brain in which NPY counteracts the negative impact of immune challenge on mood, emotional processing and stress resilience. NPY thus acts as a unique signalling molecule in the interaction of the immune system with the brain in health and disease.
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Affiliation(s)
- A. Farzi
- Research Unit of Translational Neurogastroenterology; Institute of Experimental and Clinical Pharmacology; Medical University of Graz; Graz Austria
| | - F. Reichmann
- Research Unit of Translational Neurogastroenterology; Institute of Experimental and Clinical Pharmacology; Medical University of Graz; Graz Austria
| | - P. Holzer
- Research Unit of Translational Neurogastroenterology; Institute of Experimental and Clinical Pharmacology; Medical University of Graz; Graz Austria
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Langgartner D, Füchsl AM, Uschold-Schmidt N, Slattery DA, Reber SO. Chronic subordinate colony housing paradigm: a mouse model to characterize the consequences of insufficient glucocorticoid signaling. Front Psychiatry 2015; 6:18. [PMID: 25755645 PMCID: PMC4337237 DOI: 10.3389/fpsyt.2015.00018] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 01/29/2015] [Indexed: 12/30/2022] Open
Abstract
Chronic, in particular chronic psychosocial, stress is a burden of modern societies and known to be a risk factor for numerous somatic and affective disorders (in detail referenced below). However, based on the limited existence of appropriate, and clinically relevant, animal models for studying the effects of chronic stress, the detailed behavioral, physiological, neuronal, and immunological mechanisms linking stress and such disorders are insufficiently understood. To date, most chronic stress studies in animals employ intermittent exposure to the same (homotypic) or to different (heterotypic) stressors of varying duration and intensity. Such models are only of limited value, since they do not adequately reflect the chronic and continuous situation that humans typically experience. Furthermore, application of different physical or psychological stimuli renders comparisons to the mainly psychosocial stressors faced by humans, as well as between the different stress studies almost impossible. In contrast, rodent models of chronic psychosocial stress represent situations more akin to those faced by humans and consequently seem to hold more clinical relevance. Our laboratory has developed a model in which mice are exposed to social stress for 19 continuous days, namely the chronic subordinate colony housing (CSC) paradigm, to help bridge this gap. The main aim of the current review article is to provide a detailed summary of the behavioral, physiological, neuronal, and immunological consequences of the CSC paradigm, and wherever possible relate the findings to other stress models and to the human situation.
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Affiliation(s)
- Dominik Langgartner
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, Ulm, Germany
| | - Andrea M. Füchsl
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, Ulm, Germany
| | - Nicole Uschold-Schmidt
- Laboratory of Molecular and Cellular Neurobiology, Department of Behavioural and Molecular Neurobiology, University of Regensburg, Regensburg, Germany
| | - David A. Slattery
- Department of Behavioural and Molecular Neurobiology, University of Regensburg, Regensburg, Germany
| | - Stefan O. Reber
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, Ulm, Germany
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Horowitz MA, Wertz J, Zhu D, Cattaneo A, Musaelyan K, Nikkheslat N, Thuret S, Pariante CM, Zunszain PA. Antidepressant compounds can be both pro- and anti-inflammatory in human hippocampal cells. Int J Neuropsychopharmacol 2015; 18:pyu076. [PMID: 25522414 PMCID: PMC4360247 DOI: 10.1093/ijnp/pyu076] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The increasingly recognized role of inflammation in the pathogenesis and prognosis of depression has led to a renewed focus on the immunomodulatory properties of compounds with antidepressant action. Studies have, so far, explored such properties in human blood samples and in animal models. METHODS Here we used the more relevant model of human hippocampal progenitor cells exposed to an inflammatory milieu, induced by treatment with IL-1β. This increased the levels of a series of cytokines and chemokines produced by the cells, including a dose- and time-dependent increase of IL-6. We investigated the immunomodulatory properties of four monoaminergic antidepressants (venlafaxine, sertraline, moclobemide, and agomelatine) and two omega-3 polyunsaturated fatty acids (n-3 PUFAs; eicosapentanoic acid [EPA] and docosahexanoic acid [DHA]). RESULTS We found that venlafaxine and EPA were anti-inflammatory: venlafaxine decreased IL-6, with a trend for decreases of IL-8 and IP-10, while EPA decreased the levels of IL-6, IL-15, IL-1RA, and IP-10. These effects were associated with a corresponding decrease in NF-kB activity. Unexpectedly, sertraline and DHA had pro-inflammatory effects, with sertraline increasing IFN-α and IL-6 and DHA increasing IL-15, IL-1RA, IFN-α, and IL-6, though these changes were also associated with a decrease in NF-kB activity, suggesting distinct modes of action. Agomelatine and moclobemide had no effect on IL-6 secretion. CONCLUSIONS These observations indicate that monoaminergic antidepressants and n-3 PUFAs have distinctive effects on immune processes in human neural cells. Further characterization of these actions may enable more effective personalization of treatment based on the inflammatory status of patients.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Patricia Ana Zunszain
- Section of Stress, Psychiatry and Immunology, Department of Psychological Medicine, Institute of Psychiatry, King's College London, London, UK (Dr Horowitz, Ms Wertz, Ms Zhu, Drs Cattaneo, Musaelyan, Nikkheslat, Pariante, and Zunszain); Department of Basic and Clinical Neuroscience, Centre for the Cellular Basis of Behaviour, The James Black Centre (Thuret); and IRCCS Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy (Dr Cattaneo).
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Bick J, Nguyen V, Leng L, Piecychna M, Crowley MJ, Bucala R, Mayes LC, Grigorenko EL. Preliminary associations between childhood neglect, MIF, and cortisol: potential pathways to long-term disease risk. Dev Psychobiol 2015; 57:131-9. [PMID: 25380347 PMCID: PMC4337818 DOI: 10.1002/dev.21265] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Accepted: 10/04/2014] [Indexed: 11/06/2022]
Abstract
The study examined Hypothalamus-Pituitary-Adrenal (HPA) axis and inflammatory signaling in 206 youth with histories of prenatal drug exposure and self-reported histories of maltreatment. Youth with histories of severe neglect showed elevated levels of cortisol, the end product of the HPA axis, in comparison to youth with lower or minimal levels of neglect. Histories of severe neglect also were associated with increased levels of Macrophage Migration Inhibitory Factor (MIF), a cytokine known to be intricately involved in HPA axis regulation. Salivary MIF levels also were positively associated with youth age and prenatal drug exposure. These MIF and cortisol alterations may signal pathophysiological disruptions in the neuro-endocrine and immune systems, which may lead to trajectories of increased disease risk among vulnerable youth. Our findings also provide preliminary support for the validity and reliability of a noninvasive salivary assessment of MIF.
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Affiliation(s)
- Johanna Bick
- Child Study Center, Yale School of Medicine, New Haven, CT
| | - Victoria Nguyen
- Child Study Center, Yale School of Medicine, New Haven, CT
- Yale College, New Haven, CT
| | - Lin Leng
- Department of Internal Medicine, Rheumatology, Yale School of Medicine, New Haven, CT
| | - Marta Piecychna
- Department of Internal Medicine, Rheumatology, Yale School of Medicine, New Haven, CT
| | | | - Richard Bucala
- Department of Internal Medicine, Rheumatology, Yale School of Medicine, New Haven, CT
| | - Linda C. Mayes
- Child Study Center, Yale School of Medicine, New Haven, CT
| | - Elena L. Grigorenko
- Child Study Center, Yale School of Medicine, New Haven, CT
- Moscow State University for Psychology, and Education, Moscow, Russia
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25
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Deak T, Quinn M, Cidlowski JA, Victoria NC, Murphy AZ, Sheridan JF. Neuroimmune mechanisms of stress: sex differences, developmental plasticity, and implications for pharmacotherapy of stress-related disease. Stress 2015; 18:367-80. [PMID: 26176590 PMCID: PMC4813310 DOI: 10.3109/10253890.2015.1053451] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The last decade has witnessed profound growth in studies examining the role of fundamental neuroimmune processes as key mechanisms that might form a natural bridge between normal physiology and pathological outcomes. Rooted in core concepts from psychoneuroimmunology, this review utilizes a succinct, exemplar-driven approach of several model systems that contribute significantly to our knowledge of the mechanisms by which neuroimmune processes interact with stress physiology. Specifically, we review recent evidence showing that (i) stress challenges produce time-dependent and stressor-specific patterns of cytokine/chemokine expression in the CNS; (ii) inflammation-related genes exhibit unique expression profiles in males and females depending upon individual, cooperative or antagonistic interactions between steroid hormone receptors (estrogen and glucocorticoid receptors); (iii) adverse social experiences incurred through repeated social defeat engage a dynamic process of immune cell migration from the bone marrow to brain and prime neuroimmune function and (iv) early developmental exposure to an inflammatory stimulus (carageenin injection into the hindpaw) has a lasting influence on stress reactivity across the lifespan. As such, the present review provides a theoretical framework for understanding the role that neuroimmune mechanisms might play in stress plasticity and pathological outcomes, while at the same time pointing toward features of the individual (sex, developmental experience, stress history) that might ultimately be used for the development of personalized strategies for therapeutic intervention in stress-related pathologies.
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Affiliation(s)
- Terrence Deak
- Behavioral Neuroscience Program, Department of Psychology, Binghamton University-SUNY, Binghamton, NY 13902-6000
- Address correspondence to: Terrence Deak, Ph.D., , Phone: 607-777-5918
| | - Matt Quinn
- Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
| | - John A. Cidlowski
- Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
| | - Nicole C. Victoria
- Neuroscience Institute, Georgia State University, Petit Science Center, PO Box 5030, Atlanta, GA 30302-5030
| | - Anne Z. Murphy
- Neuroscience Institute, Georgia State University, Petit Science Center, PO Box 5030, Atlanta, GA 30302-5030
| | - John F. Sheridan
- The Ohio State University College of Dentistry and Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210
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26
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Nguyen M, Stewart AM, Kalueff AV. Aquatic blues: modeling depression and antidepressant action in zebrafish. Prog Neuropsychopharmacol Biol Psychiatry 2014; 55:26-39. [PMID: 24657522 DOI: 10.1016/j.pnpbp.2014.03.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Revised: 03/03/2014] [Accepted: 03/09/2014] [Indexed: 12/20/2022]
Abstract
Depression is a serious psychiatric condition affecting millions of patients worldwide. Unipolar depression is characterized by low mood, anhedonia, social withdrawal and other severely debilitating psychiatric symptoms. Bipolar disorder manifests in alternating depressed mood and 'hyperactive' manic/hypomanic states. Animal experimental models are an invaluable tool for research into the pathogenesis of bipolar/unipolar depression, and for the development of potential treatments. Due to their high throughput value, genetic tractability, low cost and quick reproductive cycle, zebrafish (Danio rerio) have emerged as a promising new model species for studying brain disorders. Here, we discuss the developing utility of zebrafish for studying depression disorders, and outline future areas of research in this field. We argue that zebrafish represent a useful model organism for studying depression and its behavioral, genetic and physiological mechanisms, as well as for anti-depressant drug discovery.
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Affiliation(s)
- Michael Nguyen
- Department of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, VA 22908, USA; ZENEREI Institute, 309 Palmer Court, Slidell, LA 70458, USA
| | - Adam Michael Stewart
- ZENEREI Institute, 309 Palmer Court, Slidell, LA 70458, USA; International Zebrafish Neuroscience Research Consortium (ZNRC), 309 Palmer Court, Slidell, LA 70458, USA; Department of Neuroscience, University of Pittsburgh, A210 Langley Hall, Pittsburgh, PA 15260, USA.
| | - Allan V Kalueff
- ZENEREI Institute, 309 Palmer Court, Slidell, LA 70458, USA; International Zebrafish Neuroscience Research Consortium (ZNRC), 309 Palmer Court, Slidell, LA 70458, USA
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27
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Neuropharmacological effect of novel 5-HT3 receptor antagonist, N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n) on chronic unpredictable mild stress-induced molecular and cellular response: Behavioural and biochemical evidences. Pharmacol Rep 2014; 66:804-10. [DOI: 10.1016/j.pharep.2014.05.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 05/06/2014] [Accepted: 05/09/2014] [Indexed: 11/21/2022]
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28
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Wieck A, Grassi-Oliveira R, do Prado CH, Rizzo LB, de Oliveira AS, Kommers-Molina J, Viola TW, Marciano Vieira ÉL, Teixeira AL, Bauer ME. Pro-inflammatory cytokines and soluble receptors in response to acute psychosocial stress: Differential reactivity in bipolar disorder. Neurosci Lett 2014; 580:17-21. [DOI: 10.1016/j.neulet.2014.07.040] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 07/15/2014] [Accepted: 07/24/2014] [Indexed: 01/01/2023]
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Wood SK. Cardiac autonomic imbalance by social stress in rodents: understanding putative biomarkers. Front Psychol 2014; 5:950. [PMID: 25206349 PMCID: PMC4143725 DOI: 10.3389/fpsyg.2014.00950] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 08/10/2014] [Indexed: 12/17/2022] Open
Abstract
Exposure to stress or traumatic events can lead to the development of depression and anxiety disorders. In addition to the debilitating consequences on mental health, patients with psychiatric disorders also suffer from autonomic imbalance, making them susceptible to a variety of medical disorders. Emerging evidence utilizing spectral analysis of heart rate variability (HRV), a reliable non-invasive measure of cardiovascular autonomic regulation, indicates that patients with depression and various anxiety disorders (i.e., panic, social, generalized anxiety disorders, and post traumatic stress disorder) are characterized by decreased HRV. Social stressors in rodents are ethologically relevant experimental stressors that recapitulate many of the dysfunctional behavioral and physiological changes that occur in psychological disorders. In this review, evidence from clinical studies and preclinical stress models identify putative biomarkers capable of precipitating the comorbidity between disorders of the mind and autonomic dysfunction. Specifically, the role of corticotropin releasing factor, neuropeptide Y and inflammation are investigated. The impetus for this review is to highlight stress-related biomarkers that may prove critical in the development of autonomic imbalance in stress -related psychiatric disorders.
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Affiliation(s)
- Susan K Wood
- Department of Pharmacology, Physiology and Neuroscience, School of Medicine, University of South Carolina Columbia, SC, USA
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30
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Inflammatory biomarker profiles of mental disorders and their relation to clinical, social and lifestyle factors. Soc Psychiatry Psychiatr Epidemiol 2014; 49:841-9. [PMID: 24789456 DOI: 10.1007/s00127-014-0887-z] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Accepted: 04/14/2014] [Indexed: 12/18/2022]
Abstract
In the last few decades, mental health research has increasingly provided evidence supporting the role of inflammation in pathogenesis, course and treatment of mental disorders. With such a steep incline of research, resulting in a wealth of emerged findings, it has become difficult to follow developments within the field. The present review sets out to present the recent developments and to give an overview of the inflammatory profiles of depression, psychosis and bipolar disorder, as well as variations within these disorders. Moreover, mediating factors such as social environment and childhood experience are discussed, both in terms of their potential in elucidating the complex interface between the inflammation and other closely related biological systems, as well as the possibly confounding impact of various lifestyle factors. Whilst many issues in this fascinating area of research remain to be fully understood and elaborated, all current evidence suggests that inflammation plays a key role in mental disorders and may open up novel avenues for clinical treatment.
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31
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Dhabhar FS. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res 2014; 58:193-210. [DOI: 10.1007/s12026-014-8517-0] [Citation(s) in RCA: 452] [Impact Index Per Article: 41.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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32
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Coelho R, Viola TW, Walss-Bass C, Brietzke E, Grassi-Oliveira R. Childhood maltreatment and inflammatory markers: a systematic review. Acta Psychiatr Scand 2014; 129:180-92. [PMID: 24205846 DOI: 10.1111/acps.12217] [Citation(s) in RCA: 291] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/08/2013] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Childhood maltreatment (CM) has been associated with several diseases in adult life, including diabetes, obesity and mental disorders. Inflammatory conditions have been postulated as possible mediators of this relationship. The aim was to conduct a systematic review regarding the association between CM and inflammatory markers in adulthood. METHOD A literature search of the PubMed, ISI, EMBASE and PsychINFO databases was conducted. The key terms used were as follows: 'Child Maltreatment', 'Childhood Trauma', 'Early Life Stress', 'Psychological Stress', 'Emotional Stress', 'Child Abuse' and 'Child Neglect'. They were cross-referenced separately with the terms: 'C-reactive Protein (CRP)', 'Tumor Necrosis Factor', 'Cytokine', 'Interleukin', 'Inflammatory' and 'Inflammation'. RESULTS Twenty articles remained in the review after exclusion criteria were applied. Studies showed that a history of CM was associated with increased levels of CRP, fibrinogen and proinflammatory cytokines. Increased levels of circulating CRP in individuals with a history of CM were the most robust finding among the studies. Data about anti-inflammatory mediators are still few and inconsistent. CONCLUSION Childhood maltreatment is associated with a chronic inflammatory state independent of clinical comorbidities. However, studies are heterogeneous regarding CM assessment and definition. Important methodological improvements are needed to better understand the potential impact of CM on inflammatory response.
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Affiliation(s)
- R Coelho
- Centre of Studies and Research in Traumatic Stress (NEPTE), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
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Mitchell RHB, Goldstein BI. Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review. J Am Acad Child Adolesc Psychiatry 2014; 53:274-96. [PMID: 24565356 DOI: 10.1016/j.jaac.2013.11.013] [Citation(s) in RCA: 186] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Revised: 11/21/2013] [Accepted: 12/13/2013] [Indexed: 11/29/2022]
Abstract
OBJECTIVE There has been rapid growth in research regarding inflammation in neuropsychiatric disorders as it relates to youth. We therefore set out to systematically review the literature on inflammation and neuropsychiatric disorders in children and adolescents. METHOD A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were included if proinflammatory markers (PIMs) in children and/or adolescents with neuropsychiatric disorders were measured. RESULTS Sixty-seven studies were included, involving 3,952 youth. Evidence for a proinflammatory state is strongest for autism spectrum disorders (ASD). PIMs are elevated in children and adolescents with major depressive disorder (MDD), bipolar disorder (BD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), Tourette's disorder (TD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SZ). However, the data are inconsistent. Evidence for specific PIMs is equivocal at this stage, although the findings in youth with MDD, BD, and PTSD converge with the extant adult literature in these areas. Definitive conclusions are limited by methodologic factors including cross-sectional and retrospective study design, between-study differences in specific markers and methods of analysis, small sample size, and other sources of heterogeneity. CONCLUSION The literature regarding inflammation among children and adolescents with neuropsychiatric disorders represents nearly 4,000 youth. There is preliminary evidence for elevated markers of inflammation in this population. Larger, prospective studies are needed to realize the goal of inflammatory markers informing clinical practice. In the interim, present findings suggest that further examination of this topic is warranted.
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34
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Sotelo JL, Musselman D, Nemeroff C. The biology of depression in cancer and the relationship between depression and cancer progression. Int Rev Psychiatry 2014; 26:16-30. [PMID: 24716498 DOI: 10.3109/09540261.2013.875891] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The prevalence of depressive symptoms in patients with cancer exceeds that observed in the general population and depression is associated with a poorer prognosis in cancer patients. The increased prevalence is not solely explained by the psychosocial stress associated with the diagnosis. Pro-inflammatory cytokines, which induce sickness behaviour with symptoms overlapping those of clinical depression, are validated biomarkers of increased inflammation in patients with cancer. A growing literature reveals that chronic inflammatory processes associated with stress may also underlie depression symptoms in general, and in patients with cancer in particular. Therapeutic modalities, which are frequently poorly tolerated, are used in the treatment of cancer. These interventions are associated with inflammatory reactions, which may help to explain their toxicity. There is evidence that antidepressants can effectively treat symptoms of depression in cancer patients though the database is meager. Novel agents with anti-inflammatory properties may be effective alternatives for patients with treatment-resistant depression who exhibit evidence of increased inflammation.
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Affiliation(s)
- Jorge Luis Sotelo
- Department of Psychiatry and Behavioral Sciences, Leonard M. Miller School of Medicine, University of Miami Hospital , Miami, Florida
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35
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Loria AS, Ho DH, Pollock JS. A mechanistic look at the effects of adversity early in life on cardiovascular disease risk during adulthood. Acta Physiol (Oxf) 2014; 210:277-87. [PMID: 24330084 DOI: 10.1111/apha.12189] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 10/22/2013] [Accepted: 10/23/2013] [Indexed: 12/23/2022]
Abstract
Early origins of adult disease may be defined as adversity or challenges during early life that alter physiological responses and prime the organism to chronic disease in adult life. Adverse childhood experiences or early life stress (ELS) may be considered a silent independent risk factor capable of predicting future cardiovascular disease risk. Maternal separation (MatSep) provides a suitable model to elucidate the underlying molecular mechanisms by which ELS increases the risk to develop cardiovascular disease in adulthood. The aim of this review is to describe the links between behavioural stress early in life and chronic cardiovascular disease risk in adulthood. We will discuss the following: (i) adult cardiovascular outcomes in humans subjected to ELS, (ii) MatSep as an animal model of ELS as well as the limitations and advantages of this model in rodents and (iii) possible ELS-induced mechanisms that predispose individuals to greater cardiovascular risk. Overall, exposure to a behavioural stressor early in life sensitizes the response to a second stressor later in life, thus unmasking an exaggerated cardiovascular dysfunction that may influence quality of life and life expectancy in adulthood.
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Affiliation(s)
- A. S. Loria
- Section of Experimental Medicine; Department of Medicine; Georgia Regents University; Augusta GA USA
| | - D. H. Ho
- Section of Experimental Medicine; Department of Medicine; Georgia Regents University; Augusta GA USA
| | - J. S. Pollock
- Section of Experimental Medicine; Department of Medicine; Georgia Regents University; Augusta GA USA
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36
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Wellness and health omics linked to the environment: the WHOLE approach to personalized medicine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 799:1-14. [PMID: 24292959 DOI: 10.1007/978-1-4614-8778-4_1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The WHOLE approach to personalized medicine represents an effort to integrate clinical and genomic profiling jointly into preventative health care and the promotion of wellness. Our premise is that genotypes alone are insufficient to predict health outcomes, since they fail to account for individualized responses to the environment and life history. Instead, integrative genomic approaches incorporating whole genome sequences and transcriptome and epigenome profiles, all combined with extensive clinical data obtained at annual health evaluations, have the potential to provide more informative wellness classification. As with traditional medicine where the physician interprets subclinical signs in light of the person's health history, truly personalized medicine will be founded on algorithms that extract relevant information from genomes but will also require interpretation in light of the triggers, behaviors, and environment that are unique to each person. This chapter discusses some of the major obstacles to implementation, from development of risk scores through integration of diverse omic data types to presentation of results in a format that fosters development of personal health action plans.
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37
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Barrio P, Hidalgo D, Udina M. Bipolar depressive recurrence following treatment with the human monoclonal antibody denosumab: a case report. Biol Psychiatry 2013; 74:e37-8. [PMID: 23890737 DOI: 10.1016/j.biopsych.2013.06.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 06/24/2013] [Accepted: 06/25/2013] [Indexed: 12/17/2022]
Affiliation(s)
- Pablo Barrio
- Psychiatry Department, Clinical Neuroscience Institute, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain.
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38
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Morris AA, Vaccarino V. Evidence Linking Mental Health with Obesity and Metabolic Syndrome: The Role of Inflammation. Curr Nutr Rep 2013. [DOI: 10.1007/s13668-013-0054-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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39
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Allen AP, Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Biological and psychological markers of stress in humans: focus on the Trier Social Stress Test. Neurosci Biobehav Rev 2013; 38:94-124. [PMID: 24239854 DOI: 10.1016/j.neubiorev.2013.11.005] [Citation(s) in RCA: 471] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 11/01/2013] [Accepted: 11/06/2013] [Indexed: 12/24/2022]
Abstract
Validated biological and psychological markers of acute stress in humans are an important tool in translational research. The Trier Social Stress Test (TSST), involving public interview and mental arithmetic performance, is among the most popular methods of inducing acute stress in experimental settings, and reliably increases hypothalamic-pituitary-adrenal axis activation. However, although much research has focused on HPA axis activity, the TSST also affects the sympathetic-adrenal-medullary system, the immune system, cardiovascular outputs, gastric function and cognition. We critically assess the utility of different biological and psychological markers, with guidance for future research, and discuss factors which can moderate TSST effects. We outline the effects of the TSST in stress-related disorders, and if these responses can be abrogated by pharmacological and psychological treatments. Modified TSST protocols are discussed, and the TSST is compared to alternative methods of inducing acute stress. Our analysis suggests that multiple readouts are necessary to derive maximum information; this strategy will enhance our understanding of the psychobiology of stress and provide the means to assess novel therapeutic agents.
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Affiliation(s)
- Andrew P Allen
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry, University College Cork, Cork, Ireland
| | - Paul J Kennedy
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry, University College Cork, Cork, Ireland
| | - John F Cryan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry, University College Cork, Cork, Ireland
| | - Gerard Clarke
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry, University College Cork, Cork, Ireland.
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Kraneveld AD, de Theije CGM, van Heesch F, Borre Y, de Kivit S, Olivier B, Korte M, Garssen J. The neuro-immune axis: prospect for novel treatments for mental disorders. Basic Clin Pharmacol Toxicol 2013; 114:128-36. [PMID: 24118847 DOI: 10.1111/bcpt.12154] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 09/04/2013] [Indexed: 12/21/2022]
Abstract
Disturbed bidirectional pathways between the (central) nervous system and immune system have been implicated in various mental disorders, including depressive and neurodevelopmental disorders. In this minireview, the role of the neuro-immune axis and its targetability in relation to major depression and autism spectrum disorder will be discussed. All together, the management of these and possibly other multi-factorial mental disorders needs a new and integrated therapeutic approach. Pharmacologically bioactive molecules as well as medical nutrition targeting the (gut)-immune-brain axis could be such an approach.
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Affiliation(s)
- Aletta D Kraneveld
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
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41
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Alvarez P, Green PG, Levine JD. Stress in the adult rat exacerbates muscle pain induced by early-life stress. Biol Psychiatry 2013; 74:688-95. [PMID: 23706525 PMCID: PMC3760993 DOI: 10.1016/j.biopsych.2013.04.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Revised: 03/22/2013] [Accepted: 04/09/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND Early-life stress and exposure to stressful stimuli play a major role in the development of chronic widespread pain in adults. However, how they interact in chronic pain syndromes remains unclear. METHODS Dams and neonatal litters were submitted to a restriction of nesting material (neonatal limited bedding [NLB]) for 1 week. As adults, these rats were exposed to a painless sound stress protocol. The involvement of sympathoadrenal catecholamines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) in nociception was evaluated through behavioral and enzyme-linked immunosorbent assays, surgical interventions, and intrathecal antisense treatments. RESULTS Adult NLB rats exhibited mild muscle hyperalgesia, which was markedly aggravated by sound stress (peaking 15 days after exposure). Adrenal medullectomy did not modify hyperalgesia in NLB rats but prevented its aggravation by sound stress. Sustained administration of epinephrine to NLB rats mimicked sound stress effect. Intrathecal treatment with antisense directed to IL-6 receptor subunit gp130 (gp130), but not to tumor necrosis factor receptor type 1 (TNFR1), inhibited hyperalgesia in NLB rats. However, antisense against either gp130 or TNFR1 inhibited sound stress-induced enhancement of hyperalgesia. Compared with control rats, NLB rats exhibit increased plasma levels of IL-6 but decreased levels of TNFα, whereas sound stress increases IL-6 plasma levels in control rats but not in NLB rats. CONCLUSIONS Early-life stress induces a persistent elevation of IL-6, hyperalgesia, and susceptibility to chronic muscle pain, which is unveiled by exposure to stress in adults. This probably depends on an interaction between adrenal catecholamines and proinflammatory cytokines acting at muscle nociceptor level.
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Affiliation(s)
- Pedro Alvarez
- Department of Oral and Maxillofacial Surgery, University of California San Francisco,Department of Division of Neuroscience, University of California San Francisco,Corresponding author’s contact information: Dr. Jon D. Levine, Departments of Medicine, Oral and Maxillofacial Surgery and Division of Neuroscience, University of California at San Francisco, C-555, Box 0440, 521 Parnassus Avenue, San Francisco, CA 94143-0440. Phone: +1-415-476-5108, Fax: +1-415-476-6305,
| | - Paul G. Green
- Department of Oral and Maxillofacial Surgery, University of California San Francisco,Department of Division of Neuroscience, University of California San Francisco
| | - Jon D. Levine
- Department of Oral and Maxillofacial Surgery, University of California San Francisco,Department of Medicine, University of California San Francisco,Department of Division of Neuroscience, University of California San Francisco
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Masuda M, Kanzaki J. Cause of idiopathic sudden sensorineural hearing loss: The stress response theory. World J Otorhinolaryngol 2013; 3:42-57. [DOI: 10.5319/wjo.v3.i3.42] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2013] [Revised: 06/14/2013] [Accepted: 07/25/2013] [Indexed: 02/06/2023] Open
Abstract
The stress response theory is a relatively new concept about the cause of idiopathic sudden sensorineural hearing loss (ISHL). A number of possible etiologies have been proposed in the literature, as discussed in this paper, but each proposed etiology has been both supported and refuted in the literature. However, the stress response theory can integrate hypotheses that have been advocated so far. The word “stress” refers to a constellation of physical and psychological stimuli including systemic viral and bacterial illness, systemic inflammatory disorders, and physical, mental or metabolic stress. Numerous studies have demonstrated adverse effects of systemic stress on health. Stress causes changes in the immune system and cytokine network through activation of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system. Several types of catecholamine and cytokine receptors are in the cochlea cells other than capillary cells, and then they can respond to systemic stressors. However, there are few studies examining how systemic stress is associated with cochlear dysfunction. The stress response theory addresses this question. In the theory, a variety of stressors and risk factors contribute to the onset of ISHL in varying degrees. The lateral wall of the cochlea has very unique responses to systemic stressors. It plays a critical role in causing ISHL. Systemic stressors converge at the lateral wall and trigger pathological activation of nuclear factor κ-light-chain-enhancer of activated B cells, a transcriptional factor known as a stress sensor. This activation enhances local expression of genes associated with immune and inflammatory system, resulting in cochlear dysfunction. We review the original stress response theory advocated by Adams et al and the integrative stress response theory that integrates our knowledge about the etiologies of ISHL so far.
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Girotti M, Donegan JJ, Morilak DA. Influence of hypothalamic IL-6/gp130 receptor signaling on the HPA axis response to chronic stress. Psychoneuroendocrinology 2013; 38:1158-69. [PMID: 23218517 PMCID: PMC3609893 DOI: 10.1016/j.psyneuen.2012.11.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 11/02/2012] [Accepted: 11/05/2012] [Indexed: 01/30/2023]
Abstract
Abnormal basal activity and stress-evoked reactivity of the hypothalamic-pituitary-adrenal (HPA) axis are often seen in depression, implicating HPA axis dysfunction as a potentially causative or exacerbating factor. Chronic stress is also a factor in depression, but it is not known what may underlie the shift from adaptive to maladaptive HPA activity over the course of chronic stress. Interleukin 6 (IL-6), a stress-inducible cytokine that signals through gp130 and IL-6Rα receptors to activate the JAK/STAT3 signaling cascade, is elevated in some subtypes of depression, and may have a modulatory effect on HPA activation, raising the possibility that IL-6 contributes to depression through effects on the HPA axis. In this study, we examined the effects of three different stress modalities, acute footshock, chronic intermittent cold (CIC) stress and chronic unpredictable stress (CUS) on IL-6 signaling in the hypothalamus. We also investigated whether IL-6 modulates the HPA response to chronic stress, by blocking IL-6 signaling in the brain during CIC stress using either a neutralizing antibody or an inhibitor of STAT3 phosphorylation. We show that IL-6 and STAT3 in the hypothalamus are activated in response to footshock and CUS. We also found that basal IL-6 signaling through the JAK/STAT3 pathway is required for the sustained CORT response to chronic, but not acute, cold stress and therefore is a potential determinant of plasticity in the HPA axis specifically during chronic stress exposure.
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Affiliation(s)
| | | | - David A Morilak
- Corresponding author: D. A. Morilak, Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229 Ph.: 210-567-4174, Fax: 210-567-4300,
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Abstract
PURPOSE OF REVIEW Asthma is often associated with different comorbidities, mainly gastro-oesophageal reflux disease and allergic rhinitis, but also obesity, depression, diabetes mellitus and cardiovascular disease, which may affect its clinical intensity and severity. The prevalence of these comorbidities varies tremendously between studies. Nevertheless, it imposes a significant reflection on the need to explore the phenomenon in depth. RECENT FINDINGS Both clinical and basic studies have established that inflammation plays a vital role in the initiation and progression of several comorbidities. However, the role of systemic inflammation in asthma is still unclear. Understanding mechanism(s) that link(s) asthma and its comorbid diseases is essential to design an effective therapeutic approach. SUMMARY In the future, researchers must identify the weight of any comorbidity in patients with asthma, find the true mechanism(s) that link(s) it to asthma and act on these mechanisms that probably create a vicious circle. Conversely, we do not think it reasonable that the generalization of treatment with a holistic approach might affect the link(s) between asthma and its comorbidities.
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O'Donovan A, Rush G, Hoatam G, Hughes BM, McCrohan A, Kelleher C, O'Farrelly C, Malone KM. Suicidal ideation is associated with elevated inflammation in patients with major depressive disorder. Depress Anxiety 2013; 30:307-14. [PMID: 23504697 DOI: 10.1002/da.22087] [Citation(s) in RCA: 154] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 02/04/2013] [Accepted: 02/08/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Patients with major depressive disorder (MDD) who attempt or complete suicide have elevated inflammation compared to nonsuicidal patients with MDD. However, greater severity of depression and the medical lethality of suicide attempts could account for such elevated inflammation in suicide attempters and suicide completers. METHODS To clarify, we measured inflammatory markers in patients with MDD with and without high levels of suicidal ideation and in nondepressed controls (N = 124). Levels of suicidal ideation, depression severity, and recent suicide attempts were assessed by structured clinical interviews. A composite score including the inflammatory markers tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and C-reactive protein (CRP) was used as an inflammatory index. Analysis of covariance models were used to assess group differences with adjustments for age and gender. RESULTS Patients with MDD and high suicidal ideation had significantly higher inflammatory index scores than both controls, F(1,53) = 18.08, partial η(2) = .25, P < .001, and patients with MDD and lower suicidal ideation F(1,44) = 7.59, partial η(2) = .15, P = .009. In contrast, patients with lower suicidal ideation were not significantly different from controls on the inflammatory index, F(1,63) = .52, partial η(2) = .01, P = .47. Follow-up analyses indicated that differences between patients with MDD and high versus lower suicidal ideation were independent of depression severity and recent suicide attempts. CONCLUSIONS Suicidal ideation may be uniquely associated with inflammation in depressed patients.
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Affiliation(s)
- Aoife O'Donovan
- School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
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Gouin JP, Glaser R, Malarkey WB, Beversdorf D, Kiecolt-Glaser JK. Childhood abuse and inflammatory responses to daily stressors. Ann Behav Med 2013; 44:287-92. [PMID: 22714139 DOI: 10.1007/s12160-012-9386-1] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
Abstract
BACKGROUND Childhood abuse leads to greater morbidity and mortality in adulthood. Dysregulated physiological stress responses may underlie the greater health risk among abused individuals. PURPOSE This study evaluated the impact of childhood abuse on inflammatory responses to naturalistically occurring daily stressors. METHODS In this cross-sectional study of 130 older adults, recent daily stressors and childhood abuse history were evaluated using the Daily Inventory of Stressful Events and the Childhood Trauma Questionnaire. Blood samples provided data on circulating interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP). RESULTS Childhood abuse history moderated IL-6 levels but not TNF-α and CRP responses to daily stressors. Individuals with a childhood abuse history who experienced multiple stressors in the past 24 h had IL-6 levels 2.35 times greater than those of participants who reported multiple daily stressors but no early abuse history. CONCLUSION Childhood abuse substantially enhances IL-6 responses to daily stressors in adulthood.
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Alciati A, Gesuele F, Casazza G, Foschi D. The relationship between childhood parental loss and metabolic syndrome in obese subjects. Stress Health 2013; 29:5-13. [PMID: 22190357 DOI: 10.1002/smi.1435] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2011] [Revised: 08/11/2011] [Accepted: 10/26/2011] [Indexed: 11/07/2022]
Abstract
The increasing global trend of obesity is a fundamental contributor to the growing prevalence of metabolic syndrome, a cluster of medical abnormalities including impaired glucose and lipid metabolism, obesity and hypertension. Results from animal and human investigations have shown that early life stress can result in weight gain and metabolic changes. Our aim is to investigate whether a particular type of an early adverse event, i.e. parental loss during childhood, is associated with the development of metabolic syndrome in severely obese subjects. One hundred thirty-five consecutive obese patients who were seeking bariatric surgery were assessed for metabolic syndrome according to the Adult Treatment Panel (ATP) III criteria. Information regarding the experience of parental separation or bereavement before the age of 17 was collected with the use of a semi-structured interview. In our population, 31.1% of the subjects met the criteria for metabolic syndrome. No significant differences in demographic factors, health habits or psychiatric diagnosis were found between patients with and without coexisting metabolic syndrome. After adjusting for age and gender, multivariate logistic regression analysis revealed that both childhood loss of a parent and a body mass index (BMI) value greater than 50 were significant predictors of metabolic syndrome. This study provides preliminary evidence linking childhood parental loss to risk factors for the development of metabolic syndrome.
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Affiliation(s)
- Alessandra Alciati
- Department of Psychiatry, Luigi Sacco University Hospital, Milan, Italy.
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Bardelli C, Amoruso A, Manzetti E, Fresu LG, Valsesia R, Zeppegno P, Brunelleschi S. Recurrent major depressive disorder: Imbalance of neurokinin (NK)-1 and NK-2 receptor expression in monocytes. Pharmacol Res 2013; 68:24-30. [DOI: 10.1016/j.phrs.2012.10.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Revised: 10/31/2012] [Accepted: 10/31/2012] [Indexed: 11/28/2022]
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Fagundes CP, Glaser R, Kiecolt-Glaser JK. Stressful early life experiences and immune dysregulation across the lifespan. Brain Behav Immun 2013; 27:8-12. [PMID: 22771426 PMCID: PMC3518756 DOI: 10.1016/j.bbi.2012.06.014] [Citation(s) in RCA: 272] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 06/21/2012] [Accepted: 06/26/2012] [Indexed: 10/28/2022] Open
Abstract
There is considerable evidence that stressful early life events influence a variety of physical health problems later in life. Childhood adversity has been linked to elevated rates of morbidity and mortality from a number of chronic diseases. Immune dysregulation may be one potential pathway that explains this link. In this mini-review, we summarize human studies demonstrating that severe early life stressors have lasting immune consequences. We propose a model outlining potential biobehavioral pathways that explain how early life stressors leave people vulnerable to these maladaptive outcomes. Finally, we suggest ideas for future work to test different aspects of this model.
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Affiliation(s)
- Christopher P. Fagundes
- The Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Comprehensive Cancer Center
| | - Ronald Glaser
- The Institute for Behavioral Medicine Research and Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University College of Medicine, Comprehensive Cancer Center
| | - Janice K. Kiecolt-Glaser
- The Institute for Behavioral Medicine Research, Comprehensive Cancer Center, and Department of Psychiatry, The Ohio State University College of Medicine
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Koudouovoh-Tripp P, Sperner-Unterweger B. Influence of mental stress on platelet bioactivity. World J Psychiatry 2012; 2:134-47. [PMID: 24175179 PMCID: PMC3782187 DOI: 10.5498/wjp.v2.i6.134] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Revised: 10/10/2012] [Accepted: 10/23/2012] [Indexed: 02/05/2023] Open
Abstract
It is well established that various mental stress conditions contribute, or at least influence, underlying pathophysiological mechanisms in somatic, as well as in psychiatric disorders; blood platelets are supposed to represent a possible link in this respect. The anculeated platelets are the smallest corpuscular elements circulating in the human blood. They display different serotonergic markers which seem to reflect the central nervous serotonin metabolism. They are known as main effectors in haematological processes but recent research highlights their role in the innate and adaptive immune system. Platelets are containing a multitude of pro-inflammatory and immune-modulatory bioactive compounds in their granules and are expressing immune-competent surface markers. Research gives hint that platelets activation and reactivity is increased by mental stress. This leads to enhanced cross talk with the immune system via paracrine secretion, receptor interaction and formation of platelet leucocyte-aggregates. Recently it has been demonstrated that the immune system can have a remarkable impact in the development of psychiatric disorders. Therefore platelets represent an interesting research area in psychiatry and their role as a possible biomarker has been investigated. We review the influence of mental stress on what is termed platelet bioactivity in this article, which subsumes the mainly immune-modulatory activity of platelets in healthy volunteers, elderly persons with chronic care-giving strain, patients with cardiovascular diseases who are prone to psychosocial stress, as well as in patients with posttraumatic stress disorder. Research data suggest that stress enhances platelet activity, reactivity and immune-modulatory capacities.
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Affiliation(s)
- Pia Koudouovoh-Tripp
- Pia Koudouovoh-Tripp, Clinic for Biological Psychiatry, Department of Psychiatry and Psychotherapy, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
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