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Margolis AE, Dranovsky A, Pagliaccio D, Azad G, Rauh V, Herbstman J. Annual Research Review: Exposure to environmental chemicals and psychosocial stress and the development of children's learning difficulties. J Child Psychol Psychiatry 2025; 66:547-568. [PMID: 40103271 PMCID: PMC11920607 DOI: 10.1111/jcpp.14137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/12/2025] [Indexed: 03/20/2025]
Abstract
Although awareness of the role of environmental exposures in children's cognitive development is increasing, learning difficulties have not yet been a major focus of environmental health science. Learning difficulties disproportionately affect children living in economic disadvantage, yielding an 'achievement gap.' Studies examining the neurobiology of reading and math have mostly included economically advantaged youth, leaving a great deal unknown about the neural underpinnings of reading and math difficulties in youth living in disadvantaged contexts. Critically, due to environmental injustice, these youth are disproportionately exposed to environmental neurotoxicants. Herein, we review literature supporting a theoretical framework of environmentally associated phenotypes of learning difficulties. We propose that prenatal exposure to neurotoxicants and early-life exposure to psychosocial stressors increases risk for learning difficulties via effects on neural circuits that support cognitive processes which, in addition to literacy and numeracy, are integral to acquiring and performing academic skills. We describe models in which (1) prenatal exposure to air pollution has a main effect on learning via brain structure and function or associated domain-general cognitive processes and (2) a joint 'two-hit' pathway in which prenatal air pollution exposure followed by early life stress-when combined and sequential-increases risk for learning difficulties also via effects on brain structure, function, and/or associated cognitive processes. We review a select literature documenting effects of exposure to pollutants and early life stress on relevant neural circuits and associated cognitive processes in animal models and parallel findings in human epidemiologic studies. We advocate for team science in which researchers, practitioners, and policymakers collaborate to increase health literacy about environmentally associated phenotypes of learning difficulties and support the development of precision-oriented instructional and environmental intervention methods for youth living in economic disadvantage.
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Affiliation(s)
- Amy E Margolis
- Department of Psychiatry and Behavioral Health, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
- Child Mind Institute, New York, NY, USA
| | - Alex Dranovsky
- Division of Systems Neuroscience, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - David Pagliaccio
- Division of Systems Neuroscience, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Gazi Azad
- Heilbrunn Department of Population and Family Health, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Virginia Rauh
- Heilbrunn Department of Population and Family Health, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Julie Herbstman
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
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2
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Duncan AF. Interventions for Executive Function in High-Risk Infants and Toddlers. Clin Perinatol 2023; 50:103-119. [PMID: 36868701 DOI: 10.1016/j.clp.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023]
Abstract
This review summarizes the current state of evidence regarding interventions for executive function in high-risk infants and toddlers. Currently, there is a paucity of data in this area, with the interventions that have been studied highly variable in their content, dosage, target, and results. Self-regulation is the executive function construct targeted the most, with mixed results. The few studies that report later child outcomes in prekindergarten/school-aged children are encouraging, overall indicating improved cognition and behavior in the children of parents who received a parenting style intervention.
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Affiliation(s)
- Andrea F Duncan
- Division of Neonatology, Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, 2nd Floor Main, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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3
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Demaili A, Portugalov A, Dudai M, Maroun M, Akirav I, Braun K, Bock J. Epigenetic (re)programming of gene expression changes of CB1R and FAAH in the medial prefrontal cortex in response to early life and adolescence stress exposure. Front Cell Neurosci 2023; 17:1129946. [PMID: 36909279 PMCID: PMC9992175 DOI: 10.3389/fncel.2023.1129946] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 02/07/2023] [Indexed: 02/24/2023] Open
Abstract
Environmental factors, including stress, that are experienced during early life (ELS) or adolescence are potential risk factors for the development of behavioral and mental disorders later in life. The endocannabinoid system plays a major role in the regulation of stress responses and emotional behavior, thereby acting as a mediator of stress vulnerability and resilience. Among the critical factors, which determine the magnitude and direction of long-term consequences of stress exposure is age, i.e., the maturity of brain circuits during stress exposure. Thus, the present study addressed the hypotheses that ELS and adolescent stress differentially affect the expression of regulatory elements of the endocannabinoid system, cannabinoid receptor 1 (CB1R) and fatty acid amide hydrolase (FAAH) in the medial prefrontal cortex (mPFC) of adult female rats. We also tested the hypothesis that the proposed gene expression changes are epigenetically modulated via altered DNA-methylation. The specific aims were to investigate if (i) ELS and adolescent stress as single stressors induce changes in CB1R and FAAH expression (ii) ELS exposure influences the effect of adolescent stress on CB1R and FAAH expression, and (iii) if the proposed gene expression changes are paralleled by changes of DNA methylation. The following experimental groups were investigated: (1) non-stressed controls (CON), (2) ELS exposure (ELS), (3) adolescent stress exposure (forced swimming; FS), (4) ELS + FS exposure. We found an up-regulation of CB1R expression in both single-stressor groups and a reduction back to control levels in the ELS + FS group. An up-regulation of FAAH expression was found only in the FS group. The data indicate that ELS, i.e., stress during a very immature stage of brain development, exerts a buffering programming effect on gene expression changes induced by adolescent stress. The detected gene expression changes were accompanied by altered DNA methylation patterns in the promoter region of these genes, specifically, a negative correlation of mean CB1R DNA methylation with gene expression was found. Our results also indicate that ELS induces a long-term "(re)programming" effect, characterized by CpG-site specific changes within the promoter regions of the two genes that influence gene expression changes in response to FS at adolescence.
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Affiliation(s)
- Arijana Demaili
- Department of Zoology and Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Anna Portugalov
- Department of Psychology, School of Psychological Sciences, University of Haifa, Haifa, Israel.,The Integrated Brain and Behavior Research Center, University of Haifa, Haifa, Israel
| | - Michal Dudai
- Department of Psychology, School of Psychological Sciences, University of Haifa, Haifa, Israel.,The Integrated Brain and Behavior Research Center, University of Haifa, Haifa, Israel
| | - Mouna Maroun
- The Integrated Brain and Behavior Research Center, University of Haifa, Haifa, Israel.,Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
| | - Irit Akirav
- Department of Psychology, School of Psychological Sciences, University of Haifa, Haifa, Israel.,The Integrated Brain and Behavior Research Center, University of Haifa, Haifa, Israel
| | - Katharina Braun
- Department of Zoology and Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg, Magdeburg, Germany.,Center for Brain and Behavioral Science, Magdeburg, Germany
| | - Jörg Bock
- Department of Zoology and Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg, Magdeburg, Germany.,Center for Brain and Behavioral Science, Magdeburg, Germany.,Project Group (PG) Epigenetics and Structural Plasticity, Institute of Biology, Otto von Guericke University Magdeburg, Magdeburg, Germany
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Sleep, cognition and executive functioning in young children with cerebral palsy. ADVANCES IN CHILD DEVELOPMENT AND BEHAVIOR 2021; 60:285-314. [PMID: 33641797 DOI: 10.1016/bs.acdb.2020.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Children with cerebral palsy (CP) are at higher risk for sleep disturbances than their typically developing peers. In typically developing young children, lack of sufficient sleep results in deficits in cognition, behavior and executive functioning. Unfortunately, research on sleep in infancy rarely focuses on children with neurodevelopmental disabilities. Studies of older children with CP demonstrate that roughly half of children with CP have a sleep disorder, though screening for sleep disorders in children with CP is not routinely performed. Given the high prevalence of sleep abnormalities in older children with CP and the resulting adverse effects on functioning, understanding sleep derangements and how they affect cognition and executive functioning in these children at earlier ages is critical. In this chapter, we present the state of the evidence for sleep characteristics, cognition and executive functions for infants and toddlers 0-3years old with CP.
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Pagliaccio D, Herbstman JB, Perera F, Tang D, Goldsmith J, Peterson BS, Rauh V, Margolis AE. Prenatal exposure to polycyclic aromatic hydrocarbons modifies the effects of early life stress on attention and Thought Problems in late childhood. J Child Psychol Psychiatry 2020; 61:1253-1265. [PMID: 31907931 PMCID: PMC7338249 DOI: 10.1111/jcpp.13189] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/15/2019] [Accepted: 12/04/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Risk for childhood psychopathology is complex and multifactorial, implicating direct and interacting effects of familial and environmental factors. The role of environmental neurotoxicants in psychiatric risk is of growing concern, including polycyclic aromatic hydrocarbons (PAH), common in air pollution. Prenatal PAH exposure is linked to adverse physical, behavioral, and cognitive outcomes as well as increasing psychiatric risk. It is unclear whether environmental exposures, like PAH, magnify the effects of exposure to early life stress (ELS), a critical risk factor for psychopathology. The current work aimed to test potential interactions between prenatal PAH exposure and psychosocial/socioeconomic stress on psychiatric symptoms in school-age children. METHODS Data were from the Columbia Center for Children's Environmental Health Mothers and Newborns longitudinal birth cohort study. Prenatal PAH exposure was ascertained though air monitoring during pregnancy and maternal PAH-DNA adducts at delivery. Mothers reported on ELS (child age 5) and on child psychiatric symptoms across childhood (child age 5, 7, 9, and 11) using the Child Behavior Checklist (CBCL). RESULTS Significant prenatal airborne PAH × ELS interactions (FDR-corrected) predicted CBCL Attention (β = 0.22, t(307) = 3.47, p < .001, pfdr = .003) and Thought Problems T-scores (β = 0.21, t(307) = 3.29, p = .001, pfdr = .004) at age 11 (n = 319). Relative to those with lower exposure, children with higher prenatal PAH exposure exhibited stronger positive associations between ELS and CBCL Attention and Thought Problem T-scores. This interaction was also significant examining convergent ADHD measures (Conners, DuPaul) and examining maternal PAH-DNA adducts (β = 0.29, t(261) = 2.48, p = .01; n = 273). A three-way interaction with assessment wave indicated that the PAH × ELS interaction on Attention Problems was stronger later in development (β = 0.03, t(1,601) = 2.19, p = .03; n = 477). CONCLUSIONS Prenatal exposure to PAH, a common neurotoxicant in air pollution, may magnify or sustain the effects of early life psychosocial/socioeconomic stress on psychiatric outcomes later in child development. This work highlights the critical role of air pollution exposure on child mental health.
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Affiliation(s)
- David Pagliaccio
- Division of Child and Adolescent Psychiatry, New York State Psychiatric Institute, New York, NY, USA;,Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Julie B. Herbstman
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA;,Columbia Center for Children’s Environmental Health, Department of Environmental Health Sciences, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Frederica Perera
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA;,Columbia Center for Children’s Environmental Health, Department of Environmental Health Sciences, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Deliang Tang
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA;,Columbia Center for Children’s Environmental Health, Department of Environmental Health Sciences, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Jeff Goldsmith
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Bradley S. Peterson
- Department of Psychiatry, Keck School of Medicine University of Southern California, Los Angeles, CA, USA
| | - Virginia Rauh
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA;,Columbia Center for Children’s Environmental Health, Department of Environmental Health Sciences, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Amy E. Margolis
- Division of Child and Adolescent Psychiatry, New York State Psychiatric Institute, New York, NY, USA;,Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
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Martynyuk AE, Ju LS, Morey TE, Zhang JQ. Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics. World J Psychiatry 2020; 10:81-94. [PMID: 32477904 PMCID: PMC7243620 DOI: 10.5498/wjp.v10.i5.81] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/18/2020] [Accepted: 03/26/2020] [Indexed: 02/05/2023] Open
Abstract
The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jia-Qiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
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7
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Tian L, You HZ, Wu H, Wei Y, Zheng M, He L, Liu JY, Guo SZ, Zhao Y, Zhou RL, Hu X. iTRAQ-based quantitative proteomic analysis provides insight for molecular mechanism of neuroticism. Clin Proteomics 2019; 16:38. [PMID: 31719821 PMCID: PMC6839193 DOI: 10.1186/s12014-019-9259-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 10/28/2019] [Indexed: 12/21/2022] Open
Abstract
Background Neuroticism is a core personality trait and a major risk factor for several mental and physical diseases, particularly in females, who score higher on neuroticism than men, on average. However, a better understanding of the expression profiles of proteins in the circulating blood of different neurotic female populations may help elucidate the intrinsic mechanism of neurotic personality and aid prevention strategies on mental and physical diseases associated with neuroticism. Methods In our study, female subjects were screened for inclusion by the Eysenck Personality Questionnaire (EPQ), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) scales and routine physical examination. Subjects who passed the examination and volunteered to participate were grouped by neuroticism using EPQ scores (0 and 1 = low neuroticism group; > 5 = high neuroticism group). Proteins in serum samples of the two neuroticism groups were identified using isobaric tags for relative and absolute quantification (iTRAQ) technology. Results A total of 410 proteins exhibited significant differences between high and low neuroticism, 236 proteins were significantly upregulated and 174 proteins were significantly downregulated. Combine the results of GO and KEGG enrichment analysis of differences proteins between high and low neuroticism with the PPI network, it could be observed that the Alpha-synuclein (SNCA), ATP7A protein (ATP7A), Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2), cyclin-dependent kinase 6 (CDK6), myeloperoxidase (MPO), azurocidin (AZU1), Histone H2B type 1-H (HIST1H2BH), Integrin alpha-M (ITGAM) and Matrix metalloproteinase-9 (MMP9) might participate in the intrinsic mechanism of neuroticism by regulating response to catecholamine stimulus, catecholamine metabolic process, limbic system development and transcriptional misregulation in cancer pathway. Conclusions Our study revealed the characteristics of the neurotic personality proteome, which might be intrinsic mechanism of the neurotic population.
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Affiliation(s)
- Lei Tian
- 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Hong-Zhao You
- 2Department of Endocrinology, Fuwai Hospital and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100037 China
| | - Hao Wu
- 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Yu Wei
- 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Min Zheng
- 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Lei He
- 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Jin-Ying Liu
- 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Shu-Zhen Guo
- 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Yan Zhao
- 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Ren-Lai Zhou
- 3School of Psychology, Beijing Normal University, Beijing, 100875 China
| | - Xingang Hu
- 4Beijing University of Chinese Medicine Third Hospital, Beijing, 100029 China
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8
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Nurturing the preterm infant brain: leveraging neuroplasticity to improve neurobehavioral outcomes. Pediatr Res 2019; 85:166-175. [PMID: 30531968 DOI: 10.1038/s41390-018-0203-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 10/01/2018] [Accepted: 10/04/2018] [Indexed: 12/19/2022]
Abstract
An intrinsic feature of the developing brain is high susceptibility to environmental influence-known as plasticity. Research indicates cascading disruption to neurological development following preterm (PT) birth; yet, the interactive effects of PT birth and plasticity remain unclear. It is possible that, with regard to neuropsychological outcomes in the PT population, plasticity is a double-edged sword. On one side, high plasticity of rapidly developing neural tissue makes the PT brain more vulnerable to injury resulting from events, including inflammation, hypoxia, and ischemia. On the other side, plasticity may be a mechanism through which positive experience can normalize neurological development for PT children. Much of the available literature on PT neurological development is clinically weighted and focused on diagnostic utility for predicting long-term outcomes. Although diagnostic utility is valuable, research establishing neuroprotective factors is equally beneficial. This review will: (1) detail specific mechanisms through which plasticity is adaptive or maladaptive depending on the experience; (2) integrate research from neuroimaging, intervention, and clinical science fields in a summary of findings suggesting inherent plasticity of the PT brain as a mechanism to improve child outcomes; and (3) summarize how responsive caregiving experiences situate parents as agents of change in normalizing PT infant brain development.
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Marwarha G, Claycombe-Larson K, Schommer J, Ghribi O. Maternal low-protein diet decreases brain-derived neurotrophic factor expression in the brains of the neonatal rat offspring. J Nutr Biochem 2017; 45:54-66. [PMID: 28432877 PMCID: PMC5466833 DOI: 10.1016/j.jnutbio.2017.03.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 02/08/2017] [Accepted: 03/16/2017] [Indexed: 01/15/2023]
Abstract
Prenatal exposure to a maternal low-protein (LP) diet has been known to cause cognitive impairment, learning and memory deficits. However, the underlying mechanisms have not been identified. Herein, we demonstrate that a maternal LP diet causes, in the brains of the neonatal rat offspring, an attenuation in the basal expression of the brain-derived neurotrophic factor (BDNF), a neurotrophin indispensable for learning and memory. Female rats were fed either a 20% normal protein (NP) diet or an 8% LP 3 weeks before breeding and during the gestation period. Maternal LP diet caused a significant reduction in the Bdnf expression in the brains of the neonatal rats. We further found that the maternal LP diet reduced the activation of the cAMP/protein kinase A/cAMP response element binding protein (CREB) signaling pathway. This reduction was associated with a significant decrease in CREB binding to the Bdnf promoters. We also show that prenatal exposure to the maternal LP diet results in an inactive or repressed exon I and exon IV promoter of the Bdnf gene in the brain, as evidenced by fluxes in signatory hallmarks in the enrichment of acetylated and trimethylated histones in the nucleosomes that envelop the exon I and exon IV promoters, causing the Bdnf gene to be refractory to transactivation. Our study is the first to determine the impact of a maternal LP diet on the basal expression of BDNF in the brains of the neonatal rats exposed prenatally to an LP diet.
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Affiliation(s)
- Gurdeep Marwarha
- Department of Biomedical Sciences, School of Medicine & Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA
| | - Kate Claycombe-Larson
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58203, USA
| | - Jared Schommer
- Department of Biomedical Sciences, School of Medicine & Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA
| | - Othman Ghribi
- Department of Biomedical Sciences, School of Medicine & Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA.
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van Bodegom M, Homberg JR, Henckens MJAG. Modulation of the Hypothalamic-Pituitary-Adrenal Axis by Early Life Stress Exposure. Front Cell Neurosci 2017; 11:87. [PMID: 28469557 PMCID: PMC5395581 DOI: 10.3389/fncel.2017.00087] [Citation(s) in RCA: 341] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 03/13/2017] [Indexed: 12/20/2022] Open
Abstract
Exposure to stress during critical periods in development can have severe long-term consequences, increasing overall risk on psychopathology. One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis; a cascade of central and peripheral events resulting in the release of corticosteroids from the adrenal glands. Activation of the HPA-axis affects brain functioning to ensure a proper behavioral response to the stressor, but stress-induced (mal)adaptation of the HPA-axis' functional maturation may provide a mechanistic basis for the altered stress susceptibility later in life. Development of the HPA-axis and the brain regions involved in its regulation starts prenatally and continues after birth, and is protected by several mechanisms preventing corticosteroid over-exposure to the maturing brain. Nevertheless, early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood, affecting both its basal and stress-induced activity. According to the match/mismatch theory, encountering ELS prepares an organism for similar ("matching") adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context. Here, we review studies investigating the mechanistic underpinnings of the ELS-induced alterations in the structural and functional development of the HPA-axis and its key external regulators (amygdala, hippocampus, and prefrontal cortex). The effects of ELS appear highly dependent on the developmental time window affected, the sex of the offspring, and the developmental stage at which effects are assessed. Albeit by distinct mechanisms, ELS induced by prenatal stressors, maternal separation, or the limited nesting model inducing fragmented maternal care, typically results in HPA-axis hyper-reactivity in adulthood, as also found in major depression. This hyper-activity is related to increased corticotrophin-releasing hormone signaling and impaired glucocorticoid receptor-mediated negative feedback. In contrast, initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder, and future studies should investigate its neural/neuroendocrine foundation in further detail. Interestingly, experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match/mismatch theory.
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Affiliation(s)
| | | | - Marloes J. A. G. Henckens
- Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition and BehaviourRadboudumc, Nijmegen, Netherlands
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11
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Thorsell A, Nätt D. Maternal stress and diet may influence affective behavior and stress-response in offspring via epigenetic regulation of central peptidergic function. ENVIRONMENTAL EPIGENETICS 2016; 2:dvw012. [PMID: 29492293 PMCID: PMC5804527 DOI: 10.1093/eep/dvw012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 06/15/2016] [Accepted: 06/26/2016] [Indexed: 06/08/2023]
Abstract
It has been shown that maternal stress and malnutrition, or experience of other adverse events, during the perinatal period may alter susceptibility in the adult offspring in a time-of-exposure dependent manner. The mechanism underlying this may be epigenetic in nature. Here, we summarize some recent findings on the effects on gene-regulation following maternal malnutrition, focusing on epigenetic regulation of peptidergic activity. Numerous neuropeptides within the central nervous system are crucial components in regulation of homeostatic energy-balance, as well as affective health (i.e. health events related to affective disorders, psychiatric disorders also referred to as mood disorders). It is becoming evident that expression, and function, of these neuropeptides can be regulated via epigenetic mechanisms during fetal development, thereby contributing to the development of the adult phenotype and, possibly, modulating disease susceptibility. Here, we focus on two such neuropeptides, neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH), both involved in regulation of endocrine function, energy homeostasis, as well as affective health. While a number of published studies indicate the involvement of epigenetic mechanisms in CRH-dependent regulation of the offspring adult phenotype, NPY has been much less studied in this context and needs further work.
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Affiliation(s)
- Annika Thorsell
- Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience, Linköping University, SE 581 83, Linköping, Sweden
| | - Daniel Nätt
- Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience, Linköping University, SE 581 83, Linköping, Sweden
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12
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Maccari S, Polese D, Reynaert ML, Amici T, Morley-Fletcher S, Fagioli F. Early-life experiences and the development of adult diseases with a focus on mental illness: The Human Birth Theory. Neuroscience 2016; 342:232-251. [PMID: 27235745 DOI: 10.1016/j.neuroscience.2016.05.042] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 05/13/2016] [Accepted: 05/17/2016] [Indexed: 12/18/2022]
Abstract
In mammals, early adverse experiences, including mother-pup interactions, shape the response of an individual to chronic stress or to stress-related diseases during adult life. This has led to the elaboration of the theory of the developmental origins of health and disease, in particular adult diseases such as cardiovascular and metabolic disorders. In addition, in humans, as stated by Massimo Fagioli's Human Birth Theory, birth is healthy and equal for all individuals, so that mental illness develop exclusively in the postnatal period because of the quality of the relationship in the first year of life. Thus, this review focuses on the importance of programming during the early developmental period on the manifestation of adult diseases in both animal models and humans. Considering the obvious differences between animals and humans we cannot systematically move from animal models to humans. Consequently, in the first part of this review, we will discuss how animal models can be used to dissect the influence of adverse events occurring during the prenatal and postnatal periods on the developmental trajectories of the offspring, and in the second part, we will discuss the role of postnatal critical periods on the development of mental diseases in humans. Epigenetic mechanisms that cause reversible modifications in gene expression, driving the development of a pathological phenotype in response to a negative early postnatal environment, may lie at the core of this programming, thereby providing potential new therapeutic targets. The concept of the Human Birth Theory leads to a comprehension of the mental illness as a pathology of the human relationship immediately after birth and during the first year of life.
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Affiliation(s)
- Stefania Maccari
- Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France; IRCCS Neuromed, 86077, Italy; Sapienza University of Rome, 00185 Rome, Italy.
| | - Daniela Polese
- NESMOS Department, Sant'Andrea Hospital, Sapienza University of Rome, Italy; Unit of Psychiatry, Federico II University of Naples, Italy
| | - Marie-Line Reynaert
- Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France
| | | | - Sara Morley-Fletcher
- Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France
| | - Francesca Fagioli
- Prevention and early Intervention Mental Health (PIPSM) ASL Rome 1, Italy
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Gröger N, Matas E, Gos T, Lesse A, Poeggel G, Braun K, Bock J. The transgenerational transmission of childhood adversity: behavioral, cellular, and epigenetic correlates. J Neural Transm (Vienna) 2016; 123:1037-52. [DOI: 10.1007/s00702-016-1570-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 05/02/2016] [Indexed: 12/21/2022]
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Kasparek T, Theiner P, Filova A. Neurobiology of ADHD From Childhood to Adulthood: Findings of Imaging Methods. J Atten Disord 2015; 19:931-43. [PMID: 24097847 DOI: 10.1177/1087054713505322] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To review the pattern of morphological and functional brain changes in both children and adults with ADHD that emerges from the recent literature. In addition, the task of the present review is to explore how to understand the nature of the brain changes. METHODS Literature review. RESULTS Neuroimaging studies provide a multitude of information that currently allows us to expand the notions of ADHD neurobiology beyond its traditional understanding as a manifestation of frontostriatal dysfunction. They point to disorders of several other areas of the brain, particularly the anterior cingulum, the dorsolateral as well as ventrolateral prefrontal cortex, the orbitofrontal cortex, the superior parietal regions, the caudate nucleus, the thalamus, the amygdala and the cerebellum. Imaging studies point to the persistence of changes in both brain structure and function into adulthood, although there might be a tendency for improvement of caudate nucleus pathology. Changes in neuronal (dendritic) plasticity, which are under the modulatory influence of the dopaminergic system, may be in the background of disorders of brain morphology and anatomical connectivity with subsequent brain dysfunction. Growing evidence suggest that methylphenidate treatment can lead to improvement of brain changes seen in neuroimaging by its positive effect on neuroplasticity. CONCLUSION Changes in neuronal plasticity may be behind persisting brain changes in ADHD. Current treatment approaches seem to improve these neuroplastic processes, and, therefore, may have a positive effect on the neuropathology of ADHD.
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Affiliation(s)
- Tomas Kasparek
- Masaryk University, Brno, Czech Republic University Hospital Brno, Czech Republic
| | - Pavel Theiner
- Masaryk University, Brno, Czech Republic University Hospital Brno, Czech Republic
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15
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Bock J, Wainstock T, Braun K, Segal M. Stress In Utero: Prenatal Programming of Brain Plasticity and Cognition. Biol Psychiatry 2015; 78:315-26. [PMID: 25863359 DOI: 10.1016/j.biopsych.2015.02.036] [Citation(s) in RCA: 155] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 02/10/2015] [Accepted: 02/25/2015] [Indexed: 12/17/2022]
Abstract
Animal studies confirm earlier anecdotal observations in humans to indicate that early life experience has a profound impact on adult behavior, years after the original experience has vanished. These studies also highlight the role of early life adversaries in the shaping of a disordered brain. Evidence is accumulating to indicate that the epigenome, through which the environment regulates gene expression, is responsible for long-lasting effects of stress during pregnancy on brain and behavior. A possible differential effect of the environment on the epigenome may underlie the observation that only a small fraction of a population with similar genetic background deteriorates into mental disorders. Considerable progress has been made in the untangling of the epigenetic mechanisms that regulate emotional brain development. The present review focuses on the lasting effects of prenatal stress on brain plasticity and cognitive functions in human and rodent models. Although human studies stress the significance of early life experience in functional maturation, they lack the rigor inherent in controlled animal experiments. Furthermore, the analysis of molecular and cellular mechanisms affected by prenatal stress is possible only in experimental animals. The present review attempts to link human and animal studies while proposing molecular mechanisms that interfere with functional brain development.
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Affiliation(s)
- Joerg Bock
- Otto von Guericke University Magdeburg (JB, KB), Magdeburg, Germany
| | - Tamar Wainstock
- Rollins School of Public Health (TW), Emory University, Atlanta, Georgia
| | - Katharina Braun
- Otto von Guericke University Magdeburg (JB, KB), Magdeburg, Germany
| | - Menahem Segal
- Department of Neurobiology (MS) Weizmann Institute, Rehovot, Israel.
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Womersley JS, Dimatelis JJ, Russell VA. Proteomic analysis of maternal separation-induced striatal changes in a rat model of ADHD: The spontaneously hypertensive rat. J Neurosci Methods 2015; 252:64-74. [DOI: 10.1016/j.jneumeth.2015.01.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Revised: 01/25/2015] [Accepted: 01/28/2015] [Indexed: 12/15/2022]
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Archer T, Kostrzewa RM. Physical Exercise Alleviates Health Defects, Symptoms, and Biomarkers in Schizophrenia Spectrum Disorder. Neurotox Res 2015; 28:268-80. [PMID: 26174041 DOI: 10.1007/s12640-015-9543-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 06/08/2015] [Accepted: 07/06/2015] [Indexed: 02/07/2023]
Abstract
Schizophrenia spectrum disorders are characterized by symptom profiles consisting of positive and negative symptoms, cognitive impairment, and a plethora of genetic, epigenetic, and phenotypic biomarkers. Assorted animal models of these disorders and clinical neurodevelopmental indicators have implicated neurodegeneration as an element in the underlying pathophysiology. Physical exercise or activity regimes--whether aerobic, resistance, or endurance--ameliorate regional brain and functional deficits not only in affected individuals but also in animal models of the disorder. Cognitive deficits, often linked to regional deficits, were alleviated by exercise, as were quality-of-life, independent of disorder staging and risk level. Apoptotic processes intricate to the etiopathogenesis of schizophrenia were likewise attenuated by physical exercise. There is also evidence of manifest benefits endowed by physical exercise in preserving telomere length and integrity. Not least, exercise improves overall health and quality-of-life. The notion of scaffolding as the outcome of physical exercise implies the "buttressing" of regional network circuits, neurocognitive domains, anti-inflammatory defenses, maintenance of telomeric integrity, and neuro-reparative and regenerative processes.
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Affiliation(s)
- Trevor Archer
- Department of Psychology, University of Gothenburg, 405 30, Gothenburg, Sweden,
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18
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Ma CL, Sun X, Luo F, Li BM. Prefrontal cortical α2A-adrenoceptors and a possible primate model of attention deficit and hyperactivity disorder. Neurosci Bull 2015; 31:227-34. [PMID: 25822217 DOI: 10.1007/s12264-014-1514-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 02/11/2015] [Indexed: 10/23/2022] Open
Abstract
Attention deficit and hyperactivity disorder (ADHD), a prevalent syndrome in children worldwide, is characterized by impulsivity, inappropriate inattention, and/or hyperactivity. It seriously afflicts cognitive development in childhood, and may lead to chronic under-achievement, academic failure, problematic peer relationships, and low self-esteem. There are at least three challenges for the treatment of ADHD. First, the neurobiological bases of its symptoms are still not clear. Second, the commonly prescribed medications, most showing short-term therapeutic efficacy but with a high risk of serious side-effects, are mainly based on a dopamine mechanism. Third, more novel and efficient animal models, especially in nonhuman primates, are required to accelerate the development of new medications. In this article, we review research progress in the related fields, focusing on our previous studies showing that blockade of prefrontal cortical α2A-adrenoceptors in monkeys produces almost all the typical behavioral symptoms of ADHD.
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Affiliation(s)
- Chao-Lin Ma
- Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang, 330031, China,
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19
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Chocyk A, Majcher-Maślanka I, Dudys D, Przyborowska A, Wędzony K. Impact of early-life stress on the medial prefrontal cortex functions - a search for the pathomechanisms of anxiety and mood disorders. Pharmacol Rep 2014; 65:1462-70. [PMID: 24552993 DOI: 10.1016/s1734-1140(13)71506-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 10/03/2013] [Indexed: 01/21/2023]
Abstract
Although anxiety and mood disorders (MDs) are the most common mental diseases, the etiologies and mechanisms of these psychopathologies are still a matter of debate. The medial prefrontal cortex (mPFC) is a brain structure that is strongly implicated in the pathophysiology of these disorders. A growing number of epidemiological and clinical studies show that early-life stress (ELS) during the critical period of brain development may increase the risk for anxiety and MDs. Neuroimaging analyses in humans and numerous reports from animal models clearly demonstrate that ELS affects behaviors that are dependent on the mPFC, as well as neuronal activity and synaptic plasticity within the mPFC. The mechanisms engaged in ELS-induced changes in mPFC function involve alterations in the developmental trajectory of the mPFC and may be responsible for the emergence of both early-onset (during childhood and adolescence) and adulthood-onset anxiety and MDs. ELS-evoked changes in mPFC synaptic plasticity may constitute an example of metaplasticity. ELS may program brain functions by affecting glucocorticoid levels. On the molecular level, ELS-induced programming is registered by epigenetic mechanisms, such as changes in DNA methylation pattern, histone acetylation and microRNA expression. Vulnerability and resilience to ELS-related anxiety and MDs depend on the interaction between individual genetic predispositions, early-life experiences and later-life environment. In conclusion, ELS may constitute a significant etiological factor for anxiety and MDs, whereas animal models of ELS are helpful tools for understanding the pathomechanisms of these disorders.
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Affiliation(s)
- Agnieszka Chocyk
- Laboratory of Pharmacology and Brain Biostructure, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
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20
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Bock J, Rether K, Gröger N, Xie L, Braun K. Perinatal programming of emotional brain circuits: an integrative view from systems to molecules. Front Neurosci 2014; 8:11. [PMID: 24550772 PMCID: PMC3913903 DOI: 10.3389/fnins.2014.00011] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 01/17/2014] [Indexed: 02/06/2023] Open
Abstract
Environmental influences such as perinatal stress have been shown to program the developing organism to adapt brain and behavioral functions to cope with daily life challenges. Evidence is now accumulating that the specific and individual effects of early life adversity on the functional development of brain and behavior emerge as a function of the type, intensity, timing and the duration of the adverse environment, and that early life stress (ELS) is a major risk factor for developing behavioral dysfunctions and mental disorders. Results from clinical as well as experimental studies in animal models support the hypothesis that ELS can induce functional “scars” in prefrontal and limbic brain areas, regions that are essential for emotional control, learning and memory functions. On the other hand, the concept of “stress inoculation” is emerging from more recent research, which revealed positive functional adaptations in response to ELS resulting in resilience against stress and other adversities later in life. Moreover, recent studies indicate that early life experiences and the resulting behavioral consequences can be transmitted to the next generation, leading to a transgenerational cycle of adverse or positive adaptations of brain function and behavior. In this review we propose a unifying view of stress vulnerability and resilience by connecting genetic predisposition and programming sensitivity to the context of experience-expectancy and transgenerational epigenetic traits. The adaptive maturation of stress responsive neural and endocrine systems requires environmental challenges to optimize their functions. Repeated environmental challenges can be viewed within the framework of the match/mismatch hypothesis, the outcome, psychopathology or resilience, depends on the respective predisposition and on the context later in life.
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Affiliation(s)
- Jörg Bock
- PG "Epigenetics and Structural Plasticity", Institute of Biology, Otto von Guericke University Magdeburg Magdeburg, Germany ; Center for Behavioral Brain Sciences Magdeburg, Germany
| | - Kathy Rether
- PG "Epigenetics and Structural Plasticity", Institute of Biology, Otto von Guericke University Magdeburg Magdeburg, Germany ; Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg Magdeburg, Germany
| | - Nicole Gröger
- Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg Magdeburg, Germany
| | - Lan Xie
- PG "Epigenetics and Structural Plasticity", Institute of Biology, Otto von Guericke University Magdeburg Magdeburg, Germany ; Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg Magdeburg, Germany
| | - Katharina Braun
- Center for Behavioral Brain Sciences Magdeburg, Germany ; Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg Magdeburg, Germany
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21
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Kunzler J, Braun K, Bock J. Early life stress and sex-specific sensitivity of the catecholaminergic systems in prefrontal and limbic regions of Octodon degus. Brain Struct Funct 2013; 220:861-8. [PMID: 24343570 DOI: 10.1007/s00429-013-0688-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 12/06/2013] [Indexed: 01/09/2023]
Abstract
Previous work in the precocious rodent Octodon degus has shown that exposure to early life stress (ELS) (induced by repeated parental separation) results in changes of excitatory, inhibitory and modulatory transmitter systems in prefrontal and limbic regions of the male brain. The aim of this study was to test the hypothesis that catecholaminergic fibers and dopamine transporters (DAT) are differentially vulnerable towards ELS-induced neuronal changes in male and female brains. The brains of adult male and female animals exposed to repeated early life stress (1 h/day separation from the family from P1 to P21) and control animals were compared and the densities of tyrosine hydroxylase (TH)-immunoreactive structures were quantified in prefrontal cortical regions. In the nucleus accumbens (NAc) and striatum, DAT-immunoreactivity as well as TH immunoreactivity was measured. Layer II of the prelimbic cortex displayed reduced TH-fiber densities in ELS males compared to control males; this effect was not seen in females. In contrast, layer V/VI of the lateral orbitofrontal cortex displayed elevated fiber densities in ELS males compared to controls; again this difference was not observed in females. The same trend was observed for layer III/IV of the ventral orbitofrontal cortex. No sex-specific effects in response to ELS were observed for DAT, whose density was elevated in the NAc of ELS males and females. These results are in line with our working hypothesis that ELS affects the development of catecholaminergic systems and we show here that ELS-induced differences of TH-immunoreactive fibers were more pronounced in male brains than in female brains.
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Affiliation(s)
- Jan Kunzler
- Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg, Magdeburg, Germany
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22
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León Rodríguez DA, Dueñas Z. Maternal Separation during Breastfeeding Induces Gender-Dependent Changes in Anxiety and the GABA-A Receptor Alpha-Subunit in Adult Wistar Rats. PLoS One 2013; 8:e68010. [PMID: 23826356 PMCID: PMC3694908 DOI: 10.1371/journal.pone.0068010] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Accepted: 05/24/2013] [Indexed: 11/18/2022] Open
Abstract
Different models of rodent maternal separation (MS) have been used to investigate long-term neurobiological and behavioral changes, associated with early stress. However, few studies have involved the analysis of sex-related differences in central anxiety modulation. This study investigated whether MS during breastfeeding affected adult males and females in terms of anxiety and brain GABA-A receptor-alpha-subunit immunoreactivity. The brain areas analyzed were the amygdale (AM), hippocampus (HP), medial prefrontal cortex (mPFC), medial preoptic area (POA) and paraventricular nucleus (PVN). Rats were housed under a reversed light/dark cycle (lights off at 7∶00 h) with access to water and food ad libitum. Animals underwent MS twice daily during the dark cycle from postnatal day 1 to postnatal day 21. Behavior was tested when rats were 65-70 days old using the elevated plus maze and after brains were treated for immunohistochemistry. We found that separated females spent more time in the open arms and showed more head dipping behavior compared with controls. The separated males spent more time in the center of the maze and engaged in more stretching behavior than the controls. Immunohistochemistry showed that separated females had less immunostained cells in the HP, mPFC, PVN and POA, while separated males had fewer immunolabeled cells in the PFC, PVN and AM. These results could indicate that MS has gender-specific effects on anxiety behaviors and that these effects are likely related to developmental alterations involving GABA-A neurotransmission.
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Affiliation(s)
| | - Zulma Dueñas
- Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
- * E-mail:
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23
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Chocyk A, Bobula B, Dudys D, Przyborowska A, Majcher-Maślanka I, Hess G, Wędzony K. Early-life stress affects the structural and functional plasticity of the medial prefrontal cortex in adolescent rats. Eur J Neurosci 2013; 38:2089-107. [PMID: 23581639 DOI: 10.1111/ejn.12208] [Citation(s) in RCA: 115] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Accepted: 03/03/2013] [Indexed: 02/06/2023]
Abstract
Early life experiences are crucial factors that shape brain development and function due to their ability to induce structural and functional plasticity. Among these experiences, early-life stress (ELS) is known to interfere with brain development and maturation, increasing the risk of future psychopathologies, including depression, anxiety, and personality disorders. Moreover, ELS may contribute to the emergence of these psychopathologies during adolescence. In this present study, we investigated the effects of ELS, in the form of maternal separation (MS), on the structural and functional plasticity of the medial prefrontal cortex (mPFC) and anxiety-like behavior in adolescent male rats. We found that the MS procedure resulted in disturbances in mother-pup interactions that lasted until weaning and were most strongly demonstrated by increases in nursing behavior. Moreover, MS caused atrophy of the basal dendritic tree and reduced spine density on both the apical and basal dendrites in layer II/III pyramidal neurons of the mPFC. The structural changes were accompanied by an impairment of long-term potentiation processes and increased expression of key proteins, specifically glutamate receptor 1, glutamate receptor 2, postsynaptic density protein 95, αCa(2+) /calmodulin-dependent protein kinase II and αCa(2+)/calmodulin-dependent protein kinase II phosphorylated at residue Thr305, that are engaged in long-term potentiation induction and maintenance in the mPFC. We also found that the MS animals were more anxious in the light/dark exploration test. The results of this study indicate that ELS has a significant impact on the structural and functional plasticity of the mPFC in adolescents. ELS-induced adaptive plasticity may underlie the pathomechanisms of some early-onset psychopathologies observed in adolescents.
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Affiliation(s)
- Agnieszka Chocyk
- Laboratory of Pharmacology and Brain Biostructure, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
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Dahmen B, Pütz V, Herpertz-Dahlmann B, Konrad K. Early pathogenic care and the development of ADHD-like symptoms. J Neural Transm (Vienna) 2012; 119:1023-36. [PMID: 22661337 DOI: 10.1007/s00702-012-0809-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2012] [Accepted: 04/16/2012] [Indexed: 01/09/2023]
Abstract
Early pathogenic care that is characterised by disregard for the child's basic emotional needs can lead to severe global psychosocial and cognitive dysfunction and deviant developmental trajectories of brain maturation. Reactive attachment disorder (RAD) is a developmental disorder associated with early pathogenic care that is characterised by markedly disturbed ways of relating socially in most contexts. In addition to other severe emotional dysfunctions, children suffering from RAD often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms such as inattention, impulsivity and hyperactivity. It is not yet clear whether ADHD-like symptoms in children exposed to pathogenic care represent a true comorbidity of ADHD or similarities in behavioural dysfunction with a different neurodevelopmental pathway in terms of a phenocopy. In this review, we summarise the findings on the neurobiological consequences of early pathogenic care. Pathogenic care is considered a form of care by a primary caretaker involving a lack or a loss of expectable care, e.g., by early separation, frequent change in caregivers, institutionalisation or neglect. The reviewed studies suggest that a primary dysfunction of limbic brain circuits after early pathogenic care might lead to an interference by motivational or emotional cues impinging on prefrontal executive functions resulting in behavioural similarities with ADHD. Thus, the complex phenotype observed after early pathogenic care might be best described by a dimensional approach with behavioural and neurobiological similarities to ADHD coinciding to a certain degree as a function of early experience. Based on this evidence, suggestions for the treatment of ADHD-like symptoms in children after adverse early life experiences are provided.
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Affiliation(s)
- Brigitte Dahmen
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Medical Faculty, RWTH Aachen University, Neuenhofer Weg 21, 52074 Aachen, Germany.
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Bock J, Riedel A, Braun K. Differential changes of metabolic brain activity and interregional functional coupling in prefronto-limbic pathways during different stress conditions: functional imaging in freely behaving rodent pups. Front Cell Neurosci 2012; 6:19. [PMID: 22590453 PMCID: PMC3349270 DOI: 10.3389/fncel.2012.00019] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Accepted: 04/14/2012] [Indexed: 11/13/2022] Open
Abstract
The trumpet-tailed rat or degu (Octodon degus) is an established model to investigate the consequences of early stress on the development of emotional brain circuits and behavior. The aim of this study was to identify brain circuits, that respond to different stress conditions and to test if acute stress alters functional coupling of brain activity among prefrontal and limbic regions. Using functional imaging (2-Fluoro-deoxyglucose method) in 8-day-old male degu pups the following stress conditions were compared: (A) pups together with parents and siblings (control), (B) separation of the litter from the parents, (C) individual separation from parents and siblings, and (D) individual separation and presentation of maternal calls. Condition (B) significantly downregulated brain activity in the prefrontal cortex, hippocampus, nucleus accumbens (NAcc), and sensory areas compared to controls. Activity decrease was even more pronounced during condition (C), where, in contrast to all other regions, activity in the PAG was increased. Interestingly, brain activity in stress-associated brain regions such as the amygdala and habenula was not affected. In condition (D) maternal vocalizations "reactivated" brain activity in the cingulate and precentral medial cortex, NAcc, and striatum and in sensory areas. In contrast, reduced activity was measured in the prelimbic and infralimbic cortex (IL) and in the hippocampus and amygdala. Correlation analysis revealed complex, region- and situation-specific changes of interregional functional coupling among prefrontal and limbic brain regions during stress exposure. We show here for the first time that early life stress results in a widespread reduction of brain activity in the infant brain and changes interregional functional coupling. Moreover, maternal vocalizations can partly buffer stress-induced decrease in brain activity in some regions and evoked very different functional coupling patterns compared to the three other conditions.
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Affiliation(s)
- Jörg Bock
- Center for Behavioral Brain Sciences MagdeburgMagdeburg, Germany
- PG Structural Plasticity, Institute of Biology, Otto-von-Guericke UniversityMagdeburg, Germany
| | - Anett Riedel
- Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto-von-Guericke UniversityMagdeburg, Germany
| | - Katharina Braun
- Center for Behavioral Brain Sciences MagdeburgMagdeburg, Germany
- Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto-von-Guericke UniversityMagdeburg, Germany
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Braun K. The prefrontal-limbic system: development, neuroanatomy, function, and implications for socioemotional development. Clin Perinatol 2011; 38:685-702. [PMID: 22107898 DOI: 10.1016/j.clp.2011.08.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
The knowledge that neonatal emotional experience and associated learning processes are critical in the maturation of prefronto-limbic circuits emphasizes the importance of preterm and neonatal care. The further improvement of care and intervention strategies requires a deeper understanding of epigenetic mechanisms mediating experience-induced synaptic reorganization underlying the emergence of emotional and cognitive behavioral traits. Interdisciplinary research efforts are needed in which pediatricians and developmental biologists and psychologists merge their knowledge, concepts, and methodology. The hope is that the translational relevance of research efforts can be improved through a greater interaction between basic and clinical scientists.
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Affiliation(s)
- Katharina Braun
- Department of Zoology and Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg, Leipziger Street 44, Magdeburg, Germany.
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An exploration of the associations of pregnancy and perinatal features with cytokines and tryptophan/kynurenine metabolism in children with attention-deficit hyperactivity disorder (ADHD). ACTA ACUST UNITED AC 2011; 3:301-18. [PMID: 21785943 DOI: 10.1007/s12402-011-0062-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2011] [Accepted: 07/08/2011] [Indexed: 10/18/2022]
Abstract
Intra-individual variability of the characteristics of children with attention-deficit hyperactivity (ADHD) may reflect compromised glial energy supply in the synapse. We reported recently that while serum levels of a glial marker, the cytokine S100B, were not seriously altered, levels of other cytokines and tryptophan metabolites were related to symptoms, attention and variability. Here, we explore with a regression analysis whether levels of these substances were associated with features of the index pregnancy of potential aetiological significance. Serum was taken from 35 children with DSM-IV ADHD (14 on medication) and 21 typically developing controls to measure 8 cytokines (S100B, IL-2, IL-6, IL-10, IL-13, IL-16, TNF-α and IFN-γ) and 5 metabolites (Tryptophan, Kynurenine, Kynurenate [KA], 3-hydroxy-kynurenine [3HK] and 5-hydroxyindole acetic acid [5-HIAA]). The mothers received a 124-item questionnaire on features surrounding the pregnancy. (1) For children with ADHD, a shorter pregnancy and smaller birth weight were associated statistically with increased 3HK and IFN-γ and for obstetric problems with decreased TNF-α levels. (2) Maternal smoking related to decreasing kynurenine and increasing 3HK and S100B levels in ADHD children. Paternal smoking was associated with increased tryptophan in the controls and increased IL-6 levels in ADHD children. (3) The taking of supplements often related to decreasing TNF-α, increasing IL-10 and lower 5-HIAA levels in the ADHD children. Less 5-HIAA but more tryptophan was associated with earlier and later life events, respectively. (4) Increased IL-16 and 5-HIAA levels in the ADHD group related to reports of poorer infant health. Unexpectedly, more child care (seafood and time together) in ADHD than healthy families was implicated by lower tryptophan levels and an altered balance of pro-inflammatory cytokines. Across measures control families generally showed either non-significant associations or the opposite to those of the ADHD group. In ADHD children more than controls, the balance of potentially toxic or protective kynurenine metabolites and of pro- over anti-inflammatory cytokines may reflect the perinatal experience associated with stress, but not with maternal illness.
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