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Sanguino-Gómez J, Huijgens S, den Hartog M, Schenk IJM, Kluck W, Versluis TD, Krugers HJ. Neural correlates of learning and memory are altered by early-life stress. Neurobiol Learn Mem 2024; 213:107952. [PMID: 38906243 DOI: 10.1016/j.nlm.2024.107952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 04/12/2024] [Accepted: 06/09/2024] [Indexed: 06/23/2024]
Abstract
The ability to learn and remember, which is fundamental for behavioral adaptation, is susceptible to stressful experiences during the early postnatal period, such as abnormal levels of maternal care. The exact mechanisms underlying these effects still remain elusive. This study examined whether early life stress (ELS) alters memory and brain activation patterns in male mice. Therefore, we examined the expression of the immediate early genes (IEGs) c-Fos and Arc in the dentate gyrus (DG) and basolateral amygdala (BLA) after training and memory retrieval in a fear conditioning task. Furthermore, we examined the potential of RU38486 (RU486), a glucocorticoid receptor antagonist, to mitigate ELS-induced memory deficits by blocking stress signalling during adolescence. Arc::dVenus reporter mice, which allow investigating experience-dependent expression of the immediate early gene Arc also at more remote time points, were exposed to ELS by housing dams and offspring with limited bedding and nesting material (LBN) between postnatal days (PND) 2-9 and trained in a fear conditioning task at adult age. We found that ELS reduced both fear acquisition and contextual memory retrieval. RU486 did not prevent these effects. ELS reduced the number of Arc::dVenus+ cells in DG and BLA after training, while the number of c-Fos+ cells were left unaffected. After memory retrieval, ELS decreased c-Fos+ cells in the ventral DG and BLA. ELS also altered the colocalization of c-Fos+ cells with Arc::dVenus+ cells in the ventral DG, possibly indicating impaired engram allocation in the ventral DG after memory retrieval. In conclusion, this study shows that ELS alters neuronal activation patterns after fear acquisition and retrieval, which may provide mechanistic insights into enduring impact of ELS on the processing of fear memories, possibly via changes in cell (co-) activation and engram cell allocation.
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Affiliation(s)
| | - Stefan Huijgens
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Maxine den Hartog
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Inim J M Schenk
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Wenya Kluck
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Tamara D Versluis
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Harm J Krugers
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands.
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Hall AM, Kamei N, Shao M, Mun HS, Chen K, Chen Y, Baram TZ. Inhibition of Neuron-Restrictive Silencing Factor (REST/NRSF) Chromatin Binding Attenuates Epileptogenesis. eNeuro 2024; 11:ENEURO.0006-24.2024. [PMID: 38641413 PMCID: PMC11103648 DOI: 10.1523/eneuro.0006-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 04/08/2024] [Accepted: 04/15/2024] [Indexed: 04/21/2024] Open
Abstract
The mechanisms by which brain insults lead to subsequent epilepsy remain unclear. Insults including trauma, stroke, infections, and long seizures (status epilepticus, SE) increase the nuclear expression and chromatin binding of the neuron-restrictive silencing factor/RE-1 silencing transcription factor (NRSF/REST). REST/NRSF orchestrates major disruption of the expression of key neuronal genes, including ion channels and neurotransmitter receptors, potentially contributing to epileptogenesis. Accordingly, transient interference with REST/NRSF chromatin binding after an epilepsy-provoking SE suppressed spontaneous seizures for the 12 d duration of a prior study. However, whether the onset of epileptogenesis was suppressed or only delayed has remained unresolved. The current experiments determined if transient interference with REST/NRSF chromatin binding prevented epileptogenesis enduringly or, alternatively, slowed epilepsy onset. Epileptogenesis was elicited in adult male rats via systemic kainic acid-induced SE (KA-SE). We then determined if decoy, NRSF-binding-motif oligodeoxynucleotides (NRSE-ODNs), given twice following KA-SE (1) prevented REST/NRSF binding to chromatin, using chromatin immunoprecipitation, or (2) prevented the onset of spontaneous seizures, measured with chronic digital video-electroencephalogram. Blocking NRSF function transiently after KA-SE significantly lengthened the latent period to a first spontaneous seizure. Whereas this intervention did not influence the duration and severity of spontaneous seizures, total seizure number and seizure burden were lower in the NRSE-ODN compared with scrambled-ODN cohorts. Transient interference with REST/NRSF function after KA-SE delays and moderately attenuates insult-related hippocampal epilepsy, but does not abolish it. Thus, the anticonvulsant and antiepileptogenic actions of NRSF are but one of the multifactorial mechanisms generating epilepsy in the adult brain.
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Affiliation(s)
- Alicia M Hall
- Department of Pediatrics, University of California-Irvine, Irvine, California 92697
| | - Noriko Kamei
- Department of Anatomy and Neurobiology, University of California-Irvine, Irvine, California 92697
| | - Manlin Shao
- Department of Pediatrics, University of California-Irvine, Irvine, California 92697
| | - Hyun-Seung Mun
- Department of Anatomy and Neurobiology, University of California-Irvine, Irvine, California 92697
| | - Kevin Chen
- Department of Pediatrics, University of California-Irvine, Irvine, California 92697
| | - Yuncai Chen
- Department of Pediatrics, University of California-Irvine, Irvine, California 92697
| | - Tallie Z Baram
- Department of Pediatrics, University of California-Irvine, Irvine, California 92697
- Department of Anatomy and Neurobiology, University of California-Irvine, Irvine, California 92697
- Department of Neurology, University of California-Irvine, Irvine, California 92697
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Harmon IP, McCabe EA, Vergun MR, Weinstein J, Graves HL, Boldt CM, Bradley DD, Lee J, Maurice JM, Solomon-Lane TK. Multiple behavioral mechanisms shape development in a highly social cichlid fish. Physiol Behav 2024; 278:114520. [PMID: 38492910 DOI: 10.1016/j.physbeh.2024.114520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 02/21/2024] [Accepted: 03/13/2024] [Indexed: 03/18/2024]
Abstract
Early-life social experiences shape adult phenotype, yet the underlying behavioral mechanisms remain poorly understood. We manipulated early-life social experience in the highly social African cichlid fish Astatotilapia burtoni to investigate the effects on behavior and stress axis function in juveniles. Juveniles experienced different numbers of social partners in stable pairs (1 partner), stable groups (6 fish; 5 partners), and socialized pairs (a novel fish was exchanged every 5 days; 5 partners). Treatments also differed in group size (groups vs. pairs) and stability (stable vs. socialized). We then measured individual behavior and water-borne cortisol to identify effects of early-life experience. We found treatment differences in behavior across all assays: open field exploration, social cue investigation, dominant behavior, and subordinate behavior. Treatment did not affect cortisol. Principal components (PC) analysis revealed robust co-variation of behavior across contexts, including with cortisol, to form behavioral syndromes sensitive to early-life social experience. PC1 (25.1 %) differed by social partner number: juveniles with more partners (groups and socialized pairs) were more exploratory during the social cue investigation, spent less time in the territory, and were more interactive as dominants. PC5 (8.5 %) differed by stability: socialized pairs were more dominant, spent less time in and around the territory, were more socially investigative, and had lower cortisol than stable groups or pairs. Observations of the home tanks provided insights into the social experiences that may underlie these effects. These results contribute to our understanding of how early-life social experiences are accrued and exert strong, lasting effects on phenotype.
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Affiliation(s)
| | | | | | | | | | | | | | - June Lee
- Claremont McKenna College, Claremont, CA, USA
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4
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Kuhn HG, Skau S, Nyberg J. A lifetime perspective on risk factors for cognitive decline with a special focus on early events. CEREBRAL CIRCULATION - COGNITION AND BEHAVIOR 2024; 6:100217. [PMID: 39071743 PMCID: PMC11273094 DOI: 10.1016/j.cccb.2024.100217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/04/2024] [Accepted: 03/06/2024] [Indexed: 07/30/2024]
Abstract
Both Alzheimer's disease and vascular dementia are the result of disease processes that typically develop over several decades. Population studies have estimated that more than half of the risk for dementia is preventable or at least modifiable through behavioral adaptations. The association between these lifestyle factors and the risk of dementia is most evident for exposure in midlife. However, habits formed in middle age often reflect a lifetime of behavior patterns and living conditions. Therefore, individuals who, for example, are able to maintain healthy diets and regular exercise during their middle years are likely to benefit from these cognition-protective habits they have practiced throughout their lives. For numerous adult diseases, significant risks can often be traced back to early childhood. Suboptimal conditions during the perinatal period, childhood and adolescence can increase the risk of adult diseases, including stroke, heart disease, insulin resistance, hypertension and dementia. This review aims at summarizing some of the evidence for dementia risks from a life-time perspective with the goal of raising awareness for early dementia prevention and successful aging.
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Affiliation(s)
- H. Georg Kuhn
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Simon Skau
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
- Department of Pedagogical, Curricular and Professional Studies, University of Gothenburg, Gothenburg, Sweden
| | - Jenny Nyberg
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
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Bagheri F, Goudarzi I, Lashkarbolouki T, Elahdadi Salmani M, Goudarzi A, Morley-Fletcher S. Improving behavioral deficits induced by perinatal ethanol and stress exposure in adolescent male rat progeny via maternal melatonin treatment. Psychopharmacology (Berl) 2024; 241:153-169. [PMID: 37889278 DOI: 10.1007/s00213-023-06470-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 09/25/2023] [Indexed: 10/28/2023]
Abstract
BACKGROUND AND AIM Early-life stressful situations and binge drinking have been thus far acknowledged as two burdensome conditions that potentially give rise to negative outcomes and then synergistically affect brain development. In this context, the hippocampus, with the greatest number of glucocorticoid receptors (GCRs) in the brain, is responsible for regulating negative responses to stress. Prolonged glucocorticoid (GC) exposure can accordingly cause oxidative stress (OS), leading to cognitive and emotional dysfunction. Against this background, melatonin, as a powerful antioxidant and hypothalamus-pituitary-adrenal (HPA) axis regulator, was administered in this study to ameliorate cognitive impairments induced by perinatal ethanol and stress exposure in adolescent male rat progeny. METHODS Wistar rat dams were exposed to ethanol (4 g/kg) and melatonin (10 mg/kg) from gestational day (GD) 6 to postnatal day (PND) 14 and then limited nesting material (LNS) from PND0 to PND14 individually or in combination. Maternal behavior was then investigated in mothers. Afterward, the plasma corticosterone (CORT) concentration, the OS marker, the corticotropin-releasing hormone receptor type 1 (CRHR1) expression, and the GCR and brain-derived neurotrophic factor (BDNF) levels were measured in the male pups. Moreover, behavioral tasks, including the elevated plus maze (EPM), the Morris water maze (MWM), the novel object recognition (NORT), and the object-location memory (OLM) tests were completed and assessed. RESULTS The quantity and quality of maternal care significantly decreased in the mothers with dual exposure to ethanol and stress. The plasma CORT concentration in the progeny also dropped in the Ethanol + LNS group, but the risk-taking behavior elevated significantly. The ethanol and stress exposure further revealed a significant fall in the GCR and CRHR1 expression levels, compared with stress alone. The results of learning and memory tasks also indicated a significant reduction in spatial learning and memory among animals exposed to ethanol and stress. The BDNF mRNA levels correspondingly increased in the Ethanol + LNS group, compared with LNS alone. In the presence of ethanol and stress, the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities correspondingly declined. On the other hand, the malondialdehyde (MDA) levels augmented in the hippocampus of the animals with ethanol and LNS dual exposure, as compared with the control group. Melatonin treatment (MT) thus improved nursing behaviors in dams, prevented OS, enhanced the CRHR1 and GCR expression, and reduced the BDNF levels to the similar ones in the control group. The animals in the Ethanol + LNS + MT group ultimately showed an ameliorated performance at behavioral tasks, including the memory and risk-taking behavior. CONCLUSION It was concluded that MT could prevent stress response and memory impairments arising from dual exposure to ethanol and stress by inhibiting OS.
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Affiliation(s)
| | - Iran Goudarzi
- School of Biology, Damghan University, Damghan, Iran.
| | | | | | - Afsaneh Goudarzi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Morley-Fletcher
- Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale Et Fonctionnelle, 59000, Lille, France
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Mposhi A, Turner JD. How can early life adversity still exert an effect decades later? A question of timing, tissues and mechanisms. Front Immunol 2023; 14:1215544. [PMID: 37457711 PMCID: PMC10348484 DOI: 10.3389/fimmu.2023.1215544] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/14/2023] [Indexed: 07/18/2023] Open
Abstract
Exposure to any number of stressors during the first 1000 days from conception to age 2 years is important in shaping an individual's life trajectory of health and disease. Despite the expanding range of stressors as well as later-life phenotypes and outcomes, the underlying molecular mechanisms remain unclear. Our previous data strongly suggests that early-life exposure to a stressor reduces the capacity of the immune system to generate subsequent generations of naïve cells, while others have shown that, early life stress impairs the capacity of neuronal stem cells to proliferate as they age. This leads us to the "stem cell hypothesis" whereby exposure to adversity during a sensitive period acts through a common mechanism in all the cell types by programming the tissue resident progenitor cells. Furthermore, we review the mechanistic differences observed in fully differentiated cells and suggest that early life adversity (ELA) may alter mitochondria in stem cells. This may consequently alter the destiny of these cells, producing the lifelong "supply" of functionally altered fully differentiated cells.
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Gee DG. Neurodevelopmental mechanisms linking early experiences and mental health: Translating science to promote well-being among youth. AMERICAN PSYCHOLOGIST 2022; 77:1033-1045. [PMID: 36595400 PMCID: PMC9875304 DOI: 10.1037/amp0001107] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Early experiences can have profound and lasting effects on mental health. Delineating neurodevelopmental pathways related to risk and resilience following adversity exposure is critical for promoting well-being and targeting interventions. A rapidly growing cross-species literature has facilitated advances in identifying neural and behavioral mechanisms linking early experiences with mental health, highlighting a central role of corticolimbic circuitry involved in learning and emotion regulation. Building upon knowledge of corticolimbic development related to stress and buffering factors, we describe the importance of the developmental timing and experiential elements of adversity in mental health outcomes. Finally, we discuss opportunities to translate knowledge of the developing brain and early experiences to optimize interventions for youth with psychopathology and to inform policy that promotes healthy development at the societal level. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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8
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Solomon-Lane TK, Butler RM, Hofmann HA. Vasopressin mediates nonapeptide and glucocorticoid signaling and social dynamics in juvenile dominance hierarchies of a highly social cichlid fish. Horm Behav 2022; 145:105238. [PMID: 35932752 DOI: 10.1016/j.yhbeh.2022.105238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/28/2022] [Accepted: 07/18/2022] [Indexed: 11/28/2022]
Abstract
Early-life social experience can strongly affect adult behavior, yet the behavioral mechanisms underlying developmental trajectories are poorly understood. Here, we use the highly social cichlid, Burton's Mouthbrooder (Astatotilapia burtoni) to investigate juvenile social status and behavior, as well as the underlying neuroendocrine mechanisms. We placed juveniles in pairs or triads and found that they readily establish social status hierarchies, with some group structural variation depending on group size, as well as the relative body size of the group members. Next, we used intracerebroventricular injections to test the hypothesis that arginine vasopressin (AVP) regulates juvenile social behavior and status, similar to adult A. burtoni. While we found no direct behavioral effects of experimentally increasing (via vasotocin) or decreasing (via antagonist Manning Compound) AVP signaling, social interactions directed at the treated individual were significantly altered. This group-level effect of central AVP manipulation was also reflected in a significant shift in whole brain expression of genes involved in nonapeptide signaling (AVP, oxytocin, and oxytocin receptor) and the neuroendocrine stress axis (corticotropin-releasing factor (CRF), glucocorticoid receptors (GR) 1a and 1b). Further, social status was associated with the expression of genes involved in glucocorticoid signaling (GR1a, GR1b, GR2, mineralocorticoid receptor), social interactions with the dominant fish, and nonapeptide signaling activity (AVP, AVP receptor V1aR2, OTR). Together, our results considerably expand our understanding of the context-specific emergence of social dominance hierarchies in juveniles and demonstrate a role for nonapeptide and stress axis signaling in the regulation of social status and social group dynamics.
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Affiliation(s)
- Tessa K Solomon-Lane
- Department of Integrative Biology, The University of Texas at Austin, Austin, TX 78712, United States of America; Institute for Neuroscience, The University of Texas at Austin, Austin, TX 78712, United States of America.
| | - Rebecca M Butler
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, United States of America
| | - Hans A Hofmann
- Department of Integrative Biology, The University of Texas at Austin, Austin, TX 78712, United States of America; Institute for Neuroscience, The University of Texas at Austin, Austin, TX 78712, United States of America; Institute for Cell & Molecular Biology, The University of Texas at Austin, Austin, TX 78712, United States of America
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9
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Liu S, Fisher PA. Early experience unpredictability in child development as a model for understanding the impact of the COVID-19 pandemic: A translational neuroscience perspective. Dev Cogn Neurosci 2022; 54:101091. [PMID: 35217299 PMCID: PMC8860470 DOI: 10.1016/j.dcn.2022.101091] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 02/13/2022] [Accepted: 02/19/2022] [Indexed: 01/11/2023] Open
Abstract
Extensive evidence links adverse experiences during childhood to a wide range of negative consequences in biological, socioemotional, and cognitive development. Unpredictability is a core element underlying most forms of early adversity; it has been a focus of developmental research for many years and has been receiving increasing attention recently. In this article, we propose a conceptual model to describe how unpredictable and adverse early experiences affect children's neurobiological, behavioral, and psychological development in the context of the COVID-19 pandemic. We first highlight the critical role of unpredictability in child development by reviewing existing conceptual models of early adversity as they relate to subsequent development across the lifespan. Then, we employ a translational neuroscience framework to summarize the current animal- and human-based evidence on the neurobiological alterations induced by early experience unpredictability. We further argue that the COVID-19 pandemic serves as a global "natural experiment" that provides rare insight to the investigation of the negative developmental consequences of widespread, clustered, and unpredictable adverse events among children. We discuss how the pandemic helps advance the science of unpredictable early adverse experiences. As unpredictability research continues to grow, we highlight several directions for future studies and implications for policymaking and intervention practices.
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Affiliation(s)
- Sihong Liu
- Center for Translational Neuroscience, Department of Psychology, University of Oregon, Eugene, OR, United States.
| | - Philip A Fisher
- Center for Translational Neuroscience, Department of Psychology, University of Oregon, Eugene, OR, United States
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Chaudhari PR, Singla A, Vaidya VA. Early Adversity and Accelerated Brain Aging: A Mini-Review. Front Mol Neurosci 2022; 15:822917. [PMID: 35392273 PMCID: PMC8980717 DOI: 10.3389/fnmol.2022.822917] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 02/25/2022] [Indexed: 11/13/2022] Open
Abstract
Early adversity is an important risk factor that influences brain aging. Diverse animal models of early adversity, including gestational stress and postnatal paradigms disrupting dam-pup interactions evoke not only persistent neuroendocrine dysfunction and anxio-depressive behaviors, but also perturb the trajectory of healthy brain aging. The process of brain aging is thought to involve hallmark features such as mitochondrial dysfunction and oxidative stress, evoking impairments in neuronal bioenergetics. Furthermore, brain aging is associated with disrupted proteostasis, progressively defective epigenetic and DNA repair mechanisms, the build-up of neuroinflammatory states, thus cumulatively driving cellular senescence, neuronal and cognitive decline. Early adversity is hypothesized to evoke an “allostatic load” via an influence on several of the key physiological processes that define the trajectory of healthy brain aging. In this review we discuss the evidence that animal models of early adversity impinge on fundamental mechanisms of brain aging, setting up a substratum that can accelerate and compromise the time-line and nature of brain aging, and increase risk for aging-associated neuropathologies.
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11
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Ventura R, Cabib S, Babicola L, Andolina D, Di Segni M, Orsini C. Interactions Between Experience, Genotype and Sex in the Development of Individual Coping Strategies. Front Behav Neurosci 2022; 15:785739. [PMID: 34987364 PMCID: PMC8721137 DOI: 10.3389/fnbeh.2021.785739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/29/2021] [Indexed: 02/01/2023] Open
Abstract
Coping strategies, the first line of defense against adversities, develop through experience. There is consistent evidence that both genotype and sex contribute to the development of dysfunctional coping, leading to maladaptive outcomes of adverse experiences or to adaptive coping that fosters rapid recovery even from severe stress. However, how these factors interact to influence the development of individual coping strategies is just starting to be investigated. In the following review, we will consider evidence that experience, sex, and genotype influence the brain circuits and neurobiological processes involved in coping with adversities and discuss recent results pointing to the specific effects of the interaction between early experiences, genotype, and stress in the development of functional and dysfunctional coping styles.
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Affiliation(s)
- Rossella Ventura
- Department of Psychology and Centre for Research in Neurobiology D. Bovet, Sapienza University of Rome, Rome, Italy.,Department of Experimental Neurosciences, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Simona Cabib
- Department of Psychology and Centre for Research in Neurobiology D. Bovet, Sapienza University of Rome, Rome, Italy.,Department of Experimental Neurosciences, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Lucy Babicola
- Department of Psychology and Centre for Research in Neurobiology D. Bovet, Sapienza University of Rome, Rome, Italy.,Department of Experimental Neurosciences, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Diego Andolina
- Department of Psychology and Centre for Research in Neurobiology D. Bovet, Sapienza University of Rome, Rome, Italy.,Department of Experimental Neurosciences, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Matteo Di Segni
- Department of Experimental Neurosciences, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Cristina Orsini
- Department of Psychology and Centre for Research in Neurobiology D. Bovet, Sapienza University of Rome, Rome, Italy
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12
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Wang Q, Lu M, Zhu X, Gu X, Zhang T, Xia C, Yang L, Xu Y, Zhou M. Brain Mitochondrial Dysfunction: A Possible Mechanism Links Early Life Anxiety to Alzheimer’s Disease in Later Life. Aging Dis 2022; 13:1127-1145. [PMID: 35855329 PMCID: PMC9286915 DOI: 10.14336/ad.2022.0221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 02/21/2022] [Indexed: 11/01/2022] Open
Affiliation(s)
- Qixue Wang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengna Lu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xinyu Zhu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xinyi Gu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ting Zhang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chenyi Xia
- Department of Physiology, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Li Yang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Xu
- Department of Physiology, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Mingmei Zhou
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Correspondence should be addressed to: Dr. Mingmei Zhou, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. E-mail:
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13
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Gee DG. Early Adversity and Development: Parsing Heterogeneity and Identifying Pathways of Risk and Resilience. Am J Psychiatry 2021; 178:998-1013. [PMID: 34734741 DOI: 10.1176/appi.ajp.2021.21090944] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Adversity early in life is common and is a major risk factor for the onset of psychopathology. Delineating the neurodevelopmental pathways by which early adversity affects mental health is critical for early risk identification and targeted treatment approaches. A rapidly growing cross-species literature has facilitated advances in identifying the mechanisms linking adversity with psychopathology, specific dimensions of adversity and timing-related factors that differentially relate to outcomes, and protective factors that buffer against the effects of adversity. Yet, vast complexity and heterogeneity in early environments and neurodevelopmental trajectories contribute to the challenges of understanding risk and resilience in the context of early adversity. In this overview, the author highlights progress in four major areas-mechanisms, heterogeneity, developmental timing, and protective factors; synthesizes key challenges; and provides recommendations for future research that can facilitate progress in the field. Translation across species and ongoing refinement of conceptual models have strong potential to inform prevention and intervention strategies that can reduce the immense burden of psychopathology associated with early adversity.
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Affiliation(s)
- Dylan G Gee
- Department of Psychology, Yale University, New Haven, Conn
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14
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Fernández-Teruel A. Conflict between Threat Sensitivity and Sensation Seeking in the Adolescent Brain: Role of the Hippocampus, and Neurobehavioural Plasticity Induced by Pleasurable Early Enriched Experience. Brain Sci 2021; 11:brainsci11020268. [PMID: 33672653 PMCID: PMC7924176 DOI: 10.3390/brainsci11020268] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/05/2021] [Accepted: 02/14/2021] [Indexed: 01/28/2023] Open
Abstract
Adolescence is characterized both by the exacerbation of the experience of anxiety, fear or threat, on one hand, and by increased reward seeking (reward sensitivity) and risk taking on the other hand. The rise of these apparently opposite processes, i.e., threat-related anxiety and reward-related sensation seeking, seems to stem from a relatively decreased top-down inhibition of amygdala and striatal circuits by regulatory systems (e.g., prefrontal cortex, hippocampus) that mature later. The present commentary article aims to discuss recent related literature and focusses on two main issues: (i) the septo-hippocampal system (in particular the ventral hippocampus) might be a crucial region for the regulation of approach–avoidance conflict and also for the selection of the most appropriate responses during adolescence, and (ii) developmental studies involving early-life pleasurable-enriched experience (as opposed to early-life adversity) might be a useful study paradigm in order to decipher whether neuroplasticity induced by such experiences (for example, in the hippocampus and associated circuitry) may lead to better top-down inhibition and more “balanced” adolescent responses to environmental demands.
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Affiliation(s)
- Alberto Fernández-Teruel
- Department of Psychiatry & Forensic Medicine, Medical Psychology Unit, School of Medicine & Institute of Neurosciences, Autonomous University of Barcelona, Bellaterra, 08193 Barcelona, Spain
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15
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Soga T, Teo CH, Parhar I. Genetic and Epigenetic Consequence of Early-Life Social Stress on Depression: Role of Serotonin-Associated Genes. Front Genet 2021; 11:601868. [PMID: 33584798 PMCID: PMC7874148 DOI: 10.3389/fgene.2020.601868] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 12/14/2020] [Indexed: 12/22/2022] Open
Abstract
Early-life adversity caused by poor social bonding and deprived maternal care is known to affect mental wellbeing and physical health. It is a form of chronic social stress that persists because of a negative environment, and the consequences are long-lasting on mental health. The presence of social stress during early life can have an epigenetic effect on the body, possibly resulting in many complex mental disorders, including depression in later life. Here, we review the evidence for early-life social stress-induced epigenetic changes that modulate juvenile and adult social behavior (depression and anxiety). This review has a particular emphasis on the interaction between early-life social stress and genetic variation of serotonin associate genes including the serotonin transporter gene (5-HTT; also known as SLC6A4), which are key molecules involved in depression.
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Affiliation(s)
- Tomoko Soga
- Brain Research Institute, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia
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16
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Bolton JL, Schulmann A, Garcia-Curran MM, Regev L, Chen Y, Kamei N, Shao M, Singh-Taylor A, Jiang S, Noam Y, Molet J, Mortazavi A, Baram TZ. Unexpected Transcriptional Programs Contribute to Hippocampal Memory Deficits and Neuronal Stunting after Early-Life Adversity. Cell Rep 2020; 33:108511. [PMID: 33326786 PMCID: PMC7817243 DOI: 10.1016/j.celrep.2020.108511] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 07/08/2020] [Accepted: 11/19/2020] [Indexed: 01/23/2023] Open
Abstract
Early-life adversity (ELA) is associated with lifelong memory deficits, yet the responsible mechanisms remain unclear. We impose ELA by rearing rat pups in simulated poverty, assess hippocampal memory, and probe changes in gene expression, their transcriptional regulation, and the consequent changes in hippocampal neuronal structure. ELA rats have poor hippocampal memory and stunted hippocampal pyramidal neurons associated with ~140 differentially expressed genes. Upstream regulators of the altered genes include glucocorticoid receptor and, unexpectedly, the transcription factor neuron-restrictive silencer factor (NRSF/REST). NRSF contributes critically to the memory deficits because blocking its function transiently following ELA rescues spatial memory and restores the dendritic arborization of hippocampal pyramidal neurons in ELA rats. Blocking NRSF function in vitro augments dendritic complexity of developing hippocampal neurons, suggesting that NRSF represses genes involved in neuronal maturation. These findings establish important, surprising contributions of NRSF to ELA-induced transcriptional programming that disrupts hippocampal maturation and memory function.
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Affiliation(s)
- Jessica L Bolton
- Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Anton Schulmann
- Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Megan M Garcia-Curran
- Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Limor Regev
- Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Yuncai Chen
- Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Noriko Kamei
- Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Manlin Shao
- Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Akanksha Singh-Taylor
- Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Shan Jiang
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Yoav Noam
- Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Jenny Molet
- Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Ali Mortazavi
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697-4475, USA
| | - Tallie Z Baram
- Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Neurology, University of California, Irvine, Irvine, CA 92697-4475, USA.
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17
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Lin Y, Lei L, Ju LS, Xu N, Morey TE, Gravenstein N, Yang J, Martynyuk AE. Neonatal exposure to sevoflurane expands the window of vulnerability to adverse effects of subsequent exposure to sevoflurane and alters hippocampal morphology via decitabine-sensitive mechanisms. Neurosci Lett 2020; 735:135240. [PMID: 32650051 DOI: 10.1016/j.neulet.2020.135240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/09/2020] [Accepted: 07/07/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Deficiencies in neurocognitive function have been found in late childhood or adolescence in patients who had prolonged and/or repeated early-life general anesthesia. Animal studies suggest that anesthetic-induced impairment in the neuron-specific K+-2Cl- (Kcc2) Cl- exporter expression, which regulates developmental maturation of GABA type A receptor (GABAAR) signaling from excitatory to inhibitory, may play a mediating role. We tested whether the DNA methyltransferase (DNMT) inhibitor decitabine ameliorates the anesthetic's adverse effects. METHODS Sprague-Dawley male rats were injected with vehicle or decitabine 30 min before 2.1 % sevoflurane exposure for 5 h on postnatal day 5 (P5). On P19, P20, or P21, electroencephalography-detectable seizures were measured during 1 h of sevoflurane exposure, followed by collection of the trunk blood and brain tissue samples. Other rats were evaluated for changes in hippocampal CA1 dendrite morphology and gene expressions on ≥ P120. RESULTS Rats in the vehicle plus sevoflurane group responded to sevoflurane exposure on P19, P20 or P21 with electroencephalography-detectable seizures and stress-like corticosterone secretion and had altered hippocampal dendrite morphology in adulthood. These rats had expressions of Kcc2 and Dnmt genes downregulated and upregulated, respectively, in the P19 - P21 cortex and hypothalamus and the ≥ P120 hippocampus. All measured parameters in the sevoflurane-exposed rats that were pretreated with decitabine were not different from those in the control group. CONCLUSIONS Neonatal exposure to sevoflurane sensitizes rats to adverse effects of repeated exposure to the anesthetic. The anesthetic-caused changes in the decitabine-sensitive mechanisms may play a mediating role in the developmental effects of early-life anesthesia.
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Affiliation(s)
- Yunan Lin
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Lei Lei
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Ning Xu
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jianjun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States.
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18
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A Unique Mouse Model of Early Life Exercise Enables Hippocampal Memory and Synaptic Plasticity. Sci Rep 2020; 10:9174. [PMID: 32513972 PMCID: PMC7280304 DOI: 10.1038/s41598-020-66116-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 05/13/2020] [Indexed: 12/25/2022] Open
Abstract
Physical exercise is a powerful modulator of learning and memory. Mechanisms underlying the cognitive benefits of exercise are well documented in adult rodents. Exercise studies targeting postnatal periods of hippocampal maturation (specifically targeting periods of synaptic reorganization and plasticity) are lacking. We characterize a model of early-life exercise (ELE) in male and female mice designed with the goal of identifying critical periods by which exercise may have a lasting impact on hippocampal memory and synaptic plasticity. Mice freely accessed a running wheel during three postnatal periods: the 4th postnatal week (juvenile ELE, P21–27), 6th postnatal week (adolescent ELE, P35–41), or 4th-6th postnatal weeks (juvenile-adolescent ELE, P21–41). All exercise groups increased their running distances during ELE. When exposed to a subthreshold learning stimulus, juv ELE and juv-adol ELE formed lasting long-term memory for an object location memory task, whereas sedentary and adol ELE mice did not. Electrophysiological experiments revealed enhanced long-term potentiation in hippocampal CA1 in the juvenile-adolescent ELE group. I/O curves were also significantly modulated in all mice that underwent ELE. Our results suggest that early-life exercise, specifically during the 4th postnatal week, can enable hippocampal memory, synaptic plasticity, and alter hippocampal excitability when occurring during postnatal periods of hippocampal maturation.
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19
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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: 7] [Impact Index Per Article: 1.4] [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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20
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Lee J, Papa F, Jaini PA, Alpini S, Kenny T. An Epigenetics-Based, Lifestyle Medicine-Driven Approach to Stress Management for Primary Patient Care: Implications for Medical Education. Am J Lifestyle Med 2020; 14:294-303. [PMID: 32477032 PMCID: PMC7232902 DOI: 10.1177/1559827619847436] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 03/26/2019] [Accepted: 04/10/2019] [Indexed: 12/22/2022] Open
Abstract
Over 75% of patients in the primary care setting present with stress-related complaints. Curiously, patients and health care providers all too often see stress as a relatively benign sequela of many common illnesses such as heart disease, cancer, lung disease, dementia, diabetes, and mental illness. Unfortunately, various day-to-day lifestyle choices and environmental factors, unrelated to the presence of any disease, can cause stress sufficient to contribute to the development of various diseases/disorders and suboptimal health. There is evidence suggesting that counseling in stress management-oriented therapeutic interventions (as offered by lifestyle medicine-oriented practitioners) may prevent or reduce the onset, severity, duration, and/or overall burden of stress-related illnesses. Such counseling often involves considerations such as the patient's nutrition, physical activity, interest in/capacity to meditate, drug abuse/cessation, and so on. Unfortunately, lifestyle medicine-oriented approaches to stress management are rarely offered in primary care-the patient care arena wherein such counseling would likely be best received by patients. Would health care outcomes improve if primary care providers offered counseling in both stress management and positive lifestyle choices? The purpose of this article is to provide both primary care practitioners and educators in health care training programs with an introductory overview of epigenetics. An emerging field of science offering insights into how factors such as stress and lifestyle choices interact with our genes in ways that can both positively and negatively impact the various micro (eg, cellular) through macro (eg, physiologic, pathophysiologic) processes that determine our tendencies toward illness or wellness. A deeper understanding of epigenetics, as provided herein, should enable primary care providers and medical educators to more confidently advocate for the primary benefits associated with counseling in both stress reduction and the pursuit of healthy lifestyle choices.
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Affiliation(s)
- Jenny Lee
- Preventive Medicine, Loma Linda University, Loma Linda, California (JL)
- UNT Health Science Center, Fort Worth, Texas (FP, SA, TK)
- John Peter Smith Hospital, Fort Worth, Texas (PJ)
| | - Frank Papa
- Frank Papa, DO, PhD, Medical Education, UNT Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107; e-mail:
| | - Paresh Atu Jaini
- Preventive Medicine, Loma Linda University, Loma Linda, California (JL)
- UNT Health Science Center, Fort Worth, Texas (FP, SA, TK)
- John Peter Smith Hospital, Fort Worth, Texas (PJ)
| | - Sarah Alpini
- Preventive Medicine, Loma Linda University, Loma Linda, California (JL)
- UNT Health Science Center, Fort Worth, Texas (FP, SA, TK)
- John Peter Smith Hospital, Fort Worth, Texas (PJ)
| | - Tim Kenny
- Preventive Medicine, Loma Linda University, Loma Linda, California (JL)
- UNT Health Science Center, Fort Worth, Texas (FP, SA, TK)
- John Peter Smith Hospital, Fort Worth, Texas (PJ)
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21
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Mustafa J, Hodgson P, Lhussier M, Forster N, Carr SM, Dalkin SM. 'Everything takes too long and nobody is listening': Developing theory to understand the impact of advice on stress and the ability to cope. PLoS One 2020; 15:e0231014. [PMID: 32324749 PMCID: PMC7179918 DOI: 10.1371/journal.pone.0231014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 03/15/2020] [Indexed: 12/03/2022] Open
Abstract
Shrinking state spending in the UK has been accompanied by a profound restructuring of the welfare system, leading to financial insecurity for many people, culminating in extreme stress and serious deterioration of physical and mental health. Theory surrounding the impact of welfare advice on stress is lacking; this paper undertakes an in depth exploration of the experiences of stress among welfare advice seekers, considering these in light of existing substantive theories of stress and coping to generate new insight. A thematic analysis explored the experiences of stress in welfare advice seekers. Four overarching themes and twelve subthemes emerged. They are further understood utilising traditional theories of stress (Transactional Model of Stress and Coping and the Conservation of Resources theory), which then underpin the development of a ‘Stress Support Matrix’ and a holistic theory related specifically to welfare, stress and coping.
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Affiliation(s)
- Jawwad Mustafa
- Faculty of Health and Life Sciences, Northumbria University, Newcastle, United Kingdom
| | - Philip Hodgson
- Faculty of Health and Life Sciences, Northumbria University, Newcastle, United Kingdom
| | - Monique Lhussier
- Faculty of Health and Life Sciences, Northumbria University, Newcastle, United Kingdom
| | - Natalie Forster
- Faculty of Health and Life Sciences, Northumbria University, Newcastle, United Kingdom
- Fuse (The Centre for Translational Research in Public Health), Newcastle, United Kingdom
| | - Susan Mary Carr
- Faculty of Health and Life Sciences, Northumbria University, Newcastle, United Kingdom
- Fuse (The Centre for Translational Research in Public Health), Newcastle, United Kingdom
| | - Sonia Michelle Dalkin
- Faculty of Health and Life Sciences, Northumbria University, Newcastle, United Kingdom
- Fuse (The Centre for Translational Research in Public Health), Newcastle, United Kingdom
- * E-mail:
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22
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Oli MK, Krebs CJ, Kenney AJ, Boonstra R, Boutin S, Hines JE. Demography of snowshoe hare population cycles. Ecology 2020; 101:e02969. [PMID: 31922605 DOI: 10.1002/ecy.2969] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 10/16/2019] [Accepted: 11/12/2019] [Indexed: 01/16/2023]
Abstract
Cyclic fluctuations in abundance exhibited by some mammalian populations in northern habitats ("population cycles") are key processes in the functioning of many boreal and tundra ecosystems. Understanding population cycles, essentially demographic processes, necessitates discerning the demographic mechanisms that underlie numerical changes. Using mark-recapture data spanning five population cycles (1977-2017), we examined demographic mechanisms underlying the 9-10-yr cycles exhibited by snowshoe hares (Lepus americanus Erxleben) in southwestern Yukon, Canada. Snowshoe hare populations always decreased during winter and increased during summer; the balance between winter declines and summer increases characterized the four, multiyear cyclic phases: increase, peak, decline, and low. Little or no recruitment occurred during winter, but summer recruitment varied markedly across the four phases with the highest and lowest recruitment observed during the increase and decline phase, respectively. Population crashes during the decline were triggered by a substantial decline in winter survival and by a lack of subsequent summer recruitment. In contrast, initiation of the increase phase was triggered by a twofold increase in summer recruitment abetted secondarily by improvements in subsequent winter survival. We show that differences in peak density across cycles are explained by differences in overall population growth rate, amount of time available for population growth to occur, and starting population density. Demographic mechanisms underlying snowshoe hare population cycles were consistent across cycles in our study site but we do not yet know if similar demographic processes underlie population cycles in other northern snowshoe hare populations.
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Affiliation(s)
- Madan K Oli
- Department of Wildlife Ecology and Conservation, University of Florida, 110 Newins-Ziegler Hall, Gainesville, 32611, Florida, USA
| | - Charles J Krebs
- Department of Zoology, University of British Columbia, 4200 - 6270 University Blvd., Vancouver, V6T 1Z4, British Columbia, Canada
| | - Alice J Kenney
- Department of Zoology, University of British Columbia, 4200 - 6270 University Blvd., Vancouver, V6T 1Z4, British Columbia, Canada
| | - Rudy Boonstra
- Department of Biological Sciences, University of Toronto Scarborough, Toronto, M1C 1A4, Ontario, Canada
| | - Stan Boutin
- Department of Biological Sciences, University of Alberta, Edmonton, T6G 2R3, Alberta, Canada
| | - James E Hines
- USGS Patuxent Wildlife Research Center, 12311 Beech Forest Road, Patuxant, 20708, Maryland, USA
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23
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Short AK, Baram TZ. Early-life adversity and neurological disease: age-old questions and novel answers. Nat Rev Neurol 2019; 15:657-669. [PMID: 31530940 PMCID: PMC7261498 DOI: 10.1038/s41582-019-0246-5] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2019] [Indexed: 12/24/2022]
Abstract
Neurological illnesses, including cognitive impairment, memory decline and dementia, affect over 50 million people worldwide, imposing a substantial burden on individuals and society. These disorders arise from a combination of genetic, environmental and experiential factors, with the latter two factors having the greatest impact during sensitive periods in development. In this Review, we focus on the contribution of adverse early-life experiences to aberrant brain maturation, which might underlie vulnerability to cognitive brain disorders. Specifically, we draw on recent robust discoveries from diverse disciplines, encompassing human studies and experimental models. These discoveries suggest that early-life adversity, especially in the perinatal period, influences the maturation of brain circuits involved in cognition. Importantly, new findings suggest that fragmented and unpredictable environmental and parental signals comprise a novel potent type of adversity, which contributes to subsequent vulnerabilities to cognitive illnesses via mechanisms involving disordered maturation of brain 'wiring'.
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Affiliation(s)
- Annabel K Short
- Departments of Anatomy and Neruobiology, University of California-Irvine, Irvine, CA, USA
- Departments of Pediatrics, University of California-Irvine, Irvine, CA, USA
| | - Tallie Z Baram
- Departments of Anatomy and Neruobiology, University of California-Irvine, Irvine, CA, USA.
- Departments of Pediatrics, University of California-Irvine, Irvine, CA, USA.
- Departments of Neurology, University of California-Irvine, Irvine, CA, USA.
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24
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Solomon-Lane TK, Hofmann HA. Early-life social environment alters juvenile behavior and neuroendocrine function in a highly social cichlid fish. Horm Behav 2019; 115:104552. [PMID: 31276665 DOI: 10.1016/j.yhbeh.2019.06.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 04/26/2019] [Accepted: 06/28/2019] [Indexed: 12/17/2022]
Abstract
Early-life experiences can shape adult behavior, with consequences for fitness and health, yet fundamental questions remain unanswered about how early-life social experiences are translated into variation in brain and behavior. The African cichlid fish Astatotilapia burtoni, a model system in social neuroscience, is well known for its highly plastic social phenotypes in adulthood. Here, we rear juveniles in either social groups or pairs to investigate the effects of early-life social environments on behavior and neuroendocrine gene expression. We find that both juvenile behavior and neuroendocrine function are sensitive to early-life effects. Behavior robustly co-varies across multiple contexts (open field, social cue investigation, and dominance behavior assays) to form a behavioral syndrome, with pair-reared juveniles towards the end of syndrome that is less active and socially interactive. Pair-reared juveniles also submit more readily as subordinates. In a separate cohort, we measured whole brain expression of stress and sex hormone genes. Expression of glucocorticoid receptor 1a was elevated in group-reared juveniles, supporting a highly-conserved role for the stress axis mediating early-life effects. The effect of rearing environment on androgen receptor α and estrogen receptor α expression was mediated by treatment duration (1 vs. 5 weeks). Finally, expression of corticotropin-releasing factor and glucocorticoid receptor 2 decreased significantly over time. Rearing environment also caused striking differences in gene co-expression, such that expression was tightly integrated in pair-reared juveniles but not group-reared or isolates. Together, this research demonstrates the important developmental origins of behavioral phenotypes and identifies potential behavioral and neuroendocrine mechanisms.
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Affiliation(s)
- Tessa K Solomon-Lane
- Department of Integrative Biology, The University of Texas at Austin, Austin, TX 78712, United States of America; Institute for Neuroscience, The University of Texas at Austin, Austin, TX 78712, United States of America; Center for Computational Biology and Bioinformatics, The University of Texas at Austin, Austin, TX 78712, United States of America.
| | - Hans A Hofmann
- Department of Integrative Biology, The University of Texas at Austin, Austin, TX 78712, United States of America; Institute for Neuroscience, The University of Texas at Austin, Austin, TX 78712, United States of America; Center for Computational Biology and Bioinformatics, The University of Texas at Austin, Austin, TX 78712, United States of America
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25
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Tuscher JJ, Day JJ. Multigenerational epigenetic inheritance: One step forward, two generations back. Neurobiol Dis 2019; 132:104591. [PMID: 31470104 DOI: 10.1016/j.nbd.2019.104591] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 07/22/2019] [Accepted: 08/26/2019] [Indexed: 02/08/2023] Open
Abstract
Modifications to DNA and histone proteins serve a critical regulatory role in the developing and adult brain, and over a decade of research has established the importance of these "epigenetic" modifications in a wide variety of brain functions across the lifespan. Epigenetic patterns orchestrate gene expression programs that establish the phenotypic diversity of various cellular classes in the central nervous system, play a key role in experience-dependent gene regulation in the adult brain, and are commonly implicated in neurodevelopmental, psychiatric, and neurodegenerative disease states. In addition to these established roles, emerging evidence indicates that epigenetic information can potentially be transmitted to offspring, giving rise to inter- and trans-generational epigenetic inheritance phenotypes. However, our understanding of the cellular events that participate in this information transfer is incomplete, and the ability of this transfer to overcome complete epigenetic reprogramming during embryonic development is highly controversial. This review explores the existing literature on multigenerational epigenetic mechanisms in the central nervous system. First, we focus on the cellular mechanisms that may perpetuate or counteract this type of information transfer, and consider how epigenetic modification in germline and somatic cells regulate important aspects of cellular and organismal development. Next, we review the potential phenotypes resulting from ancestral experiences that impact gene regulatory modifications, including how these changes may give rise to unique metabolic phenotypes. Finally, we discuss several caveats and technical limitations that influence multigenerational epigenetic effects. We argue that studies reporting multigenerational epigenetic changes impacting the central nervous system must be interpreted with caution, and provide suggestions for how epigenetic information transfer can be mechanistically disentangled from genetic and environmental influences on brain function.
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Affiliation(s)
- Jennifer J Tuscher
- Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| | - Jeremy J Day
- Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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Bolton JL, Short AK, Simeone KA, Daglian J, Baram TZ. Programming of Stress-Sensitive Neurons and Circuits by Early-Life Experiences. Front Behav Neurosci 2019; 13:30. [PMID: 30833892 PMCID: PMC6387907 DOI: 10.3389/fnbeh.2019.00030] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 02/04/2019] [Indexed: 12/22/2022] Open
Abstract
Early-life experiences influence brain structure and function long-term, contributing to resilience or vulnerability to stress and stress-related disorders. Therefore, understanding the mechanisms by which early-life experiences program specific brain cells and circuits to shape life-long cognitive and emotional functions is crucial. We identify the population of corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamic paraventricular nucleus (PVN) as a key, early target of early-life experiences. Adverse experiences increase excitatory neurotransmission onto PVN CRH cells, whereas optimal experiences, such as augmented and predictable maternal care, reduce the number and function of glutamatergic inputs onto this cell population. Altered synaptic neurotransmission is sufficient to initiate large-scale, enduring epigenetic re-programming within CRH-expressing neurons, associated with stress resilience and additional cognitive and emotional outcomes. Thus, the mechanisms by which early-life experiences influence the brain provide tractable targets for intervention.
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Affiliation(s)
- Jessica L Bolton
- Departments of Pediatrics, Anatomy/Neurobiology, Neurology, University of California, Irvine, Irvine, CA, United States
| | - Annabel Katherine Short
- Departments of Pediatrics, Anatomy/Neurobiology, Neurology, University of California, Irvine, Irvine, CA, United States
| | - Kristina A Simeone
- Departments of Pediatrics, Anatomy/Neurobiology, Neurology, University of California, Irvine, Irvine, CA, United States
| | - Jennifer Daglian
- Departments of Pediatrics, Anatomy/Neurobiology, Neurology, University of California, Irvine, Irvine, CA, United States
| | - Tallie Z Baram
- Departments of Pediatrics, Anatomy/Neurobiology, Neurology, University of California, Irvine, Irvine, CA, United States
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Ergang BC, Molle RD, Reis RS, Rodrigues DM, Mucellini AB, Toazza R, Cunha ACDA, Silveira PP, Manfro GG, Machado TD. Perceived maternal care is associated with emotional eating in young adults. Physiol Behav 2018; 201:91-94. [PMID: 30578893 DOI: 10.1016/j.physbeh.2018.12.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 12/16/2018] [Accepted: 12/17/2018] [Indexed: 10/27/2022]
Abstract
INTRODUCTION Early life adversity, including the perception of poor quality of maternal care, is associated with long-term metabolic and psychosocial consequences. The negative quality of mother/child relationship is associated with emotional overeating in young children, which is defined by eating in response to emotional arousal states such as fear, anger or anxiety. However, it is not known if this association persists through adolescence. Therefore, we aimed at verifying if maternal care during infancy can influence emotional eating in young adults. METHODS Seventy-five adolescents, residents of Porto Alegre, who participated in the PROTAIA Program (anxiety disorder in childhood and adolescence program), answered the Parental Bonding Instrument (PBI - assessment of perceived maternal care), and the Dutch Eating Behavior Questionnaire (DEBQ). Regression analysis models were built to predict Emotional Eating, a domain of the DEBQ, using maternal care, gender, and anxiety as independent variables. RESULTS The model was statistically significant when adjusted for potential confounders (r2 = 0.272; p < 0.0001). Emotional eating was significantly predicted by levels of maternal care, anxiety and gender (beta = -0.316; p = 0.006). CONCLUSION The results demonstrated a negative association between the quality of maternal care and emotional eating in young adults, suggesting that the early environment could be involved on the development of eating disorders or on the differential eating behavior in adolescents with emotional disorders.
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Affiliation(s)
- Bárbara Cristina Ergang
- Graduação em Nutrição, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2400, CEP 90035-003,Porto Alegre, RS, Brazil.
| | - Roberta Dalle Molle
- Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2400, Largo Eduardo Zaccaro Faraco, CEP 90035-003 Porto Alegre, RS, Brazil
| | - Roberta Sena Reis
- Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2400, Largo Eduardo Zaccaro Faraco, CEP 90035-003 Porto Alegre, RS, Brazil
| | - Danitsa Marcos Rodrigues
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Brazil, Rua Sarmento Leite, 500, Sala 107 (Campus Centro), CEP 90046-900 - Porto Alegre, RS, Brazil
| | - Amanda Brondani Mucellini
- Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2400 - 2° andar, Santana, CEP 90035-003 Porto Alegre, RS, Brazil
| | - Rudinéia Toazza
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Brazil, Rua Sarmento Leite, 500, Sala 107 (Campus Centro), CEP 90046-900 - Porto Alegre, RS, Brazil
| | - Ana Carla de Araújo Cunha
- Graduação em Nutrição, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2400, CEP 90035-003,Porto Alegre, RS, Brazil
| | - Patrícia Pelufo Silveira
- Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2400, Largo Eduardo Zaccaro Faraco, CEP 90035-003 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Brazil, Rua Sarmento Leite, 500, Sala 107 (Campus Centro), CEP 90046-900 - Porto Alegre, RS, Brazil
| | - Gisele Gus Manfro
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Brazil, Rua Sarmento Leite, 500, Sala 107 (Campus Centro), CEP 90046-900 - Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2400 - 2° andar, Santana, CEP 90035-003 Porto Alegre, RS, Brazil
| | - Tania Diniz Machado
- Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2400, Largo Eduardo Zaccaro Faraco, CEP 90035-003 Porto Alegre, RS, Brazil
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Bearer EL, Mulligan BS. Epigenetic Changes Associated with Early Life Experiences: Saliva, A Biospecimen for DNA Methylation Signatures. Curr Genomics 2018; 19:676-698. [PMID: 30532647 PMCID: PMC6225450 DOI: 10.2174/1389202919666180307150508] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 08/21/2017] [Accepted: 03/04/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Adverse Childhood Experiences (ACEs), which include traumatic injury, are associated with poor health outcomes in later life, yet the biological mechanisms mediating this association are unknown. Neurocircuitry, immune system and hormone regulation differ from normal in adults reporting ACEs. These systems could be affected by epigenetic changes, including methylation of cytosine (5mC) in genomic DNA, activated by ACEs. Since 5mC levels influence gene expression and can be long-lasting, altered 5mC status at specific sites or throughout the genome is hypothesized to influence mental and physical outcomes after ACE(s). Human and animal studies support this, with animal models allowing experiments for attributing causality. Here we provide a lengthy introduction and background on 5mC and the impact of early life adversity. OBJECTIVE Next we address the issue of a mixture of cell types in saliva, the most accessible biospecimen for 5mC analysis. Typical human bio-specimens for 5mC analysis include saliva or buccal swabs, whole blood or types of blood cells, tumors and post-mortem brain. In children saliva is the most accessible biospecimen, but contains a mixture of keratinocytes and white blood cells, as do buccal swabs. Even in saliva from the same individual at different time points, cell composition may differ widely. Similar issues affect analysis in blood, where nucleated cells represent a wide array of white blood cell types. Unless variations in ratios of these cells between each sample are included in the analysis, results can be unreliable. METHODS Several different biochemical assays are available to test for site-specific methylation levels genome-wide, each producing different information, with high-density arrays being the easiest to use, and bisulfite whole genome sequencing the most comprehensive. We compare results from different assays and use high-throughput computational processing to deconvolve cell composition in saliva samples. RESULTS Here we present examples demonstrating the critical importance of determining the relative contribution of blood cells versus keratinocytes to the 5mC profile found in saliva. We further describe a strategy to perform a reference-based computational correction for cell composition, and therefore to identify differential methylation patterns due to experience, or for the diagnosis of phenotypes that correlate between traits, such as hormone levels, trauma status and various mental health outcomes. CONCLUSION Specific sites that respond to adversity with altered methylation levels in either blood cells, keratinocytes or both can be identified by this rigorous approach, which will then be useful as diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Elaine L. Bearer
- Address correspondence to this author at the Department of Pathology MSC 08-4640, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA; Tel: 505-272-2404; Fax: 505-272-8084; E-mails: ;
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Hill MN, Eiland L, Lee TTY, Hillard CJ, McEwen BS. Early life stress alters the developmental trajectory of corticolimbic endocannabinoid signaling in male rats. Neuropharmacology 2018; 146:154-162. [PMID: 30496752 DOI: 10.1016/j.neuropharm.2018.11.036] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 11/15/2018] [Accepted: 11/24/2018] [Indexed: 01/19/2023]
Abstract
Early-life stress modulates the development of cortico-limbic circuits and increases vulnerability to adult psychopathology. Given the important stress-buffering role of endocannabinoid (eCB) signaling, we performed a comprehensive investigation of the developmental trajectory of the eCB system and the impact of exposure to early life stress induced by repeated maternal separation (MS; 3 h/day) from postnatal day 2 (PND2) to PND12. Tissue levels of the eCB molecules anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured after MS exposures, as well under basal conditions at juvenile (PND14), adolescent (PND40) and adult (PND70) timepoints in the prefrontal cortex (PFC), amygdala and hippocampus. We also examined the effects of MS on CB1 receptor binding in these three brain regions at PND40 and PND70. AEA content was found to increase from PND2 into adulthood in a linear manner across all brain regions, while 2-AG was found to exhibit a transient spike during the juvenile period (PND12-14) within the amygdala and PFC, but increased in a linear manner across development in the hippocampus. Exposure to MS resulted in bidirectional changes in AEA and 2-AG tissue levels within the amygdala and hippocampus and produced a sustained reduction in eCB function in the hippocampus at adulthood. CB1 receptor densities across all brain regions were generally found to be downregulated later in life following exposure to MS. Collectively, these data demonstrate that early life stress can alter the normative ontogeny of the eCB system, resulting in a sustained deficit in eCB function, particularly within the hippocampus, in adulthood.
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Affiliation(s)
- Matthew N Hill
- Hotchkiss Brain Institute, Departments of Cell Biology & Anatomy and Psychiatry, University of Calgary, Calgary, AB, Canada; Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.
| | - Lisa Eiland
- Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA
| | - Tiffany T Y Lee
- Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA; Department of Psychology, University of British Columbia, Vancouver, BC, Canada
| | - Cecilia J Hillard
- Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Bruce S McEwen
- Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.
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Lemche E. Early Life Stress and Epigenetics in Late-onset Alzheimer's Dementia: A Systematic Review. Curr Genomics 2018; 19:522-602. [PMID: 30386171 PMCID: PMC6194433 DOI: 10.2174/1389202919666171229145156] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Revised: 07/27/2017] [Accepted: 12/12/2017] [Indexed: 11/22/2022] Open
Abstract
Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing. Discussed are relevant ELS studies, and findings from three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance. For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation mechanisms were published for the compiled loci. Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR, INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the well-known LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis, DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT, MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling, TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy.
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Affiliation(s)
- Erwin Lemche
- Section of Cognitive Neuropsychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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Fan SJ, Sun AB, Liu L. Epigenetic modulation during hippocampal development. Biomed Rep 2018; 9:463-473. [PMID: 30546873 DOI: 10.3892/br.2018.1160] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/11/2018] [Indexed: 12/24/2022] Open
Abstract
The hippocampus is located in the limbic system and is vital in learning ability, memory formation and emotion regulation, and is associated with depression, epilepsy and mental retardation in an abnormal developmental situation. Several factors have been found to modulate the development of the hippocampus, and epigenetic modification have a crucial effect in this progress. The present review summarizes the epigenetic modifications, including DNA methylation, histone acetylation, and non-coding RNAs, regulating all stages of hippocampal development, focusing on the growth of Ammons horn and the dentate gyrus in humans and rodents. These modifications may significantly affect hippocampal development and health in addition to cognitive processes.
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Affiliation(s)
- Si-Jing Fan
- Department of Pharmacology, Medical School of Yangtze University, Jingzhou, Hubei 434023, P.R. China.,Laboratory of Neuronal and Brain Diseases Modulation, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - An-Bang Sun
- Laboratory of Neuronal and Brain Diseases Modulation, Yangtze University, Jingzhou, Hubei 434023, P.R. China.,Department of Anatomy, Medical School of Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Lian Liu
- Department of Pharmacology, Medical School of Yangtze University, Jingzhou, Hubei 434023, P.R. China.,Laboratory of Neuronal and Brain Diseases Modulation, Yangtze University, Jingzhou, Hubei 434023, P.R. China
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Köhler JC, Gröger N, Lesse A, Guara Ciurana S, Rether K, Fegert J, Bock J, Braun K. Early-Life Adversity Induces Epigenetically Regulated Changes in Hippocampal Dopaminergic Molecular Pathways. Mol Neurobiol 2018; 56:3616-3625. [PMID: 30173406 PMCID: PMC6476847 DOI: 10.1007/s12035-018-1199-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 06/26/2018] [Indexed: 12/17/2022]
Abstract
Early-life adversity (ELA) represents a major risk factor for the development of behavioral dysfunctions and mental disorders later in life. On the other hand, dependent on type, time point, and duration, ELA exposure can also induce adaptations, which result in better stress coping and resilience later in life. Guided by the hypothesis that chronic exposure to ELA results in dysfunctional brain and behavior, whereas short exposure to ELA may result in resilience, the behavioral and neurobiological consequences of long-term separation stress (LTSS) and short-term separation stress (STSS) were compared in a mouse model for ELA. In line with our hypothesis, we found that LTSS induced depressive-like behavior, whereas STSS reduced depressive-like behavioral symptoms. We then tested the hypothesis that the opposite behavioral outcomes of the two stress paradigms may be mediated by functional, epigenetically regulated changes of dopaminergic modulation in the hippocampal formation. We found that STSS exposure elevated dopamine receptor D1 (DRD1) gene expression and decreased gene expression of its downstream modulator DARPP-32 (32-kDa dopamine- and cAMP-regulated phosphoprotein), which was paralleled by decreased H3 acetylation at its gene promoter region. In contrast, LTSS elevated DARPP-32 gene expression, which was not paralleled by changes in histone acetylation and DRD1 gene expression. These findings indicate that short- and long-term neonatal exposure to ELA induces changes in dopaminergic molecular pathways, some of which are epigenetically regulated and which either alleviate or aggravate depressive-like symptoms later in life.
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Affiliation(s)
- Jana C Köhler
- Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg, Leipziger Straße 44, Bldg. 91, 39120, Magdeburg, Germany.,PG "Epigenetics and Structural Plasticity", Institute of Biology, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - N Gröger
- Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg, Leipziger Straße 44, Bldg. 91, 39120, Magdeburg, Germany
| | - A Lesse
- Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg, Leipziger Straße 44, Bldg. 91, 39120, Magdeburg, Germany
| | - S Guara Ciurana
- Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg, Leipziger Straße 44, Bldg. 91, 39120, Magdeburg, Germany
| | - K Rether
- Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg, Leipziger Straße 44, Bldg. 91, 39120, Magdeburg, Germany
| | - J Fegert
- Klinik für Kinder- und Jugendpsychiatrie/Psychotherapie, Universitätsklinikum Ulm, Ulm, Germany
| | - J Bock
- PG "Epigenetics and Structural Plasticity", Institute of Biology, Otto von Guericke University Magdeburg, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Magdeburg, Germany
| | - Katharina Braun
- Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University Magdeburg, Leipziger Straße 44, Bldg. 91, 39120, Magdeburg, Germany. .,Center for Behavioral Brain Sciences, Magdeburg, Germany.
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Frías-Lasserre D, Villagra CA, Guerrero-Bosagna C. Stress in the Educational System as a Potential Source of Epigenetic Influences on Children's Development and Behavior. Front Behav Neurosci 2018; 12:143. [PMID: 30057532 PMCID: PMC6053942 DOI: 10.3389/fnbeh.2018.00143] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 06/25/2018] [Indexed: 11/24/2022] Open
Abstract
Despite current advances on the relevance of environmental cues and epigenetic mechanisms in biological processes, including behavior, little attention has been paid to the potential link between epigenetic influences and educational sciences. For instance, could the learning environment and stress determine epigenetic marking, affecting students' behavior development? Could this have consequences on educational outcomes? So far, it has been shown that environmental stress influences neurological processes and behavior both in humans and rats. Through epigenetic mechanisms, offspring from stressed individuals develop altered behavior without any exposure to traumatizing experiences. Methylated DNA and noncoding RNAs regulate neurological processes such as synaptic plasticity and brain cortex development in children. The malfunctioning of these processes is associated with several neurological disorders, and these findings open up new avenues for the design of enriched environments for education and therapy. In this article, we discuss current cases of stress and behavioral disorders found in youngsters, and highlight the importance of considering epigenetic processes affecting the development of cognitive abilities and learning within the educational environment and for the development of teaching methodologies.
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Affiliation(s)
- Daniel Frías-Lasserre
- Instituto de Entomología, Universidad Metropolitana de Ciencias de la Educación, Santiago, Chile
| | - Cristian A. Villagra
- Instituto de Entomología, Universidad Metropolitana de Ciencias de la Educación, Santiago, Chile
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Vogel Ciernia A, Laufer BI, Dunaway KW, Mordaunt CE, Coulson RL, Totah TS, Stolzenberg DS, Frahm JC, Singh-Taylor A, Baram TZ, LaSalle JM, Yasui DH. Experience-dependent neuroplasticity of the developing hypothalamus: integrative epigenomic approaches. Epigenetics 2018; 13:318-330. [PMID: 29613827 DOI: 10.1080/15592294.2018.1451720] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Augmented maternal care during the first postnatal week promotes life-long stress resilience and improved memory compared with the outcome of routine rearing conditions. Recent evidence suggests that this programming commences with altered synaptic connectivity of stress sensitive hypothalamic neurons. However, the epigenomic basis of the long-lived consequences is not well understood. Here, we employed whole-genome bisulfite sequencing (WGBS), RNA-sequencing (RNA-seq), and a multiplex microRNA (miRNA) assay to examine the effects of augmented maternal care on DNA cytosine methylation, gene expression, and miRNA expression. A total of 9,439 differentially methylated regions (DMRs) associated with augmented maternal care were identified in male offspring hypothalamus, as well as a modest but significant decrease in global DNA methylation. Differentially methylated and expressed genes were enriched for functions in neurotransmission, neurodevelopment, protein synthesis, and oxidative phosphorylation, as well as known stress response genes. Twenty prioritized genes were identified as highly relevant to the stress resiliency phenotype. This combined unbiased approach enabled the discovery of novel genes and gene pathways that advance our understanding of the epigenomic mechanisms underlying the effects of maternal care on the developing brain.
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Affiliation(s)
- Annie Vogel Ciernia
- a Department of Medical Microbiology and Immunology , University of California , Davis , CA , USA
| | - Benjamin I Laufer
- a Department of Medical Microbiology and Immunology , University of California , Davis , CA , USA
| | - Keith W Dunaway
- a Department of Medical Microbiology and Immunology , University of California , Davis , CA , USA
| | - Charles E Mordaunt
- a Department of Medical Microbiology and Immunology , University of California , Davis , CA , USA
| | - Rochelle L Coulson
- a Department of Medical Microbiology and Immunology , University of California , Davis , CA , USA
| | - Theresa S Totah
- a Department of Medical Microbiology and Immunology , University of California , Davis , CA , USA
| | | | - Jaime C Frahm
- c Center for Comparative Medicine , University of California , Davis , CA , USA
| | - Akanksha Singh-Taylor
- d Department of Pediatrics and Anatomy/Neurobiology , University of California , Irvine , CA , USA
| | - Tallie Z Baram
- d Department of Pediatrics and Anatomy/Neurobiology , University of California , Irvine , CA , USA
| | - Janine M LaSalle
- a Department of Medical Microbiology and Immunology , University of California , Davis , CA , USA.,e UC Davis Genome Center , UC Davis , Davis , CA , USA.,f UC Davis MIND Institute , UC Davis , Davis , CA , USA
| | - Dag H Yasui
- a Department of Medical Microbiology and Immunology , University of California , Davis , CA , USA
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35
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Sandman CA, Curran MM, Davis EP, Glynn LM, Head K, Baram TZ. Cortical Thinning and Neuropsychiatric Outcomes in Children Exposed to Prenatal Adversity: A Role for Placental CRH? Am J Psychiatry 2018; 175:471-479. [PMID: 29495899 PMCID: PMC5930042 DOI: 10.1176/appi.ajp.2017.16121433] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE The authors sought to assess associations among early-life exposure to adversity, the development and maturation of neurons and brain circuits, and neurodevelopmental outcomes. Specifically, they examined whether fetal exposure to placental corticotropin-releasing hormone (CRH), a molecule conveying maternal signals to the fetus, predicts brain growth and neuropsychiatric outcomes in school-age children. METHOD In a large, well-characterized prospective cohort, concentrations of placental CRH (pCRH) in maternal plasma were determined during five intervals during gestation. When the children reached school age, their brain structures were examined using MRI, and emotional and cognitive tests assessing internalizing and externalizing behaviors and attention were administered (N=97, 49 of them girls). RESULTS Levels of pCRH during gestation predicted structural and functional brain outcomes in children. Specifically, fetal exposure to elevated pCRH levels was associated with thinning of selective cortical regions and with commensurate cognitive and emotional deficits. The relations among fetal exposure to pCRH, cortical thinning, and childhood function were sex specific. CONCLUSIONS In view of the established effects of CRH on maturation and arborization of cortical neurons, and the major contribution of dendrites to cortical volume, these findings position pCRH as an important mediator of the consequences of early-life adversity on neuropsychiatric outcomes.
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Affiliation(s)
- Curt A Sandman
- From the Departments of Psychiatry and Human Behavior, Anatomy and Neurobiology, Pediatrics, and Neurology, University of California, Irvine; the Department of Psychology, University of Denver, Denver; and the Department of Psychology, Chapman University, Orange, Calif
| | - Megan M Curran
- From the Departments of Psychiatry and Human Behavior, Anatomy and Neurobiology, Pediatrics, and Neurology, University of California, Irvine; the Department of Psychology, University of Denver, Denver; and the Department of Psychology, Chapman University, Orange, Calif
| | - Elysia Poggi Davis
- From the Departments of Psychiatry and Human Behavior, Anatomy and Neurobiology, Pediatrics, and Neurology, University of California, Irvine; the Department of Psychology, University of Denver, Denver; and the Department of Psychology, Chapman University, Orange, Calif
| | - Laura M Glynn
- From the Departments of Psychiatry and Human Behavior, Anatomy and Neurobiology, Pediatrics, and Neurology, University of California, Irvine; the Department of Psychology, University of Denver, Denver; and the Department of Psychology, Chapman University, Orange, Calif
| | - Kevin Head
- From the Departments of Psychiatry and Human Behavior, Anatomy and Neurobiology, Pediatrics, and Neurology, University of California, Irvine; the Department of Psychology, University of Denver, Denver; and the Department of Psychology, Chapman University, Orange, Calif
| | - Tallie Z Baram
- From the Departments of Psychiatry and Human Behavior, Anatomy and Neurobiology, Pediatrics, and Neurology, University of California, Irvine; the Department of Psychology, University of Denver, Denver; and the Department of Psychology, Chapman University, Orange, Calif
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Abstract
Purpose of Review Psychological stress can impact memory systems in several different ways. In individuals with healthy defense and coping systems, stress results in the formation of negatively valenced memories whose ability to induce emotional and somatic distress subsides with time. Vulnerable individuals, however, go on to develop stress-related disorders such as post-traumatic stress disorder (PTSD) and suffer from significant memory abnormalities. Whether expressed as intrusive trauma memories, partial amnesia, or dissociative amnesia, such abnormalities are thought to be the core source of patients' symptoms, which are often debilitating and implicate an entire socio-cognitive-affective spectrum. Recent Findings With this in mind, and focusing on stress-responsive hippocampal microcircuits, this article highlights recent advances in the neurobiology of memory that allow us to (1) isolate and visualize memory circuits, (2) change their activity using genetic tools and state-dependent manipulations, and (3) directly examine their impact on socio-affective circuits and global network connectivity. By integrating these approaches, we are now in a position to address important questions that have troubled psychiatry for a long time-questions such as are traumatic memories special, and why are stress effects on memory diverse. Summary Furthering our fundamental understanding of memory in the framework of adaptive and maladaptive stress responses has the potential to boost the development of new treatments that can benefit patients suffering from psychological trauma.
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37
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Langenhof MR, Komdeur J. Why and how the early-life environment affects development of coping behaviours. Behav Ecol Sociobiol 2018; 72:34. [PMID: 29449757 PMCID: PMC5805793 DOI: 10.1007/s00265-018-2452-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 01/19/2018] [Accepted: 01/25/2018] [Indexed: 01/02/2023]
Abstract
Understanding the ways in which individuals cope with threats, respond to challenges, make use of opportunities and mediate the harmful effects of their surroundings is important for predicting their ability to function in a rapidly changing world. Perhaps one of the most essential drivers of coping behaviour of adults is the environment experienced during their early-life development. Although the study of coping, defined as behaviours displayed in response to environmental challenges, has a long and rich research history in biology, recent literature has repeatedly pointed out that the processes through which coping behaviours develop in individuals are still largely unknown. In this review, we make a move towards integrating ultimate and proximate lines of coping behaviour research. After broadly defining coping behaviours (1), we review why, from an evolutionary perspective, the development of coping has become tightly linked to the early-life environment (2), which relevant developmental processes are most important in creating coping behaviours adjusted to the early-life environment (3), which influences have been shown to impact those developmental processes (4) and what the adaptive significance of intergenerational transmission of coping behaviours is, in the context of behavioural adaptations to a fast changing world (5). Important concepts such as effects of parents, habitat, nutrition, social group and stress are discussed using examples from empirical studies on mammals, fish, birds and other animals. In the discussion, we address important problems that arise when studying the development of coping behaviours and suggest solutions.
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Affiliation(s)
- M. Rohaa Langenhof
- Behavioural Physiology and Ecology Group, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands
| | - Jan Komdeur
- Behavioural Physiology and Ecology Group, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands
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38
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Di Segni M, Andolina D, Luchetti A, Babicola L, D'Apolito LI, Pascucci T, Conversi D, Accoto A, D'Amato FR, Ventura R. Unstable Maternal Environment Affects Stress Response in Adult Mice in a Genotype-Dependent Manner. Cereb Cortex 2018; 26:4370-4380. [PMID: 26400917 DOI: 10.1093/cercor/bhv204] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Early postnatal events exert powerful effects on development, inducing persistent functional alterations in different brain network, such as the catecholamine prefrontal-accumbal system, and increasing the risk of developing psychiatric disorders later in life. However, a vast body of literature shows that the interaction between genetic factors and early environmental conditions is crucial for expression of psychopathologies in adulthood. We evaluated the long-lasting effects of a repeated cross-fostering (RCF) procedure in 2 inbred strains of mice (C57BL/6J, DBA/2), known to show a different susceptibility to the development and expression of stress-induced psychopathologies. Coping behavior (forced swimming test) and preference for a natural reinforcing stimulus (saccharine preference test) were assessed in adult female mice of both genotypes. Moreover, c-Fos stress-induced activity was assessed in different brain regions involved in stress response. In addition, we evaluated the enduring effects of RCF on catecholamine prefrontal-accumbal response to acute stress (restraint) using, for the first time, a new "dual probes" in vivo microdialysis procedure in mouse. RCF experience affects behavioral and neurochemical responses to acute stress in adulthood in opposite direction in the 2 genotypes, leading DBA mice toward an "anhedonic-like" phenotype and C57 mice toward an increased sensitivity for a natural reinforcing stimulus.
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Affiliation(s)
- Matteo Di Segni
- Santa Lucia Foundation, 00143 Rome, Italy.,Department of Psychology and "Daniel Bovet" Center and
| | - Diego Andolina
- Santa Lucia Foundation, 00143 Rome, Italy.,Department of Science and Biomedical Technologies, University of L'Aquila, 67010 L'Aquila, Italy
| | - Alessandra Luchetti
- Cell Biology and Neurobiology Institute, National Research Council, 00143 Rome, Italy
| | - Lucy Babicola
- Department of Psychology and "Daniel Bovet" Center and
| | - Lina Ilaras D'Apolito
- Department of Biology and Biotechnology "Charles Darwin,""La Sapienza" University, 00181 Rome, Italy
| | - Tiziana Pascucci
- Santa Lucia Foundation, 00143 Rome, Italy.,Department of Psychology and "Daniel Bovet" Center and
| | - David Conversi
- Santa Lucia Foundation, 00143 Rome, Italy.,Department of Psychology and "Daniel Bovet" Center and
| | | | - Francesca R D'Amato
- Cell Biology and Neurobiology Institute, National Research Council, 00143 Rome, Italy.,Institut Universitaire en Santé Mentale de Québec, Laval University, Quebec, Canada
| | - Rossella Ventura
- Santa Lucia Foundation, 00143 Rome, Italy.,Department of Psychology and "Daniel Bovet" Center and
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NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience. Mol Psychiatry 2018; 23:648-657. [PMID: 28070121 PMCID: PMC5503824 DOI: 10.1038/mp.2016.240] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 11/05/2016] [Accepted: 11/14/2016] [Indexed: 01/12/2023]
Abstract
Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent re-programming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.
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40
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Sensitivity to cocaine in adult mice is due to interplay between genetic makeup, early environment and later experience. Neuropharmacology 2017; 125:87-98. [DOI: 10.1016/j.neuropharm.2017.07.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 07/04/2017] [Accepted: 07/14/2017] [Indexed: 12/31/2022]
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41
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Ishikawa C, Shiga T. The postnatal 5-HT 1A receptor regulates adult anxiety and depression differently via multiple molecules. Prog Neuropsychopharmacol Biol Psychiatry 2017; 78:66-74. [PMID: 28483674 DOI: 10.1016/j.pnpbp.2017.04.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 04/14/2017] [Accepted: 04/14/2017] [Indexed: 11/16/2022]
Abstract
Serotonin (5-HT) and the 5-HT1A receptor during development are known to modulate anxiety and depression in later life. However, the brain mechanisms linking the postnatal 5-HT system and adult behavior remain unknown. Here, we examined the effects of pharmacological 5-HT1A receptor activation during the postnatal period on anxiety and depression-like behavior in adult BALB/c male mice. To elucidate the underlying mechanisms, we measured mRNA expression of the 5-HT1A receptor, brain-derived neurotrophic factor (BDNF), GABAA receptor subunits, and AMPA receptor subunits in the medial prefrontal cortex (mPFC), amygdala, and hippocampus. Treatment with the selective 5-HT reuptake inhibitor (fluoxetine) and 5-HT1A receptor agonist (8-OH-DPAT) during the postnatal period decreased anxiety-like behavior in adulthood, whereas only 8-OH-DPAT treatment increased depression-like behavior. Concomitantly with the behavioral effects, postnatal treatment with fluoxetine and 8-OH-DPAT decreased the mRNA expression of the GABAA receptor α3 subunit in the mPFC and ventral hippocampus in adulthood, while 8-OH-DPAT, but not fluoxetine, decreased the mRNA expression of the 5-HT1A receptor and BDNF in the mPFC and the GABAA receptor α2 subunit in the mPFC and ventral hippocampus. On the basis of the correlative changes between behavior and mRNA expression, these results suggest that the GABAA receptor α3 subunit in the mPFC and ventral hippocampus may regulate anxiety-like behavior. In contrast, depression-like behavior may be regulated by the 5-HT1A receptor and BDNF in the mPFC and by the GABAA receptor α2 subunit in the mPFC and ventral hippocampus. In summary, activation of the 5-HT1A receptor during the postnatal period may reduce anxiety levels, but increase depression levels during adulthood via different multiple molecules in the mPFC and ventral hippocampus.
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Affiliation(s)
- Chihiro Ishikawa
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
| | - Takashi Shiga
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan; Department of Neurobiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan.
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42
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Dirven BCJ, Homberg JR, Kozicz T, Henckens MJAG. Epigenetic programming of the neuroendocrine stress response by adult life stress. J Mol Endocrinol 2017; 59:R11-R31. [PMID: 28400482 DOI: 10.1530/jme-17-0019] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 03/17/2017] [Indexed: 12/11/2022]
Abstract
The hypothalamic-pituitary-adrenal (HPA) axis is critically involved in the neuroendocrine regulation of stress adaptation, and the restoration of homeostasis following stress exposure. Dysregulation of this axis is associated with stress-related pathologies like major depressive disorder, post-traumatic stress disorder, panic disorder and chronic anxiety. It has long been understood that stress during early life can have a significant lasting influence on the development of the neuroendocrine system and its neural regulators, partially by modifying epigenetic regulation of gene expression, with implications for health and well-being in later life. Evidence is accumulating that epigenetic plasticity also extends to adulthood, proposing it as a mechanism by which psychological trauma later in life can long-lastingly affect HPA axis function, brain plasticity, neuronal function and behavioural adaptation to neuropsychological stress. Further corroborating this claim is the phenomenon that these epigenetic changes correlate with the behavioural consequences of trauma exposure. Thereby, epigenetic modifications provide a putative molecular mechanism by which the behavioural phenotype and transcriptional/translational potential of genes involved in HPA axis regulation can change drastically in response to environmental challenges, and appear an important target for treatment of stress-related disorders. However, improved insight is required to increase their therapeutic (drug) potential. Here, we provide an overview of the growing body of literature describing the epigenetic modulation of the (primarily neuroendocrine) stress response as a consequence of adult life stress and interpret the implications for, and the challenges involved in applying this knowledge to, the identification and treatment of stress-related psychiatric disorders.
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MESH Headings
- Animals
- Anxiety/genetics
- Anxiety/metabolism
- Anxiety/physiopathology
- Brain/metabolism
- Brain/physiopathology
- DNA Methylation
- Depressive Disorder, Major/genetics
- Depressive Disorder, Major/metabolism
- Depressive Disorder, Major/physiopathology
- Epigenesis, Genetic
- Histones/genetics
- Histones/metabolism
- Homeostasis
- Humans
- Hypothalamo-Hypophyseal System/metabolism
- Hypothalamo-Hypophyseal System/physiopathology
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Neurons/metabolism
- Neurons/pathology
- Neurotransmitter Agents/metabolism
- Pituitary-Adrenal System/metabolism
- Pituitary-Adrenal System/physiopathology
- Receptors, Glucocorticoid/genetics
- Receptors, Glucocorticoid/metabolism
- Receptors, Mineralocorticoid/genetics
- Receptors, Mineralocorticoid/metabolism
- Stress, Psychological/genetics
- Stress, Psychological/metabolism
- Stress, Psychological/physiopathology
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Affiliation(s)
- B C J Dirven
- Department of AnatomyDonders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Cognitive NeuroscienceDonders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - J R Homberg
- Department of Cognitive NeuroscienceDonders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - T Kozicz
- Department of AnatomyDonders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - M J A G Henckens
- Department of Cognitive NeuroscienceDonders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
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43
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Naninck EFG, Oosterink JE, Yam K, Vries LP, Schierbeek H, Goudoever JB, Verkaik‐Schakel R, Plantinga JA, Plosch T, Lucassen PJ, Korosi A. Early micronutrient supplementation protects against early stress‐induced cognitive impairments. FASEB J 2016; 31:505-518. [DOI: 10.1096/fj.201600834r] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 10/04/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Eva F. G. Naninck
- Swammerdam Institute for Life Sciences, Center for NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands
| | - J. Efraim Oosterink
- Department of Mother and Child, Emma Children's HospitalAcademic Medical CenterAmsterdamThe Netherlands
| | - Kit‐Yi Yam
- Swammerdam Institute for Life Sciences, Center for NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands
| | - Lennart P. Vries
- Swammerdam Institute for Life Sciences, Center for NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands
| | - Henk Schierbeek
- Department of Mother and Child, Emma Children's HospitalAcademic Medical CenterAmsterdamThe Netherlands
| | - Johannes B. Goudoever
- Department of Mother and Child, Emma Children's HospitalAcademic Medical CenterAmsterdamThe Netherlands
| | - Rikst‐Nynke Verkaik‐Schakel
- Department of Obstetrics and GynecologyUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | - Josèe A. Plantinga
- Department of Obstetrics and GynecologyUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | - Torsten Plosch
- Department of Obstetrics and GynecologyUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | - Paul J. Lucassen
- Swammerdam Institute for Life Sciences, Center for NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands
| | - Aniko Korosi
- Swammerdam Institute for Life Sciences, Center for NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands
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44
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Machado TD, Dalle Molle R, Reis RS, Rodrigues DM, Mucellini AB, Minuzzi L, Franco AR, Buchweitz A, Toazza R, Ergang BC, Cunha ACDA, Salum GA, Manfro GG, Silveira PP. Interaction between perceived maternal care, anxiety symptoms, and the neurobehavioral response to palatable foods in adolescents. Stress 2016; 19:287-94. [PMID: 27295200 DOI: 10.1080/10253890.2016.1191464] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Studies in rodents have shown that early life trauma leads to anxiety, increased stress responses to threatening situations, and modifies food intake in a new environment. However, these associations are still to be tested in humans. This study aimed to verify complex interactions among anxiety diagnosis, maternal care, and baseline cortisol on food intake in a new environment in humans. A community sample of 32 adolescents and young adults was evaluated for: psychiatric diagnosis using standardized interviews, maternal care using the Parental Bonding Inventory (PBI), caloric consumption in a new environment (meal choice at a snack bar), and salivary cortisol. They also performed a brain fMRI task including the visualization of palatable foods vs. neutral items. The study found a three-way interaction between anxiety diagnosis, maternal care, and baseline cortisol levels on the total calories consumed (snacks) in a new environment. This interaction means that for those with high maternal care, there were no significant associations between cortisol levels and food intake in a new environment. However, for those with low maternal care and who have an anxiety disorder (affected), cortisol was associated with higher food intake; whereas for those with low maternal care and who did not have an anxiety disorder (resilient), cortisol was negatively associated with lower food intake. In addition, higher anxiety symptoms were associated with decreased activation in the superior and middle frontal gyrus when visualizing palatable vs. neutral items in those reporting high maternal care. These results in humans mimic experimental research findings and demonstrate that a combination of anxiety diagnosis and maternal care moderate the relationship between the HPA axis functioning, anxiety, and feeding behavior in adolescents and young adults.
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Affiliation(s)
- Tania Diniz Machado
- a Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre , Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
| | - Roberta Dalle Molle
- a Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre , Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
| | - Roberta Sena Reis
- a Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre , Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
| | - Danitsa Marcos Rodrigues
- b Programa de Pós-Graduação em Neurociências , Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
| | - Amanda Brondani Mucellini
- c Programa de Pós-Graduação em Ciências Médicas: Psiquiatria. Faculdade de Medicina , Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
| | - Luciano Minuzzi
- d Department of Psychiatry and Behavioural Neurosciences , McMaster University , Hamilton , ON , Canada
| | - Alexandre Rosa Franco
- e PUCRS, Instituto do Cérebro (InsCer), Programa de Pós-Graduação em Medicina e Ciências da Saúde , Porto Alegre , Brazil
- f PUCRS, Faculdade de Medicina , Programa de Pós-Graduação em Medicina e Ciências da Saúde , Porto Alegre , Brazil
- g PUCRS, Faculdade de Engenharia , Programa de Pós-Graduação em Engenharia Elétrica , Porto Alegre , Brazil
| | - Augusto Buchweitz
- e PUCRS, Instituto do Cérebro (InsCer), Programa de Pós-Graduação em Medicina e Ciências da Saúde , Porto Alegre , Brazil
- f PUCRS, Faculdade de Medicina , Programa de Pós-Graduação em Medicina e Ciências da Saúde , Porto Alegre , Brazil
- h PUCRS, Faculdade de Letras , Programa de Pós-Graduação em Letras , Linguística , Porto Alegre , Brazil
| | - Rudineia Toazza
- b Programa de Pós-Graduação em Neurociências , Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
| | - Bárbara Cristina Ergang
- i Graduação em Nutrição: Faculdade de Medicina , Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
| | - Ana Carla de Araújo Cunha
- i Graduação em Nutrição: Faculdade de Medicina , Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
| | - Giovanni Abrahão Salum
- c Programa de Pós-Graduação em Ciências Médicas: Psiquiatria. Faculdade de Medicina , Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
| | - Gisele Gus Manfro
- b Programa de Pós-Graduação em Neurociências , Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
- c Programa de Pós-Graduação em Ciências Médicas: Psiquiatria. Faculdade de Medicina , Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
| | - Patrícia Pelufo Silveira
- a Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre , Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
- b Programa de Pós-Graduação em Neurociências , Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
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Jia M, Liu WX, Yang JJ, Xu N, Xie ZM, Ju LS, Ji MH, Martynyuk AE, Yang JJ. Role of histone acetylation in long-term neurobehavioral effects of neonatal Exposure to sevoflurane in rats. Neurobiol Dis 2016; 91:209-220. [PMID: 27001149 DOI: 10.1016/j.nbd.2016.03.017] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 03/11/2016] [Accepted: 03/17/2016] [Indexed: 01/16/2023] Open
Abstract
Human studies, and especially laboratory studies, provide evidence that early life exposure to general anesthesia may affect neurocognitive development via largely unknown mechanisms. We explored whether hippocampal histone acetylation had a role in neurodevelopmental effects of sevoflurane administered to neonatal rats. Male Sprague-Dawley rats were exposed to 3% sevoflurane or were subjected to maternal separation only for 2h daily at postnatal days 6, 7, and 8. The histone deacetylase inhibitor, sodium butyrate (250mg/kg, intraperitoneally), or saline was administered starting 2h prior to anesthesia or maternal separation and continued daily until the end of behavioral tests, which were performed between postnatal days 33 and 50. Upon completion of the behavioral tests, the brain tissues were harvested for further analysis. Rats neonatally exposed to sevoflurane exhibited decreased freezing time in the fear conditioning contextual test and increased escape latency, decreased time in target quadrant, and number of platform crossings in the Morris water maze test. The sevoflurane-exposed rats had lower hippocampal density of dendritic spines, reduced levels of the brain-derived neurotrophic factor, c-fos protein, microtubule-associated protein 2, synapsin1, postsynaptic density protein 95, pCREB/CREB, CREB binding protein, and acetylated histones H3 and H4, and increased levels of histone deacetylases 3 and 8. These neurobehavioral abnormalities were normalized in the sevoflurane-exposed rats treated with sodium butyrate. Our findings provide evidence that neonatal exposure to sevoflurane induces neurobehavioral abnormalities and long-lasting alterations in histone acetylation; normalization of histone acetylation may alleviate the neurodevelopmental side effects of the anesthetic.
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Affiliation(s)
- Min Jia
- Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Wen-Xue Liu
- Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Jiao-Jiao Yang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China
| | - Ning Xu
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China
| | - Ze-Min Xie
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China
| | - Ling-Sha Ju
- Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Mu-Huo Ji
- Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida, Gainesville, Florida, USA.,McKnight Brain Institute, University of Florida, Gainesville, Florida, USA
| | - Jian-Jun Yang
- Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.,Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China
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Moreno Gudiño H, Carías Picón D, de Brugada Sauras I. Dietary choline during periadolescence attenuates cognitive damage caused by neonatal maternal separation in male rats. Nutr Neurosci 2015; 20:327-335. [DOI: 10.1080/1028415x.2015.1126444] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Hayarelis Moreno Gudiño
- Department of Experimental Psychology and Physiology of behavior, University of Granada, Spain
- Department of Biological and Biochemical Processes, Simón Bolívar University, Caracas, Venezuela
| | - Diamela Carías Picón
- Department of Biological and Biochemical Processes, Simón Bolívar University, Caracas, Venezuela
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Abstract
In human adults, learning and memory under acute stress are characterized by an increased use of rigid habitual response strategies at the cost of flexible cognitive strategies. The immediate effects of stress on cognitive functioning early in life are not well understood. Here we show experimentally that acute stress leads human infants to perform habitual behavior rigidly. We found that 15-mo-old infants exposed to stress thereafter kept performing a previously effective action, even after the action suddenly became ineffective. Infants in a no-stress control group flexibly adjusted their behavior by disengaging from the newly ineffective action in favor of exploring an alternative action. This finding demonstrates that stress impairs infants' ability to adjust their behavior to changing circumstances.
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Pusalkar M, Suri D, Kelkar A, Bhattacharya A, Galande S, Vaidya VA. Early stress evokes dysregulation of histone modifiers in the medial prefrontal cortex across the life span. Dev Psychobiol 2015; 58:198-210. [PMID: 26395029 DOI: 10.1002/dev.21365] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 09/11/2015] [Indexed: 12/12/2022]
Abstract
Early stress has been hypothesized to recruit epigenetic mechanisms to mediate persistent molecular, cellular, and behavioral changes. Here, we have examined the consequence of the early life stress of maternal separation (ES) on the gene expression of several histone modifiers that regulate histone acetylation and methylation within the medial prefrontal cortex (mPFC), a key limbic brain region that regulates stress responses and mood-related behavior. ES animals exhibit gene regulation of both writer (histone acetyltransferases and histone methyltransferases) and eraser (histone deacetylases and histone lysine demethylases) classes of histone modifiers. While specific histone modifiers (Kat2a, Smyd3, and Suv420h1) and the sirtuin, Sirt4 were downregulated across life within the mPFC of ES animals, namely at postnatal Day 21, 2 months, and 15 months of age, we also observed gene regulation restricted to these specific time points. Despite the decline noted in expression of several histone modifiers within the mPFC following ES, this was not accompanied by any change in global or residue-specific H3 acetylation and methylation. Our findings indicate that ES results in the regulation of several histone modifiers within the mPFC across life, and suggest that such perturbations may contribute to the altered prefrontal structural and functional plasticity observed following early adversity.
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Affiliation(s)
- Madhavi Pusalkar
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Deepika Suri
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Ashwin Kelkar
- Centre of Excellence in Epigenetics, Indian Institute of Science Education and Research, Pune, Maharashtra, India
| | - Amrita Bhattacharya
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Sanjeev Galande
- Centre of Excellence in Epigenetics, Indian Institute of Science Education and Research, Pune, Maharashtra, India
| | - Vidita A Vaidya
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India.
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50
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The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases. eNeuro 2015; 2:eN-REV-0010-15. [PMID: 26465007 PMCID: PMC4596026 DOI: 10.1523/eneuro.0010-15.2015] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 06/11/2015] [Accepted: 06/18/2015] [Indexed: 12/21/2022] Open
Abstract
REST [RE1-silencing transcription factor (also called neuron-restrictive silencer factor)] is known to repress thousands of possible target genes, many of which are neuron specific. To date, REST repression has been investigated mostly in stem cells and differentiating neurons. Current evidence demonstrates its importance in adult neurons as well. Low levels of REST, which are acquired during differentiation, govern the expression of specific neuronal phenotypes. REST-dependent genes encode important targets, including transcription factors, transmitter release proteins, voltage-dependent and receptor channels, and signaling proteins. Additional neuronal properties depend on miRNAs expressed reciprocally to REST and on specific splicing factors. In adult neurons, REST levels are not always low. Increases occur during aging in healthy humans. Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity. Whether neuronal increases in REST are protective or detrimental remains a subject of debate. Examples of CA1 hippocampal neuron protection upon depolarization, and of neurodegeneration upon glutamate treatment and hypoxia have been reported. REST participation in psychiatric and neurological diseases has been shown, especially in Alzheimer’s disease and Huntington’s disease, as well as epilepsy. Distinct, complex roles of the repressor in these different diseases have emerged. In conclusion, REST is certainly very important in a large number of conditions. We suggest that the conflicting results reported for the role of REST in physiology, pathology, and disease depend on its complex, direct, and indirect actions on many gene targets and on the diverse approaches used during the investigations.
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