Maternal Separation Enhances Conditioned Fear and Decreases the mRNA Levels of the Neurotensin Receptor 1 Gene with Hypermethylation of This Gene in the Rat Amygdala

Toda, Hiroyuki; Boku, Shuken; Nakagawa, Shin; Inoue, Takeshi; Kato, Akira; Takamura, Naoki; Song, Ning; Nibuya, Masashi; Koyama, Tsukasa; Kusumi, Ichiro

doi:10.1371/journal.pone.0097421

Cited by 51 publications

(39 citation statements)

References 67 publications

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“…Postnatal maternal separation alters H3K27 tri-methylation at the gene encoding N-methyl-D-aspartate receptor (Grin2b) in the hippocampus with implications for learning and memory (Rodenas-Ruano et al, 2012). Within the amygdala, maternal separation has been found to increase DNA methylation of the neurotensin receptor (Ntsr1) associated with reduced Ntsr1 mRNA and increased freezing behavior during fear conditioning (Toda et al, 2014). In the pituitary, long-term decreases in cytosine methylation of the proopiomelanocortin (Pomc) gene, a key factor in neuroendocrine stress responses, is observed in maternally separated mice .…”

Section: Maternal Neglect In Rodents and Primatesmentioning

confidence: 99%

Early-Life Experience, Epigenetics, and the Developing Brain

Kundaković

Champagne

2014

Neuropsychopharmacol

253

182

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Development is a dynamic process that involves interplay between genes and the environment. In mammals, the quality of the postnatal environment is shaped by parent-offspring interactions that promote growth and survival and can lead to divergent developmental trajectories with implications for later-life neurobiological and behavioral characteristics. Emerging evidence suggests that epigenetic factors (ie, DNA methylation, posttranslational histone modifications, and small noncoding RNAs) may have a critical role in these parental care effects. Although this evidence is drawn primarily from rodent studies, there is increasing support for these effects in humans. Through these molecular mechanisms, variation in risk of psychopathology may emerge, particularly as a consequence of early-life neglect and abuse. Here we will highlight evidence of dynamic epigenetic changes in the developing brain in response to variation in the quality of postnatal parent-offspring interactions. The recruitment of epigenetic pathways for the biological embedding of early-life experience may also have transgenerational consequences and we will describe and contrast two routes through which this transmission can occur: experience dependent vs germline inheritance. Finally, we will speculate regarding the future directions of epigenetic research and how it can help us gain a better understanding of the developmental origins of psychiatric dysfunction.

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Section: Maternal Neglect In Rodents and Primatesmentioning

confidence: 99%

Early-Life Experience, Epigenetics, and the Developing Brain

Kundaković

Champagne

2014

Neuropsychopharmacol

253

182

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“…A third psychological stressor is maternal separation, which more closely models the increased incidence of PTSD in individuals that have experienced childhood stress. This procedure, which involves separation of pups from the mother for a few hours each day in early postnatal life, enhances contextual fear memory in adulthood (Toda et al 2014).…”

Section: Stress-enhanced Fear Learning Modelsmentioning

confidence: 99%

“…Some SEFL protocols use an early-life stressor, such as maternal separation, rather than an acute stressor in adulthood, and find that it prevents the infantile amnesia that typically occurs when fear conditioning is performed in early life (Callaghan et al 2013;Quinn et al 2014). Unfortunately, the effects of early-life stress on fear conditioning performed in adulthood are mixed, with some reporting an enhancement (Toda et al 2014) and others an impairment (Stevenson et al 2009). Additional work is needed to clarify the parameters of an SEFL model that reflects the effect of early-life adversity on later trauma.…”

Section: The Neuroepigenetics Of Stress-enhanced Fear Learningmentioning

confidence: 99%

“…Additional work is needed to clarify the parameters of an SEFL model that reflects the effect of early-life adversity on later trauma. However, once established, studying the underlying epigenetic mechanisms will be extremely important (Toda et al 2014). Another SEFL approach has been to use Long Evans rats, an outbred strain, to identify the individual rats that are susceptible or resilient to the effects of stress in adulthood on fear conditioning (Rau et al 2005).…”

Section: The Neuroepigenetics Of Stress-enhanced Fear Learningmentioning

confidence: 99%

“…Ntsr1 encodes the receptor for neurotensin 1, an endogenous neuropeptide implicated in anxiety and densely expressed in the amygdala. The authors report that an SEFL model involving maternal separation was associated with decreased Ntsr1 mRNA and increased methylation of its promoter (Toda et al 2014). Fkbp5 is a crucial regulator of glucocorticoid receptor (GR) and in turn, the sensitivity of the hypothalamic pituitary axis that mediates stress responses.…”

Section: The Neuroepigenetics Of Stress-enhanced Fear Learningmentioning

confidence: 99%

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The potential of epigenetics in stress-enhanced fear learning models of PTSD

et al. 2016

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Prolonged distress and dysregulated memory processes are the core features of post-traumatic stress disorder (PTSD) and represent the debilitating, persistent nature of the illness. However, the neurobiological mechanisms underlying the expression of these symptoms are challenging to study in human patients. Stress-enhanced fear learning (SEFL) paradigms, which encompass both stress and memory components in rodents, are emerging as valuable preclinical models of PTSD. Rodent models designed to study the long-term mechanisms of either stress or fear memory alone have identified a critical role for numerous epigenetic modifications to DNA and histone proteins. However, the epigenetic modifications underlying SEFL remain largely unknown. This review will provide a brief overview of the epigenetic modifications implicated in stress and fear memory independently, followed by a description of existing SEFL models and the few epigenetic mechanisms found to date to underlie SEFL. The results of the animal studies discussed here highlight neuroepigenetics as an essential area for future research in the context of PTSD through SEFL studies, because of its potential to identify novel candidates for neurotherapeutics targeting stress-induced pathogenic memories.Post-traumatic stress disorder (PTSD) is triggered by experiencing or witnessing a traumatic event and is characterized by pathogenic memory (e.g., recurrent, involuntary memories that trigger intense stress), avoidance of reminders, hyperarousal and reactivity, negative mood, cognitive alterations, and a persistence of symptoms for at least 1 mo. Although only a fraction of people exposed to trauma develop PTSD, a history of stress exposure prior to witnessing a traumatic event increases the risk (Breslau et al. 2014). Therefore, some animal models of PTSD use multidimensional stress and fear memory paradigms to model the disorder. In stress-enhanced fear learning (SEFL), a rodent is exposed to a stressor or combination of stressors prior to undergoing classical fear conditioning. Models that utilize SEFL closely reproduce many core symptoms of PTSD, including enhanced fear learning, generalized anxiety, heightened startle, and impaired extinction.

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RDoC and translational perspectives on the genetics of trauma‐related psychiatric disorders

Montalvo-Ortiz

Hudziak

Kaufman

2015

American J of Med Genetics Pt B

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Individuals with a history of child abuse are at high risk for depression, anxiety disorders, aggressive behavior, and substance use problems. The goal of this paper is to review studies of the genetics of these stress-related psychiatric disorders. An informative subset of studies that examined candidate gene by environment (GxE) predictors of these psychiatric problems in individuals maltreated as children is reviewed, together with extant genome wide association studies (GWAS). Emerging findings on epigenetic changes associated with adverse early experiences are also reviewed. Meta-analytic support and replicated findings are evident for several genetic risk factors; however, extant research suggests the effects are pleiotropic. Genetic factors are not associated with distinct psychiatric disorders, but rather diverse clinical phenotypes. Research also suggests adverse early life experiences are associated with changes in gene expression of multiple known candidate genes, genes involved in DNA transcription and translation, and genes necessary for brain circuitry development, with changes in gene expression reported in key brain structures implicated in the pathophysiology of psychiatric and substance use disorders. The finding of pleiotropy highlights the value of using the Research Domain Criteria (RDoC) framework in future studies of the genetics of stress-related psychiatric disorders, and not trying simply to link genes to multifaceted clinical syndromes, but to more limited phenotypes that map onto distinct neural circuits. Emerging work in the field of epigenetics also suggests that translational studies that integrate numerous unbiased genome-wide approaches will help to further unravel the genetics of stress-related psychiatric disorders.

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Maternal Separation Enhances Conditioned Fear and Decreases the mRNA Levels of the Neurotensin Receptor 1 Gene with Hypermethylation of This Gene in the Rat Amygdala

Cited by 51 publications

References 67 publications

Early-Life Experience, Epigenetics, and the Developing Brain

Early-Life Experience, Epigenetics, and the Developing Brain

The potential of epigenetics in stress-enhanced fear learning models of PTSD

RDoC and translational perspectives on the genetics of trauma‐related psychiatric disorders

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