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Introduction: Adolescence, a critical phase of human neurodevelopment, is marked by a tremendous reorganization of the brain and accompanied by improved cognitive performance. This development is driven in part by gene expression, which in turn is partly regulated by DNA methylation (DNAm). Methods: We collected brain imaging, cognitive assessments, and DNAm in a longitudinal cohort of approximately 200 typically developing participants, aged 9-14. This data, from three time points roughly 1 year apart, was used to explore the relationships between seven cytosine-phosphate-guanine (CpG) sites in genes highly expressed in brain tissues (GRIN2D, GABRB3, KCNC1, SLC12A9, CHD5, STXBP5, and NFASC), seven networks of grey matter (GM) volume change, and scores from seven cognitive tests. Results: The demethylation of the CpGs as well as the rates of change in DNAm were significantly related to improvements in total, crystalized, and fluid cognition scores, executive function, episodic memory, and processing speed, as well as several networks of GM volume increases and decreases that highlight typical patterns of brain maturation. Discussion: Our study provides a first look at the DNAm of genes involved in myelination, excitatory and inhibitory receptors, and connectivity, how they are related to the large-scale changes occurring in the brain structure as well as cognition during adolescence. [ABSTRACT FROM AUTHOR]

Introduction: Adolescence, a critical phase of human neurodevelopment, is marked by a tremendous reorganization of the brain and accompanied by improved cognitive performance. This development is driven in part by gene expression, which in turn is partly regulated by DNA methylation (DNAm).Methods: We collected brain imaging, cognitive assessments, and DNAm in a longitudinal cohort of approximately 200 typically developing participants, aged 9–14. This data, from three time points roughly 1 year apart, was used to explore the relationships between seven cytosine–phosphate–guanine (CpG) sites in genes highly expressed in brain tissues (GRIN2D, GABRB3, KCNC1, SLC12A9, CHD5, STXBP5, and NFASC), seven networks of grey matter (GM) volume change, and scores from seven cognitive tests.Results: The demethylation of the CpGs as well as the rates of change in DNAm were significantly related to improvements in total, crystalized, and fluid cognition scores, executive function, episodic memory, and processing speed, as well as several networks of GM volume increases and decreases that highlight typical patterns of brain maturation.Discussion: Our study provides a first look at the DNAm of genes involved in myelination, excitatory and inhibitory receptors, and connectivity, how they are related to the large-scale changes occurring in the brain structure as well as cognition during adolescence.

DNA methylation plays a key role in neural cell fate and provides a molecular link between early life stress and later-life behavioral phenotypes. Here, studies that combine neuroimaging methods and DNA methylation analysis in pediatric population with a history of adverse experiences were systematically reviewed focusing on: targeted genes and neural correlates; statistical models used to examine the link between DNA methylation and neuroimaging data also considering early life stress and behavioral outcomes. We identified 8 studies that report associations between DNA methylation and brain structure/functions in infants, school age children and adolescents faced with early life stress condition (e.g., preterm birth, childhood maltreatment, low socioeconomic status, and less-than optimal caregiving). Results showed that several genes were investigated (e.g., OXTR, SLC6A4, FKBP5, and BDNF) and different neuroimaging techniques were performed (MRI and f-NIRS). Statistical model used ranged from correlational to more complex moderated mediation models. Most of the studies (n = 5) considered DNA methylation and neural correlates as mediators in the relationship between early life stress and behavioral phenotypes. Understanding what role DNA methylation and neural correlates play in interaction with early life stress and behavioral outcomes is crucial to promote theory-driven studies as the future direction of this research fields.

DNA methylation plays a key role in neural cell fate and provides a molecular link between early life stress and later-life behavioral phenotypes. Here, studies that combine neuroimaging methods and DNA methylation analysis in pediatric population with a history of adverse experiences were systematically reviewed focusing on: targeted genes and neural correlates; statistical models used to examine the link between DNA methylation and neuroimaging data also considering early life stress and behavioral outcomes. We identified 8 studies that report associations between DNA methylation and brain structure/functions in infants, school age children and adolescents faced with early life stress condition (e.g., preterm birth, childhood maltreatment, low socioeconomic status, and less-than optimal caregiving). Results showed that several genes were investigated (e.g., OXTR , SLC6A4 , FKBP5 , and BDNF) and different neuroimaging techniques were performed (MRI and f -NIRS). Statistical model used ranged from correlational to more complex moderated mediation models. Most of the studies (n = 5) considered DNA methylation and neural correlates as mediators in the relationship between early life stress and behavioral phenotypes. Understanding what role DNA methylation and neural correlates play in interaction with early life stress and behavioral outcomes is crucial to promote theory-driven studies as the future direction of this research fields. [ABSTRACT FROM AUTHOR]

Oxytocin has anxiolytic properties whose mechanisms of action are still being identified. DNA methylation in the promoter region of the oxytocin receptor gene (OXTR), an epigenetic modification that putatively reflects a downtuning of the oxytocin system, has previously been implicated in the regulation of fear-related responses through the amygdala. In this study, we attempted to characterize the relationship between methylation of OXTR and anxiogenesis using two distinct endophenotypes: autonomic nervous system activity and subcortical brain structure. In 79 participants, we found that increased OXTR methylation is associated with attenuated resting parasympathetic tone, measured using high-frequency heart rate variability. Further, we found that this relationship is mediated by brain morphology, such that OXTR methylation is associated with increased gray matter of the central amygdala which is, in turn, associated with decreased parasympathetic tone. These results further our understanding of epigenetic regulation of the human oxytocin system and its role in anxiogenesis. [ABSTRACT FROM AUTHOR]

Neuroimaging epigenetics is an interdisciplinary application of epigenetics to cognitive neuroscience that seeks to identify molecular and neural predictors of human behavior. This approach can be sensitive to the dynamic interaction between biological predisposition and environmental influences, and is potentially more informative than an approach using static genetic code. Recent work in this field has generated considerable enthusiasm, yet caution is warranted since any novel cross-disciplinary approach lacks a set of established conventions or standards. In this paper we review existing research in the field of imaging epigenetics, outline important caveats and considerations, and suggest a set of guidelines for researchers conducting this work. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC) enzymes have been demonstrated as critical components in maintaining chromatin homeostasis, CNS development, and normal brain function. Evidence in mouse models links HDAC expression to learning, memory, and mood-related behaviors; small molecule HDAC inhibitor tool compounds have been used to demonstrate the importance of specific HDAC subtypes in modulating CNS-disease-related behaviors in rodents. So far, no direct evidence exists to understand the quantitative changes in HDAC target engagement that are necessary to alter biochemistry and behavior in a living animal. Understanding the relationship between target engagement and in vivo effect is essential in refining new ways to alleviate disease. We describe here, using positron emission tomography (PET) imaging of rat brain, the in vivo target engagement of a subset of class I/IIb HDAC enzymes implicated in CNS-disease (HDAC subtypes 1, 2, 3, and 6). We found marked differences in the brain penetrance of tool compounds from the hydroxamate and benzamide HDAC inhibitor classes and resolved a novel, highly brain penetrant benzamide, CN147, chronic treatment with which resulted in an antidepressant-like effect in a rat behavioral test. Our work highlights a new translational path for understanding the molecular and behavioral consequences of HDAC target engagement.