Daniel Almeida

Association of a History of Child Abuse With Impaired Myelination in the Anterior Cingulate Cortex: Convergent Epigenetic, Transcriptional, and Morphological Evidence

OBJECTIVE Child abuse has devastating and long-lasting consequences, considerably increasing the lifetime risk of negative mental health outcomes such as depression and suicide. Yet the neurobiological processes underlying this heightened vulnerability remain poorly understood. The authors investigated the hypothesis that epigenetic, transcriptomic, and cellular adaptations may occur in the anterior cingulate cortex as a function of child abuse. METHOD Postmortem brain samples from human subjects (N=78) and from a rodent model of the impact of early-life environment (N=24) were analyzed. The human samples were from depressed individuals who died by suicide, with (N=27) or without (N=25) a history of severe child abuse, as well as from psychiatrically healthy control subjects (N=26). Genome-wide DNA methylation and gene expression were investigated using reduced representation bisulfite sequencing and RNA sequencing, respectively. Cell type-specific validation of differentially methylated loci was performed after fluorescence-activated cell sorting of oligodendrocyte and neuronal nuclei. Differential gene expression was validated using NanoString technology. Finally, oligodendrocytes and myelinated axons were analyzed using stereology and coherent anti-Stokes Raman scattering microscopy. RESULTS A history of child abuse was associated with cell type-specific changes in DNA methylation of oligodendrocyte genes and a global impairment of the myelin-related transcriptional program. These effects were absent in the depressed suicide completers with no history of child abuse, and they were strongly correlated with myelin gene expression changes observed in the animal model. Furthermore, a selective and significant reduction in the thickness of myelin sheaths around small-diameter axons was observed in individuals with history of child abuse. CONCLUSIONS The results suggest that child abuse, in part through epigenetic reprogramming of oligodendrocytes, may lastingly disrupt cortical myelination, a fundamental feature of cerebral connectivity.

Childhood maltreatment and stress-related psychopathology: the epigenetic memory hypothesis.

Childhood maltreatment (CM) is all too frequent among western societies, with an estimated prevalence of 10 to 15%. CM associates with increased risk of several psychiatric disorders, and therefore represents a worrying public and socioeconomic burden. While associated clinical outcomes are well characterized, determining by which mechanisms early-life adverse experiences affect mental health over the lifespan is a major challenge. Epigenetic mechanisms, in particular DNA methylation, represent a form of molecular memory that may modify brain function over extended periods of time, as well as serve as a bio-marker of behavioral phenotypes associated with CM. Here, we review human studies suggesting that DNA methylation is a crucial substrate mediating neurobiological consequences of CM throughout life, thereby potentiating maladaptive behavioral patterns and psychopathological risk.

Gonads and strife: Sex hormones vary according to sexual orientation for women and stress indices for both sexes.

This study assessed sexual orientation and psychobiological stress indices in relation to salivary sex hormones as part of a well-validated laboratory-based stress paradigm. Participants included 87 healthy adults that were on average 25 years old who self-identified as lesbian/bisexual women (n=20), heterosexual women (n=21), gay/bisexual men (n=26), and heterosexual men (n=20). Two saliva samples were collected fifteen minutes before and fifteen minutes after exposure to a modified Trier Social Stress Test to determine testosterone, estradiol, and progesterone concentrations via enzyme-immune assaying. Mean sex hormones were further tested in association to stress indices related to cortisol systemic output (area under the curve with respect to ground) based on ten measures throughout the two-hour visit, allostatic load indexed using 21 biomarkers, and perceived stress assessed using a well-validated questionnaire. Results revealed that lesbian/bisexual women had higher overall testosterone and progesterone concentrations than heterosexual women, while no differences were found among gay/bisexual men in comparison to heterosexual men. Lesbian/bisexual women and heterosexual men showed positive associations between mean estradiol concentrations and allostatic load, while gay/bisexual men and heterosexual women showed positive associations between mean testosterone and cortisol systemic output. In summary, sex hormone variations appear to vary according to sexual orientation among women, but also as a function of cortisol systemic output, allostatic load, and perceived stress for both sexes.

A Slice of the Suicidal Brain: What Have Postmortem Molecular Studies Taught Us?

Suicide ranks amongst the leading causes of death worldwide. Contemporary models of suicide risk posit that suicide results from the interaction of distal and proximal factors, including neurobiological, psychological/clinical, and social factors. While a wealth of neurobiological studies aimed at identifying biological processes associated with suicidal behaviour have been conducted over the last decades, the more recent development of arrays and high-throughput sequencing methods have led to an increased capacity and interest in the study of genomic factors. Postmortem studies are a unique tool to directly investigate genomic processes that may be dysregulated in the suicidal brain. In this review, we discuss postmortem literature investigating functional genomic studies of suicide, particularly focusing on epigenetic mechanisms.

Epigenetic regulation of the kappa opioid receptor gene by an insertion–deletion in the promoter region

Preclinical and clinical studies have demonstrated that the kappa opioid receptor (KOR) regulates reward, hedonic tone and emotions. At therapeutic level, on-going clinical trials are assessing the potential of targeting the KOR for the management of depression, anxiety disorders and substance use disorders. However, genetic polymorphisms in the KOR gene that potentially contribute to its implication in these phenotypes have been poorly studied. Here we investigated an insertion-deletion in the promoter region of KOR (rs35566036), recently associated with alcohol addiction, in a cohort of depressed subjects who died by suicide, as well as psychiatrically healthy individuals. Focusing on 3 brain regions (anterior insula, anterior cingulate cortex, and mediodorsal thalamus), we characterized the functional impact of this structural variant on the expression and patterns of DNA methylation of the KOR gene, using qPCR and targeted Bisulfite-Sequencing, respectively. While there was no significant change in the expression of KOR as a function of the insertion-deletion, or as a function of disease status in any brain region, we found that this variant strongly determines DNA methylation in KOR promoter, leading to a significant decrease in methylation levels of 8 nearby CpG dinucleotides located approximately 500 base pairs upstream the transcription start site. In addition, our results suggest a possible association between the insertion-deletion and depression; however, this result should be tested in larger populations. In sum, in this study we uncovered an epigenetic mechanism potentially contributing to KOR dysfunction in carriers of the insertion-deletion.

Evidence of Reduced Agmatine Concentrations in the Cerebral Cortex of Suicides

Abstract Background The polyamines are a group of ubiquitous low-molecular–weight aliphatic molecules that play an essential role in various physiological functions of the mammalian CNS. Previous literature has indicated alterations in the expression of polyamine-related genes in the brains of individuals who died by suicide, including downregulation of spermidine/spermine N1-acetyltransferase, a key enzyme involved in polyamine catabolism. One such polyamine, agmatine, has been shown to act as an antidepressant in animal models of depressive-like behavior. However, agmatine concentrations have not been explored in postmortem human brain of individuals who died by suicide. Methods To measure agmatine in postmortem human brain tissue, we employed our previously published high-resolution capillary gas chromatography in combination with mass spectrometry method. Using this method, we analyzed agmatine levels in a total of 120 tissue samples from Brodmann areas 4, 11, and 44 of 40 male subjects comprising controls (n=13), individuals who died by suicide and met criteria for major depressive disorder (n=14), and subjects who died by suicide and did not meet criteria for major depressive disorder (n=13). Results Agmatine fell within the expected nanomolar range and was significantly reduced in the cortex of suicides, irrespective of meeting criteria for major depressive disorder compared with controls. Conclusions This is the first gas chromatography-mass spectrometry study to analyze agmatine concentrations in human postmortem brain of individuals who died by suicide. These results add to our mechanistic understanding of the role that the polyamine stress response pathway may play in the neurobiology of major depression and/or suicide.

The Epigenetics of Early Life Adversity: Current Limitations and Possible Solutions

Adverse experiences during sensitive postnatal developmental periods can disrupt the calibration of fundamental systems and increase the risk of a wide range of adult disease states, including psychiatric illnesses. Accumulating evidence suggests that epigenetic modifications involving DNA methylation, posttranslational histone modifications, and noncoding RNAs may be a key mediating factor in this disruption. Accumulating evidence from both animal models and human studies suggests that early life adversity alters the epigenome at multiple loci across the genome, but that the specific alterations, and the associated transcriptomic and psychiatric outcomes may be dependent on multiple individual factors. Here we will review the current findings on early life adversity associated alterations of the epigenome in animal models and humans, discuss current limitations, and highlight possible solutions and future directions.

Recent Progress in Functional Genomic Studies of Depression and Suicide

According to the WHO approximately 350 million individuals worldwide are affected by depression, making it the global leading cause of disability. Depression also closely associates with suicide. The last three decades have seen a wealth of genetic studies aiming to identify genes associated with depression and suicidal behavior, whereas more recent advances in our understanding of how the genome is functionally regulated, coupled with developments in high-throughput sequencing methods, have led to an increased capacity and interest in the study of functional genomics. These studies provide us with a unique opportunity to understand how the brain is regulated and to more directly investigate genomic processes that may be at fault in the depressed and suicidal brain. In this review, we discuss recent advances in studies investigating transcriptomic and epigenomic studies of depression and suicide.