Maternal, not paternal, PTSD is related to increased risk for PTSD in offspring of Holocaust survivors

BACKGROUND: A significant association between parental PTSD and the occurrence of PTSD in offspring has been noted, consistent with the idea that risk for the development of PTSD is transmitted from parent to child. Two recent reports linking maternal PTSD and low offspring cortisol prompted us to examine the relative contributions of maternal vs. paternal PTSD in the prediction of PTSD and other psychiatric diagnoses in offspring. METHODS: One hundred seventeen men and 167 women, recruited from the community, were evaluated using a comprehensive psychiatric battery designed to identify traumatic life experiences and lifetime psychiatric diagnoses. 211 of these subjects were the adult offspring of Holocaust survivors and 73 were demographically comparable Jewish controls. Participants were further subdivided based on whether their mother, father, neither, or both parents met diagnostic criteria for lifetime PTSD. RESULTS: A higher prevalence of lifetime PTSD, mood, anxiety disorders, and to a lesser extent, substance abuse disorders, was observed in offspring of Holocaust survivors than controls. The presence of maternal PTSD was specifically associated with PTSD in adult offspring of Holocaust survivors. However, other psychiatric diagnoses did not show specific effects associated with maternal PTSD. CONCLUSION: The tendency for maternal PTSD to make a greater contribution than paternal PTSD to PTSD risk suggests that classic genetic mechanisms are not the sole model of transmission, and paves way for the speculation that epigenetic factors may be involved. In contrast, PTSD in any parent contributes to risk for depression, and parental traumatization is associated with increased anxiety disorders in offspring.     

The omniscient placenta: Metabolic and epigenetic regulation of fetal programming

Fetal development could be considered a sensitive period wherein exogenous insults and changes to the maternal milieu can have long-term impacts on developmental programming. The placenta provides the fetus with protection and necessary nutrients for growth, and responds to maternal cues and changes in nutrient signaling through multiple epigenetic mechanisms. The X-linked enzyme O-linked-N-acetylglucosamine transferase (OGT) acts as a nutrient sensor that modifies numerous proteins to alter various cellular signals, including major epigenetic processes. This review describes epigenetic alterations in the placenta in response to insults during pregnancy, the potential links of OGT as a nutrient sensor to placental epigenetics, and the implications of placental epigenetics in long-term neurodevelopmental programming. We describe the role of placental OGT in the sex-specific programming of hypothalamic–pituitary–adrenal (HPA) axis programming deficits by early prenatal stress as an example of how placental signaling can have long-term effects on neurodevelopment.     

Noncoding RNAs: Stress,Glucocorticoids, and Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is a pathologic response to trauma that impacts ～8% of the population and is highly comorbid with other disorders, such as traumatic brain injury. PTSD affects multiple biological systems throughout the body, including the hypothalamic-pituitary-adrenal axis, cortical function, and the immune system, and while the study of the biological underpinnings of PTSD and related disorders are numerous, the roles of noncoding RNAs (ncRNAs) are just emerging. Moreover, deep sequencing has revealed that ncRNAs represent most of the transcribed mammalian genome. Here, we present developing evidence that ncRNAs are involved in critical aspects of PTSD pathophysiology. In that regard, we summarize the roles of three classes of ncRNAs in PTSD and related disorders: microRNAs, long-noncoding RNAs, and retrotransposons. This review evaluates findings from both animal and human studies with a special focus on the role of ncRNAs in hypothalamic-pituitary-adrenal axis abnormalities and glucocorticoid dysfunction in PTSD and traumatic brain injury. We conclude that ncRNAs may prove to be useful biomarkers to facilitate personalized medicines for trauma-related brain disorders.     

Acute and Post-Traumatic Stress Disorders: A biased nervous system

Acute stress disorder and post-traumatic stress disorder are generally triggered by an exceptionally intense threat. The consequences of this traumatogenic situation are explored here in chronological order, from exposure to the threat to development of symptoms. Such a situation may disrupt the equilibrium between two fundamental brain circuits, referred to as the “defensive” and “cognitive”. The defensive circuit triggers the stress response as well as the formation of implicit memory. The cognitive circuit triggers the voluntary response and the formation of explicit autobiographical memory. During a traumatogenic situation, the defensive circuit could be over-activated while cognitive circuit is under-activated. In the most severe cases, overactivation of the defensive circuit may cause its brutal deactivation, resulting in dissociation. Here, we address the underlying neurobiological mechanisms at every scale: from neurons to behaviors, providing a detailed explanatory model of trauma.     

Neurogenetic Approaches to Stress and Fear in Humans as Pathophysiological Mechanisms for Posttraumatic Stress Disorder

In this review article, genetic variation associated with brain responses related to acute and chronic stress reactivity and fear learning in humans is presented as an important mechanism underlying posttraumatic stress disorder. We report that genes related to the regulation of the hypothalamic-pituitary-adrenal axis, as well as genes that modulate serotonergic, dopaminergic, and neuropeptidergic functions or plasticity, play a role in this context. The strong overlap of the genetic targets involved in stress and fear learning suggests that a dimensional and mechanistic model of the development of posttraumatic stress disorder based on these constructs is promising. Genome-wide genetic analyses on fear and stress mechanisms are scarce. So far, reliable replication is still lacking for most of the molecular genetic findings, and the proportion of explained variance is rather small. Further analysis of neurogenetic stress and fear learning needs to integrate data from animal and human studies.     

Additive Effects of Stress and Alcohol Exposure on Accelerated Epigenetic Aging in Alcohol Use Disorder

BackgroundStress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood.MethodsWe constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model. The effects of MS stress on health outcomes and epigenetic aging were assessed in a sample of 615 patients with AUD and control subjects using epigenetic clocks and DNA methylation–based telomere length. Statistical analysis with an additive model using MS stress and a MS for alcohol consumption (MS alcohol) was conducted. Results were replicated in 2 independent cohorts (Generation Scotland, N = 7028 and the Grady Trauma Project, N = 795).ResultsComposite score of stress and MS stress were strongly associated with heavy alcohol consumption, trauma experience, epigenetic age acceleration (EAA), and shortened DNA methylation–based telomere length in AUD. Together, MS stress and MS alcohol additively showed strong stepwise increases in EAA. Replication analyses showed robust association between MS stress and EAA in the Generation Scotland and Grady Trauma Project cohorts.ConclusionsA methylation-derived score tracking stress exposure is associated with various stress-related phenotypes and EAA. Stress and alcohol have additive effects on aging, offering new insights into the pathophysiology of premature aging in AUD and, potentially, other aspects of gene dysregulation in this disorder.     

Maternal prenatal symptoms of depression and down regulation of placental monoamine oxidase A expression

Objective

Maternal prenatal symptoms of depression and anxiety have been associated with altered neurodevelopmental outcomes in the child. These effects may be mediated in part by altered placental function, with increased fetal 5-hydroxytryptamine (5-HT) exposure being one possible mechanism. The current study aimed to determine whether maternal symptoms of depression or anxiety were associated with decreased placental expression of monoamine oxidase A (MAO A), the enzyme which metabolises 5-HT into 5-hydroxyindoleacetic acid. The localisation of MAO A in the placenta was also investigated.

Methods

Pregnant women were recruited one day prior to elective caesarean and assessed using psychometric tests for symptoms of depression (Edinburgh Depression Scale) and anxiety (Spielberger State/Trait Index). Villous trophoblast tissue was extracted from each placenta and used for subsequent gene expression analysis (N = 62). Localisation was studied using immunohistochemistry, with a specific polyclonal antibody.

Results

Increasing symptoms of maternal depression were associated with a reduction in placental MAO A expression (r = − 0.339, p = 0.007, N = 62). There was a trend for a similar correlation with symptoms of maternal trait anxiety, but not with state anxiety. MAO A was localised to the syncytiotrophoblast, the tissue between maternal and fetal blood.

Conclusions

These findings support the hypothesis that maternal mood is associated with altered placental function. A reduction in placental MAO A expression is consistent with a subsequent increase in fetal exposure to 5-HT.     

The Maternal Adversity,Vulnerability and Neurodevelopment Project: Theory and Methodology

Objective:

To describe the theory and methodology of the multi-wave, prospective Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) study. The goal of MAVAN is to examine the pre- and postnatal influences, and their interaction, in determining individual differences in mental health.

Method:

MAVAN is a community-based, birth cohort study of pregnant Canadian mothers and their offspring. Dyads are assessed longitudinally, with multiple assessments of both mother and child in home and laboratory across the child’s development. Study measures, including assessments of cognitive and emotional function, are described. The study uses a candidate gene approach to examine gene–environment interdependence in specific developmental outcomes. Finally, the study includes measures of both brain-based phenotypes and metabolism to explore comorbidities associated with child obesity. One of the unique features of the MAVAN protocol is the extensive measures of the mother–child interaction. The relation between these measures will be discussed.

Results:

Evidence from the MAVAN project shows interesting results about maternal care, families, and child outcomes. In our review, preliminary analyses showing the correlations between measures of maternal care are reported. As predicted, early evidence suggests that maternal care measures are positively correlated, over time.

Conclusions:

This review provides evidence for the feasibility and value of laboratory-based measures embedded within a longitudinal birth cohort study. Though retention of the samples has been a challenge of MAVAN, they are within a comparable range to other studies of this nature. Indeed, the trade-off of somewhat greater participant burden has allowed for a rich database. The results yielded from the MAVAN project will not only describe typical development but also possible targets for intervention. Understanding certain endophenotypes will shed light on the pathogenesis of various mental and physical disorders, as well as their interrelation.     

Epigenetics and psychoneuroimmunology: Mechanisms and models

In this Introduction to the Named Series “Epigenetics, Brain, Behavior, and Immunity” an overview of epigenetics is provided with a consideration of the nature of epigenetic regulation including DNA methylation, histone modification and chromatin re-modeling. Illustrative examples of recent scientific developments are highlighted to demonstrate the influence of epigenetics in areas of research relevant to those who investigate phenomena within the scientific discipline of psychoneuroimmunology. These examples are presented in order to provide a perspective on how epigenetic analysis will add insight into the molecular processes that connect the brain with behavior, neuroendocrine responsivity and immune outcome.     

Event centrality and secondary traumatization among Holocaust survivors' offspring and grandchildren: A three-generation study

The present study examined the intergenerational transmission of the Holocaust trauma in relation to levels of secondary traumatization and event centrality across three generations in a cross-sectional survey. Participants included 92 Holocaust survivor-offspring-grandchild triads (Holocaust G1-G2-G3) and 67 comparison triads (Comparison G1-G2-G3). Holocaust G1 reported higher levels of post-traumatic stress disorder (PTSD) symptoms relative to Comparison G1. Holocaust G2 and G3 reported significantly higher secondary traumatization relative to Comparison G2 and G3, respectively. Holocaust G3 also reported significantly higher scores in event centrality relative to Comparison G3. In survivor families, the indirect effect of PTSD symptoms in Holocaust G1 predicted Holocaust G2's secondary traumatization, which subsequently predicted Holocaust G3's secondary traumatization. Moreover, PTSD symptoms in Holocaust G1 predicted Holocaust G3's event centrality through secondary traumatization in both Holocaust G2 and G3 and event centrality in Holocaust G2. In the comparison groups, trauma transmission was not observed in three generations. Findings elucidate unique intergenerational transmission of the Holocaust trauma in survivor families, which comprise both personal and societal constituents. Moreover, the findings show that event centrality is a distinctive mechanism in intergenerational transmission in survivor families.     

Driving the Next Generation: Paternal Lifetime Experiences Transmitted via Extracellular Vesicles and Their Small RNA Cargo

Epidemiological studies provide strong evidence for the impact of diverse paternal life experiences on offspring neurodevelopmental disease risk. While these associations are well established, the molecular mechanisms underlying these intergenerational transmissions remain elusive, though recent studies focusing on the influence of paternal experience before conception have implicated germ cell epigenetic programming. Any model accounting for the germline transfer of nongenetic information from sire to offspring must include certain components, such as 1) a vector to carry any signal from the paternal compartment to the maternal reproductive tract and future embryo; 2) a molecular signal, encoded by a paternal experience, to carry this memory and enact downstream responses; and 3) a target cell or tissue to receive the signal and convert it into an effect on embryonic development. We explore the current understanding of the potential processes and candidate factors that may serve as these components. We specifically discuss the growing appreciation for the importance of extracellular vesicles in these processes, beginning with their known role in delivering potential signals, including small RNAs, to sperm, the prototypical vector, during their posttesticular maturation. Finally, we explore the possibility that paternal extracellular vesicles could themselves serve as vectors, delivering signals not only to gametes or the zygote but also to tissues of the maternal reproductive tract to influence fetal development.     

Paternal Alcohol Abuse: Relationship Between Child Adjustment, Parental Characteristics, and Family Functioning

This study examines possible risk factors associated with child adjustment in a sample of children with alcohol abusing fathers in Norway (N = 37). Factors included are socio-economic status, severity of the fathers' alcohol abuse, parental psychological problems, and family functioning. Children of alcohol abusing fathers were found to have more adjustment problems assessed by CBCL compared to a general population sample. The findings further suggest that child adjustment in families with paternal alcohol abuse is the result of an accumulation of risk factors rather than the effects of the paternal alcohol abuse alone. Both general environmental risk factors (psychological problems in the fathers, family climate, family health and conflicts) and environmental factors related to the parental alcohol abuse (severity of the alcohol abuse, the child's level of exposure to the alcohol abuse, changes in routines and rituals due to drinking) were related to child adjustment. The results indicate the need to obtain both parents' assessments of child adjustment, as the fathers' assessment was associated with different risk factors compared to the mothers'.     

Posttraumatic Stress Disorder and Suicidal Behavior: Indirect Effects of Impaired Social Functioning

Social functioning is negatively impacted by the presence of PTSD, while increasing risk of suicidal behavior among individuals with PTSD. However, little research has examined the specific role of social functioning in the association between PTSD and suicidal behavior. Parallel multiple indirect effects analyses were performed to understand the unique indirect effects of four aspects of social functioning. Indirect effects of PTSD on suicidal ideation were significant through three pathways: interpersonal conflict, perceived family support, and interpersonal apprehension. Perceived family support was the only indirect pathway significantly associated with suicide attempt. Findings suggest that social functioning should be assessed and potentially targeted during treatment to help modify the risk for suicidal behavior among individuals with PTSD.