Tania L. Roth

Epigenetic pathways in PTSD: how traumatic experiences leave their signature on the genome

This research topic focuses on epigenetic components of PTSD. Epigenetic mechanisms are a class of molecular mechanisms by which environmental influences, including stress, can interact with the genome to have long-term consequences for brain plasticity and behavior. Articles herein include empirical reports and reviews that link stress and trauma with epigenetic alterations in humans and animal models of earlyor later-life stress. Themes present throughout the collection include: DNA methylation is a useful biomarker of stress and treatment outcome in humans; epigenetic programming of stress-sensitive physiological systems early in development confers an enhanced risk on disease development upon re-exposure to trauma or stress; and, long-lived fear memories are associated with epigenetic alterations in fear memory and extinction brain circuitry.

Chapter 26 – The Social Environment and Epigenetics in Psychiatry

Social factors, particularly those that are encountered early in life such as parental care, can have profound effects on neurobiological trajectories and long-term consequences for mental health. It has been largely accepted that normal brain development depends upon a complex interplay between genetic and environmental factors. The field of behavioral epigenetics has provided novel approaches with which to examine additional mechanisms by which experiences can become “biologically embedded,” influencing the development and maintenance of behavioral adaptations to environmental challenges. In this chapter, we will discuss several examples of epigenetic studies in rodent models and human cohorts that have been used to examine the influence of social factors on behavioral and mental health outcomes. We will highlight discoveries in the field that relate to epigenetic mechanisms that may mediate risk and resilience to psychosocial stress and other social experiences, and discuss the manner in which recent high-throughput technologies are changing the nature of questions posed and the answers uncovered in this emerging field.

Epigenetic Landscapes of the Adversity-Exposed Brain

It is understood that adversity during development has the power to alter behavioral trajectories, and the role of the epigenome in that relationship is currently under intense investigation. Several studies in both nonhuman animals and humans have established a link between early adversity and epigenetic regulation of genes heavily implicated in the stress response, plasticity and cognition, and psychiatric disorders such as depression and anxiety. Thus the relatively recent surge of studies centering on the epigenetic outcomes of stress has great potential to inform treatments and interventions for psychiatric disorder precipitated by early adversity. Here we review what we know and what we do not know, and suggest approaches to help further elucidate the relationship between early adversity, epigenetics, and behavior.

Sex Differences in Early Postnatal Microglial Colonization of the Developing Rat Hippocampus Following a Single-Day Alcohol Exposure

Microglia are involved in various homeostatic processes in the brain, including phagocytosis, apoptosis, and synaptic pruning. Sex differences in microglia colonization of the developing brain have been reported, but have not been established following alcohol insult. Developmental alcohol exposure represents a neuroimmune challenge that may contribute to cognitive dysfunction prevalent in humans with Fetal Alcohol Spectrum Disorders (FASD) and in rodent models of FASD. Most studies have investigated neuroimmune activation following adult alcohol exposure or following multiple exposures. The current study uses a single day binge alcohol exposure model (postnatal day [PD] 4) to examine sex differences in the neuroimmune response in the developing rat hippocampus on PD5 and 8. The neuroimmune response was evaluated through measurement of microglial number and cytokine gene expression at both time points. Male pups had higher microglial number compared to females in many hippocampal subregions on PD5, but this difference disappeared by PD8, unless exposed to alcohol. Expression of pro-inflammatory marker CD11b was higher on PD5 in alcohol-exposed (AE) females compared to AE males. After alcohol exposure, C-C motif chemokine ligand 4 (CCL4) was significantly increased in female AE pups on PD5 and PD8. Tumor necrosis factor-α (TNF-α) levels were also upregulated by AE in males on PD8. The results demonstrate a clear difference between the male and female neuroimmune response to an AE challenge, which also occurs in a time-dependent manner. These findings are significant as they add to our knowledge of specific sex-dependent effects of alcohol exposure on microglia within the developing brain.

Pharmacological Manipulation of DNA Methylation in Adult Female Rats Normalizes Behavioral Consequences of Early-Life Maltreatment

Exposure to adversity early in development alters brain and behavioral trajectories. Data continue to accumulate that epigenetic mechanisms are a mediating factor between early-life adversity and adult behavioral phenotypes. Previous work from our laboratory has shown that female Long-Evans rats exposed to maltreatment during infancy display both aberrant forced swim behavior and patterns of brain DNA methylation in adulthood. Therefore, we examined the possibility of rescuing the aberrant forced swim behavior in maltreated-adult females by administering an epigenome-modifying drug (zebularine) at a dose previously shown to normalize DNA methylation. We found that zebularine normalized behavior in the forced swim test in maltreated females such that they performed at the levels of controls (females that had been exposed to only nurturing care during infancy). These data help link DNA methylation to an adult phenotype in our maltreatment model, and more broadly provide additional evidence that non-targeted epigenetic manipulations can change behavior associated with early-life adversity.

Epigenetic Advances in Behavioral and Brain Sciences Have Relevance for Public Policy

Nature and nurture work together to drive development, behavior, and health. Behavioral epigenetics research has uncovered underlying mechanisms for how this happens. Children’s early years in development may offer the greatest opportunity for environmental and experiential factors to influence the epigenome (chemical compounds telling our genes what to do), but evidence suggests it is never too late. The policy implications of this research are vast, including relevance for child development, health, and disease intervention and prevention.

Annual Research Review: Epigenetic mechanisms and environmental shaping of the brain during sensitive periods of development: Epigenetic mechanisms and environmental shaping of the brain

Experiences during early development profoundly affect development of the central nervous system (CNS) to impart either risk for or resilience to later psychopathology. Work in the developmental neuroscience field is providing compelling data that epigenetic marking of the genome may underlie aspects of this process. Experiments in rodents continue to show that experiences during sensitive periods of development influence DNA methylation patterns of several genes. These experience-induced DNA methylation patterns represent stable epigenetic modifications that alter gene transcription throughout the lifespan and promote specific behavioral outcomes. We discuss the relevance of these findings to humans, and also briefly discuss these findings in the broader contexts of cognition and psychiatric disorder. We conclude by discussing the implications of these observations for future research.

Epigenetics of Memory Processes

Publisher Summary This chapter discusses the epigenetics of memory processes. Epigenetic mechanisms have some necessary role in the dynamic nature of the adult CNS in response to the environment, and that epigenetic regulation of gene transcription facilitates memory formation. Studies also indicate that manipulation of such mechanisms can restore learning and memory deficits in several rodent models of neurodegeneration and brain injury. Seminal studies continue to demonstrate that the histone proteins and DNA that comprise chromatin are targets of neuronal signaling pathways involved in CNS plasticity and memory formation. Epigenetics is defined as the covalent modification of chromatin that influences activity-dependent changes in gene expression. These changes can be transient, underlying the dynamic regulation of gene activity states, or they can be long-term and responsible for lasting alterations in gene activity states. The combination of dynamic and stable components renders chromatin an ideal substrate for signal integration and storage of cellular information in the CNS. Concerning the field of learning and memory, there are two basic molecular epigenetic mechanisms that are currently studied—post-translational modifications of histone proteins and direct covalent methylation of cytosines. Histones are proteins that organize DNA in the nucleus. There are eight histone proteins (histones 2A, 2B, 3, and 4, with two copies of each molecule) at the heart of the chromatin core.