Tamara B. Franklin

Epigenetic transmission of the impact of early stress across generations.

BACKGROUND Traumatic experiences in early life are risk factors for the development of behavioral and emotional disorders. Such disorders can persist through adulthood and have often been reported to be transmitted across generations. METHODS To investigate the transgenerational effect of early stress, mice were exposed to chronic and unpredictable maternal separation from postnatal day 1 to 14. RESULTS We show that chronic and unpredictable maternal separation induces depressive-like behaviors and alters the behavioral response to aversive environments in the separated animals when adult. Most of the behavioral alterations are further expressed by the offspring of males subjected to maternal separation, despite the fact that these males are reared normally. Chronic and unpredictable maternal separation also alters the profile of DNA methylation in the promoter of several candidate genes in the germline of the separated males. Comparable changes in DNA methylation are also present in the brain of the offspring and are associated with altered gene expression. CONCLUSIONS These findings highlight the negative impact of early stress on behavioral responses across generations and on the regulation of DNA methylation in the germline.

Neural Mechanisms of Stress Resilience and Vulnerability

Exposure to stressful events can be differently perceived by individuals and can have persistent sequelae depending on the level of stress resilience or vulnerability of each person. The neural processes that underlie such clinically and socially important differences reside in the anatomical, functional, and molecular connectivity of the brain. Recent work has provided novel insight into some of the involved biological mechanisms that promises to help prevent and treat stress-related disorders. In this review, we focus on causal and mechanistic evidence implicating altered functions and connectivity of the neuroendocrine system, and of hippocampal, cortical, reward, and serotonergic circuits in the establishment and the maintenance of stress resilience and vulnerability. We also touch upon recent findings suggesting a role for epigenetic mechanisms and neurogenesis in these processes and briefly discuss promising avenues of future investigation.

Influence of Early Stress on Social Abilities and Serotonergic Functions across Generations in Mice

Exposure to adverse environments during early development is a known risk factor for several psychiatric conditions including antisocial behavior and personality disorders. Here, we induced social anxiety and altered social recognition memory in adult mice using unpredictable maternal separation and maternal stress during early postnatal life. We show that these social defects are not only pronounced in the animals directly subjected to stress, but are also transmitted to their offspring across two generations. The defects are associated with impaired serotonergic signaling, in particular, reduced 5HT1A receptor expression in the dorsal raphe nucleus, and increased serotonin level in a dorsal raphe projection area. These findings underscore the susceptibility of social behaviors and serotonergic pathways to early stress, and the persistence of their perturbation across generations.

Epigenetic inheritance in mammals: Evidence for the impact of adverse environmental effects

The epigenome is the overall epigenetic state of a cell and represents the ensemble of chromatin modifications. It is an essential mechanism for the regulation of the genome that depends on modifications of DNA and histones but does not involve any change of the DNA sequence. It was previously assumed that in order for appropriate cellular development and differentiation to occur in mammals, the epigenome was fully erased and reestablished between generations. However, several examples of incomplete erasure at specific genes have been reported, and this is suggested to be associated with the epigenetic inheritance of gene profiles. Although the existence of such a mode of inheritance has been controversial, there is increasing evidence that it does occur in rodents and humans. In this review, we discuss the evidence that adverse environmental factors can affect not only the individuals directly exposed to these factors but also their offspring. Because the epigenome is sensitive to environmental influence and, in some cases, can, in part, be transmitted across generations, it provides a potential mechanism for the transgenerational transmission of the impact of environmental factors. Environmental factors examined include exposure to toxicants, diet, and postnatal care, and DNA methylation is the main mechanism discussed in this review.

Inheritable effect of unpredictable maternal separation on behavioral responses in mice

The long-term impact of early stress on behavior and emotions is well documented in humans, and can be modeled in experimental animals. In mice, maternal separation during early postnatal development induces poor and disorganized maternal care, and results in behavioral deficits that persist through adulthood. Here, we examined the long-term effect of unpredictable maternal separation combined with maternal stress on behavior and its transmissibility. We report that unpredictable maternal separation from birth to postnatal day 14 in C57Bl/6J mice has mild behavioral effects in the animals when adult, but that its combination with maternal stress exacerbates this effect. Further, the behavioral deficits are transmitted to the following generation through females, an effect that is independent of maternal care and is not affected by cross-fostering. The combined manipulation does not alter basic components of the hypothalamic–pituitary–adrenal axis but decreases the expression of the corticotropin releasing factor receptor 2 (CRFR2) in several nuclei of the amygdala and the hypothalamus in the brain of maternal-separated females. These results suggest a non-genomic mode of transmission of the impact of early stress in mice.

Early life stress in fathers improves behavioural flexibility in their offspring

Traumatic experiences in childhood can alter behavioural responses and increase the risk for psychopathologies across life, not only in the exposed individuals but also in their progeny. In some conditions, such experiences can however be beneficial and facilitate the appraisal of adverse environments later in life. Here we expose newborn mice to unpredictable maternal separation combined with unpredictable maternal stress (MSUS) for 2 weeks and assess the impact on behaviour in the offspring when adult. We show that MSUS in male mice favours goal-directed behaviours and behavioural flexibility in the adult offspring. This effect is accompanied by epigenetic changes involving histone post-translational modifications at the mineralocorticoid receptor (MR) gene and decreased MR expression in the hippocampus. Mimicking these changes pharmacologically in vivo reproduces the behavioural phenotype. These findings highlight the beneficial impact that early adverse experiences can have in adulthood, and the implication of epigenetic modes of gene regulation.

The prevalence of epigenetic mechanisms in the regulation of cognitive functions and behaviour

A complex interplay between the pattern of DNA methylation and a large and growing number of post-translational modifications (PTMs) of histones contribute to the epigenetic regulation of gene transcription. This epigenetic regulation involves histone acetylation, phosphorylation and methylation, and is now known to be important for several forms and phases of long-term memory. Anomalies in the epigenome have also been demonstrated to be critical factors in a number of cognitive and behavioural disorders. The epigenetic mechanisms that contribute to these deficits include: first, the dysregulation of key components of the epigenetic machinery; second, alterations in the expression of genes important for cognition and behaviour by epigenetic mechanisms; third, instability at trinucleotide repeats; and fourth, the breakdown of major epigenetic processes like imprinting and X-chromosome inactivation. Thus, both pharmacological and environmental interventions that act on epigenetic mechanisms provide a promising tool for the treatment of a wide variety of cognitive and behavioural disorders.

The involvement of epigenetic defects in mental retardation.

Mental retardation is a group of cognitive disorders with a significant worldwide prevalence rate. This high rate, together with the considerable familial and societal burden resulting from these disorders, makes it an important focus for prevention and intervention. While the diseases associated with mental retardation are diverse, a significant number are linked with disruptions in epigenetic mechanisms, mainly due to loss-of-function mutations in genes that are key components of the epigenetic machinery. Additionally, several disorders classed as imprinting syndromes are associated with mental retardation. This review will discuss the epigenetic abnormalities associated with mental retardation, and will highlight their importance for diagnosis, treatment, and prevention of these disorders.

Mapping of CBV changes in 5-HT1A terminal fields by functional MRI in the mouse brain

Visualization of brain activity in humans and animals using functional magnetic resonance imaging (fMRI) is an established method for translational neuropsychopharmacology. It is useful to study the activity of defined brain structures, however it requires further refinement to allow more specific cellular analyses, like for instance, the activity of selected pools of brain cells. Here, we investigated brain activity in serotonergic pathways in the adult mouse brain by using acute pharmacological challenge of 5-hydroxytryptamine (5-HT) 1A receptors. We show that administration of the 5-HT(1A) receptor agonist 8-OH-DPAT prompts a dose-dependent reduction in local cerebral blood volume (CBV) in brain areas rich in neurons expressing post-synaptic 5-HT(1A) receptor, including the prefrontal cortex, hippocampus and amygdalar nuclei. Region-specific inhibition of the response by co-injection of 8-OH-DPAT with the selective 5-HT(1A) receptor antagonist WAY-100635, or in 5-HT(1A) knock-out mice, suggests that 5-HT(1A) receptors are the primary targets of the agonist. Overall, the data demonstrate the feasibility of mapping region-specific serotonergic transmission in the adult mouse brain in vivo by non-invasive fMRI. The method opens novel perspectives for investigating 5-HT(1A) receptor functions in mouse models of human pathologies resulting from a dysfunction of the 5-HT(1A) receptor or the serotonergic system, including depression and anxiety.

The Neural Bases of Emotions

The term “emotion” is understood intuitively but is difficult to define, and currently there is no real consensus in the literature as to its meaning. It is commonly described as a mental state, associated with bodily changes, which arise spontaneously but are consciously felt. Thus, emotions can encompass a wide range of personal states accompanied by a number of observable behaviors and physiological changes. Great progress in the understanding of the neural bases for emotion has been made in the past decades. However, several fundamental questions related to emotions and the processing of emotional information remain unanswered. The field of affective neuroscience addresses these questions by investigating how emotions and mood are represented in the brain. Currently research interests lie in delineating which neural structures and networks are required for emotional responses, and further identifying the molecular mechanisms acting in these brain areas. Other important questions include how emotional events are learned and stored, and how changes in the functioning of the mechanisms and networks engaged during emotional processing lead to mood disorders such as depression and anxiety disorders. This chapter will address past and present theories on the question of “What is emotion?” and will outline our current understanding of the neural mechanisms involved in emotional processing.