Environmental regulation of the neural epigenome

AbstractParental effects are a major source of phenotypic plasticity. Moreover, there is evidence from studies with a wide range of species that the relevant parental signals are influenced by the quality of the parental environment. The link between the quality of the environment and the nature of the parental signal is consistent with the idea that parental effects, whether direct or indirect, might serve to influence the phenotype of the offspring in a manner that is consistent with the prevailing environmental demands. In this review we explore recent studies from the field of ‘environmental epigenetics’ that suggest that (1) DNA methylation states are far more variable than once thought and that, at least within specific regions of the genome, there is evidence for both demethylation and remethylation in post-mitotic cells and (2) that such remodeling of DNA methylation can occur in response to environmentally-driven, intracellular signaling pathways. Thus, studies of variation in mother–offspring interactions in rodents suggest that parental signals operate during pre- and/or post-natal life to influence the DNA methylation state at specific regions of the genome leading to sustained changes in gene expression and function. We suggest that DNA methylation is a candidate mechanism for parental effects on phenotypic variation

Hidden Markov Model Analysis of Maternal Behavior Patterns in Inbred and Reciprocal Hybrid Mice

Individual variation in maternal care in mammals shows a significant heritable component, with the maternal behavior of daughters resembling that of their mothers. In laboratory mice, genetically distinct inbred strains show stable differences in maternal care during the first postnatal week. Moreover, cross fostering and reciprocal breeding studies demonstrate that differences in maternal care between inbred strains persist in the absence of genetic differences, demonstrating a non-genetic or epigenetic contribution to maternal behavior. In this study we applied a mathematical tool, called hidden Markov model (HMM), to analyze the behavior of female mice in the presence of their young. The frequency of several maternal behaviors in mice has been previously described, including nursing/grooming pups and tending to the nest. However, the ordering, clustering, and transitions between these behaviors have not been systematically described and thus a global description of maternal behavior is lacking. Here we used HMM to describe maternal behavior patterns in two genetically distinct mouse strains, C57BL/6 and BALB/c, and their genetically identical reciprocal hybrid female offspring. HMM analysis is a powerful tool to identify patterns of events that cluster in time and to determine transitions between these clusters, or hidden states. For the HMM analysis we defined seven states: arched-backed nursing, blanket nursing, licking/grooming pups, grooming, activity, eating, and sleeping. By quantifying the frequency, duration, composition, and transition probabilities of these states we were able to describe the pattern of maternal behavior in mouse and identify aspects of these patterns that are under genetic and nongenetic inheritance. Differences in these patterns observed in the experimental groups (inbred and hybrid females) were detected only after the application of HMM analysis whereas classical statistical methods and analyses were not able to highlight them

Subclinical Epileptiform Process in Patients with Unipolar Depression and Its Indirect Psychophysiological Manifestations

BACKGROUND: According to recent clinical findings epileptiform activity in temporolimbic structures may cause depressive and other psychiatric symptoms that may occur independently of any seizure in patient's history. In addition in these patients subclinical seizure-like activity with indirect clinical manifestations likely may occur in a form of various forms of cognitive, affective, memory, sensory, behavioral and somatic symptoms (the so-called complex partial seizure-like symptoms). A typical characteristic of epileptiform changes is increased neural synchrony related to spreading of epileptiform activity between hemispheres even in subclinical conditions i.e. without seizures. These findings suggest a hypothesis that measures reflecting a level of synchronization and information transfer between hemispheres could reflect spreading of epileptiform activity and might be related to complex partial seizure-like symptoms. METHODS AND FINDINGS: Suitable data for such analysis may provide various physiological signals reflecting brain laterality, as for example bilateral electrodermal activity (EDA) that is closely related to limbic modulation influences. With this purpose we have performed measurement and analysis of bilateral EDA and compared the results with psychometric measures of complex partial seizure-like symptoms, depression and actually experienced stress in 44 patients with unipolar depression and 35 healthy controls. The results in unipolar depressive patients show that during rest conditions the patients with higher level of complex partial seizure like symptoms (CPSI) display increased level of EDA transinformation (PTI) calculated between left and right EDA records (Spearman correlation between CPSI and PTI is r = 0.43, p = 0.004). CONCLUSIONS: The result may present potentially useful clinical finding suggesting that increased EDA transinformation (PTI) could indirectly indicate increased neural synchrony as a possible indicator of epileptiform activity in unipolar depressive patients treated by serotoninergic antidepresants

Deficient maternal care resulting from immunological stress during pregnancy is associated with a sex-dependent enhancement of conditioned fear in the offspring

Activation of maternal stress response systems during pregnancy has been associated with altered postpartum maternal care and subsequent abnormalities in the offspring’s brain and behavioral development. It remains unknown, however, whether similar effects may be induced by exposure to immunological stress during pregnancy. The present study was designed to address this issue in a mouse model of prenatal immune activation by the viral mimic polyriboinosinic–polyribocytidilic acid (PolyI:C). Pregnant mice were exposed to PolyI:C-induced immune challenge or sham treatment, and offspring born to PolyI:C- and sham-treated dams were simultaneously cross-fostered to surrogate rearing mothers, which had either experienced inflammatory or vehicle treatment during pregnancy. We evaluated the effects of the maternal immunological manipulation on postpartum maternal behavior, and we assessed the prenatal and postnatal maternal influences on anxiety- and fear-related behavior in the offspring at the peri-adolescent and adult stage of development. We found that PolyI:C treatment during pregnancy led to changes in postpartum maternal behavior in the form of reduced pup licking/grooming and increased nest building activity. Furthermore, the adoption of neonates by surrogate rearing mothers, which had experienced PolyI:C-induced immunological stress during pregnancy, led to enhanced conditioned fear in the peri-adolescent and adult offspring, an effect that was exclusively seen in female but not male subjects. Unconditioned (innate) anxiety-related behavior as assessed in the elevated plus maze and open field explorations tests were not affected by the prenatal and postnatal manipulations. Our results thus highlight that being raised by gestationally immune-challenged surrogate mothers increases the vulnerability for specific forms of fear-related behavioral pathology in later life, and that this association may be mediated by deficits in postpartum maternal care. This may have important implications for the identification and characterization of early-life risk factors involved in the developmental etiology of fear-related neuropsychiatric disorders

Broad Epigenetic Signature of Maternal Care in the Brain of Adult Rats

BACKGROUND: Maternal care is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCORTICOID RECEPTOR) gene in the hippocampus of both rats and humans. In the rat, these effects are reversed by cross-fostering, demonstrating that they are defined by epigenetic rather than genetic processes. However, epigenetic changes at a single gene promoter are unlikely to account for the range of outcomes and the persistent change in expression of hundreds of additional genes in adult rats in response to differences in maternal care. METHODOLOGY/PRINCIPAL FINDINGS: We examine here using high-density oligonucleotide array the state of DNA methylation, histone acetylation and gene expression in a 7 million base pair region of chromosome 18 containing the NR3C1 gene in the hippocampus of adult rats. Natural variations in maternal care are associated with coordinate epigenetic changes spanning over a hundred kilobase pairs. The adult offspring of high compared to low maternal care mothers show epigenetic changes in promoters, exons, and gene ends associated with higher transcriptional activity across many genes within the locus examined. Other genes in this region remain unchanged, indicating a clustered yet specific and patterned response. Interestingly, the chromosomal region containing the protocadherin-α, -β, and -γ (Pcdh) gene families implicated in synaptogenesis show the highest differential response to maternal care. CONCLUSIONS/SIGNIFICANCE: The results suggest for the first time that the epigenetic response to maternal care is coordinated in clusters across broad genomic areas. The data indicate that the epigenetic response to maternal care involves not only single candidate gene promoters but includes transcriptional and intragenic sequences, as well as those residing distantly from transcription start sites. These epigenetic and transcriptional profiles constitute the first tiling microarray data set exploring the relationship between epigenetic modifications and RNA expression in both protein coding and non-coding regions across a chromosomal locus in the mammalian brain

Differences in Mouse Maternal Care Behavior – Is There a Genetic Impact of the Glucocorticoid Receptor?

Depressive episodes are frequently preceded by stressful life events. Evidence from genetic association studies suggests a role for the glucocorticoid receptor (GR), an essential element in the regulation of stress responses, in the pathophysiology of the disorder. Since the stress response system is affected by pregnancy and postpartum-associated changes, it has also been implicated in the pathophysiology of postpartum depression. Using a 2×2 factorial design, we investigated whether a heterozygous deletion of GR would influence maternal care behavior in C57BL/6 and Balb/c mice, two inbred strains known to display qualitative differences in this behavior. Behavioral observation was carried out between postnatal days 1 and 7, followed by a pup retrieval test on postnatal days 7 or 8. While previously noted inter-strain differences were confirmed for different manifestations of caring behavior, self-maintenance and neglecting behaviors as well as the pup retrieval test, no strain-independent effect of the GR mutation was noted. However, an interaction between GR genotype and licking/grooming behavior was observed: it was down-regulated in heterozygous C57BL/6 mice to the level recorded for Balb/c mice. Home cage observation poses minimal disturbance of the dam and her litter as compared to more invasive assessments of dams' emotional behavior. This might be a reason for the absence of any overall effects of the GR mutation, particularly since GR heterozygous animals display a depressive-like phenotype under stressful conditions only. Still, the subtle effect we observed may point towards a role of GR in postpartum affective disorders

Maternal Environment Influences Cocaine Intake in Adulthood in a Genotype-Dependent Manner

Background: Accumulating epidemiological evidence points to the role of genetic background as a modulator of the capacity of adverse early experiences to give rise to mental illness. However, direct evidence of such gene-environment interaction in the context of substance abuse is scarce. In the present study we investigated whether the impact of early life experiences on cocaine intake in adulthood depends on genetic background. In addition, we studied other behavioral dimensions associated with drug abuse, i.e. anxiety- and depression-related behaviors. Methodology/Principal Findings: For this purpose, we manipulated the maternal environment of two inbred mouse strains, the C57BL/6J and DBA/2J by fostering them with non-related mothers, i.e. the C3H/HeN and AKR strains. These mother strains show respectively high and low pup-oriented behavior. As adults, C57BL/6J and DBA/2J were tested either for cocaine intravenous self-administration or in the elevated plus-maze and forced swim test (FST). We found that the impact of maternal environment on cocaine use and a depression-related behavior depends upon genotype, as cocaine self-administration and behavior in the FST were influenced by maternal environment in DBA/2J, but not in C57BL/6J mice. Anxiety was not influenced by maternal environment in either strain. Conclusions/Significance: Our experimental approach could contribute to the identification of the psychobiological factor

Transient Gastric Irritation in the Neonatal Rats Leads to Changes in Hypothalamic CRF Expression, Depression- and Anxiety-Like Behavior as Adults

A disturbance of the brain-gut axis is a prominent feature in functional bowel disorders (such as irritable bowel syndrome and functional dyspepsia) and psychological abnormalities are often implicated in their pathogenesis. We hypothesized that psychological morbidity in these conditions may result from gastrointestinal problems, rather than causing them.Functional dyspepsia was induced by neonatal gastric irritation in male rats. 10-day old male Sprague-Dawley rats received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days. At 8-10 weeks of age, rats were tested with sucrose preference and forced-swimming tests to examine depression-like behavior. Elevated plus maze, open field and light-dark box tests were used to test anxiety-like behaviors. ACTH and corticosterone responses to a minor stressor, saline injection, and hypothalamic CRF expression were also measured.Behavioral tests revealed changes of anxiety- and depression-like behaviors in IA-treated, but not control rats. As compared with controls, hypothalamic and amygdaloid CRF immunoreactivity, basal levels of plasma corticosterone and stress-induced ACTH were significantly higher in IA-treated rats. Gastric sensory ablation with resiniferatoxin had no effect on behaviors but treatment with CRF type 1 receptor antagonist, antalarmin, reversed the depression-like behavior in IA-treated ratsThe present results suggest that transient gastric irritation in the neonatal period can induce a long lasting increase in depression- and anxiety-like behaviors, increased expression of CRF in the hypothalamus, and an increased sensitivity of HPA axis to stress. The depression-like behavior may be mediated by the CRF1 receptor. These findings have significant implications for the pathogenesis of psychological co-morbidity in patients with functional bowel disorders

C-tactile afferents: Cutaneous mediators of oxytocin release during affiliative tactile interactions?

Low intensity, non-noxious, stimulation of cutaneous somatosensory nerves has been shown to trigger oxytocin release and is associated with increased social motivation, plus reduced physiological and behavioural reactivity to stressors. However, to date, little attention has been paid to the specific nature of the mechanosensory nerves which mediate these effects. In recent years, the neuroscientific study of human skin nerves (microneurography studies on single peripheral nerve fibres) has led to the identification and characterisation of a class of touch sensitive nerve fibres named C-tactile afferents. Neither itch nor pain receptive, these unmyelinated, low threshold mechanoreceptors, found only in hairy skin, respond optimally to low force/velocity stroking touch. Notably, the speed of stroking which c-tactile afferents fire most strongly to is also that which people perceive to be most pleasant. The social touch hypothesis posits that this system of nerves has evolved in mammals to signal the rewarding value of physical contact in nurturing and social interactions. In support of this hypothesis, in this paper we review the evidence that cutaneous stimulation directly targeted to optimally activate c-tactile afferents reduces physiological arousal, carries a positive affective value and, under healthy conditions, inhibits responses to painful stimuli. These effects mirror those, we also review, which have been reported following endogenous release and exogenous administration of oxytocin. Taken together this suggests C-tactile afferent stimulation may mediate oxytocin release during affiliative tactile interactions