Currently, the pathogenesis of depression remains poorly understood, leading to many patients receiving ineffective treatment. Resveratrol has demonstrated beneficial effects in the prevention and treatment of depression. However, it remains unknown whether resveratrol administration can counteract depression-like behaviors by regulating the SIRT1/NF-κB signaling pathway.

Male C57BL/6 mice were randomly assigned to a control group, a depression group, and a resveratrol group. The depression model was established using chronic unpredictable mild stress (CUMS) for 5 weeks. Behavioral tests were conducted to assess depressive-like behaviors. The expression levels of SIRT1 and NF-κB in the hippocampus of mice and BV2 microglial cells were measured. After 5 weeks of modeling, the results indicated that mice in the depression group exhibited significant depressive-like behaviors and inhibited activation of the SIRT1/NF-κB signaling pathway. In contrast, resveratrol administration effectively reversed these changes. Results from in vitro experiments showed that LPS stimulation increased microglial activity and downregulated the SIRT1/NF-κB signaling pathway in microglia; however, resveratrol treatment mitigated these effects.

Our findings suggested that resveratrol can alleviate CUMS-induced depression-like behaviors via the activation of the Sirt1/NF-κB pathway in microglia.

Major depressive disorder (MDD) is a complex, common, and moderately heritable illness, and accumulating evidence suggests that psychological stress may affect male fertility. Mounting evidence indicates sncRNAs in sperm are sensitive to environmental changes and mediate the inheritance of paternally acquired metabolic and mental traits. In order to know the impact of psychological stress on reproduction and alterations in sperm sncRNAs, in this study, depressive-like mice induced by chronic unpredictable mild stimulation (CUMS) were used to investigate the impact of psychological stress on reproduction and alterations in sperm sncRNAs. The results showed that CUMS treatments for 4 weeks induced depressive behavior in male mice and significantly affected sperm quality. The results obtained from small RNA sequencing indicated that alterations occurred in the distribution and composition of small non-coding RNAs (sncRNAs), encompassing PIWI-interacting RNAs (piRNAs), rRNA-derived small RNAs (rsRNAs), and tRNA-derived small RNAs (tsRNAs). Furthermore, the offspring of male mice with depressive-like behavior have a significant reduction in survival rate at 21 days after birth, and those that did survive displayed an increased susceptibility to depression. This study provides some theoretical support for understanding the effects of psychological stress on reproduction, as well as information exchange from psychological stimulation to germ cells, and then from germ cells to next generation.

Environmental factors affect not only paternal condition but may translate into the following generations where sperm-mediated small RNAs (sRNAs) can contribute to the transmission of paternal effects. sRNAs play a key role in the male germ line in genome maintenance and repair, and particularly in response to environmental stress and the resulting increase in transposable element (TE) activity. Here, we investigated how the social environment (high competition, low competition) of male zebrafish Danio rerio affects sRNAs in sperm and how these are linked to gene expression and TE activity in their offspring. In a first experiment, we collected sperm samples after exposing males to each social environment for 2 weeks to test for differentially expressed sperm micro- (miRNA) and piwi-interacting RNAs (piRNA). In a separate experiment, we performed in vitro fertilisations after one 2-week period using a split-clutch design to control for maternal effects and collected embryos at 24 h to test for differentially expressed genes and TEs. We developed new computational prediction tools to link sperm sRNAs with differentially expressed TEs and genes in the embryos. Our results support the idea that the molecular stress response in the male germ line has significant down-stream effects on the molecular pathways, and we provide a direct link between sRNAs, TEs and gene expression.

Recent studies support the influence of paternal lifestyle and diet before conception on the health of the offspring via epigenetic inheritance through sperm DNA methylation, histone modification, and small non-coding RNA (sncRNA) expression and regulation. Smoking may induce DNA hypermethylation in genes related to anti-oxidation and insulin resistance. Paternal diet and obesity are associated with greater risks of metabolic dysfunction in offspring via epigenetic alterations in the sperm. Metabolic changes, such as high blood glucose levels and increased body weight, are commonly observed in the offspring of fathers subjected to chronic stress, in addition to an enhanced risk of depressive-like behaviour and increased sensitivity to stress in both the F0 and F1 generations. DNA methylation is correlated with alterations in sperm quality and the ability to fertilise oocytes, possibly via a differentially regulated MAKP81IP3 signalling pathway. Paternal exposure to toxic endocrine-disrupting chemicals (EDCs) is also linked to the transgenerational transmission of increased predisposition to disease, infertility, testicular disorders, obesity, and polycystic ovarian syndrome (PCOS) in females through epigenetic changes during gametogenesis. As the success of assisted reproductive technology (ART) is also affected by paternal diet, BMI, and alcohol consumption, its outcomes could be improved by modifying factors that are dependent on male lifestyle choices and environmental factors. This review discusses the importance of epigenetic signatures in sperm-including DNA methylation, histone retention, and sncRNA-for sperm functionality, early embryo development, and offspring health. We also discuss the mechanisms by which paternal lifestyle and environmental factors (obesity, smoking, EDCs, and stress) may impact the sperm epigenome.

Prenatal maternal stress (PNMS) determines lifetime mental and physical health. Here, we show in rats that PNMS has consequences for placental function and fetal brain development across four generations (F0-F3). Using a systems biology approach, comprehensive DNA methylation (DNAm), miRNA, and mRNA profiling revealed a moderate impact of PNMS in the F1 generation, but drastic changes in F2 and F3 generations, suggesting compounding effects of PNMS with each successive generation. Both maternal and placental miRNA gene targets included de novo DNA methyltransferases, indicating robust PNMS-induced disruption in the complex epigenetic regulatory network between miRNAs and DNAm. Transgenerational programming mainly involved genes and biological pathways associated with neurological and psychiatric diseases which were linked to maternal-fetal crosstalk facilitated by the placenta. The highly correlated placenta-brain profiles support the use of placenta as a noninvasive biomarker resource to predict pathological changes in the neonatal brain. The transgenerational persistence of critical DNAm, miRNA and mRNA signatures may explain familial non-genetic disease risks.

The paternal environment prior to conception has been demonstrated to influence offspring physiology and behavior, with the sperm epigenome (including noncoding RNAs) proposed as a potential facilitator of non-genetic inheritance. Whilst the maternal gut microbiome has been established as an important influence on offspring development, the impact of the paternal gut microbiome on offspring development, health and behavior is largely unknown. Gut microbiota have major influences on immunity, and thus we hypothesized that they may be relevant to paternal immune activation (PIA) modulating epigenetic inheritance in mice. Therefore, male C57BL/6J mice (F0) were orally administered non-absorbable antibiotics via drinking water in order to substantially deplete their gut microbiome. Four weeks after administration of the antibiotics (gut microbiome depletion), F0 male mice were then mated with naïve female mice. The F1 offspring of the microbiome-depleted males had reduced body weight as well as altered gut morphology (shortened colon length). F1 females showed significant alterations in affective behaviors, including measures of anxiety and depressive-like behaviors, indicating altered development. Analysis of small noncoding RNAs in the sperm of F0 mice revealed that gut microbiome depletion is associated with differential expression of 8 different PIWI-interacting RNAs (piRNAs), each of which has the potential to modulate the expression of multiple downstream gene targets, and thus influence epigenetic inheritance and offspring development. This study demonstrates that the gut-germline axis influences sperm small RNA profiles and offspring physiology, with specific impacts on offspring affective and/or coping behaviors. These findings may have broader implications for other animal species with comparable gut microbiota, intergenerational epigenetics and developmental biology, including humans.

Understanding and assessing dairy cattle behavior is critical for developing sustainable breeding programs and management practices. The behavior of individual animals can provide valuable information on their health and welfare status, improve reproductive management, and predict efficiency traits such as feed efficiency and milking efficiency. Routine genetic evaluations of animal behavior traits can contribute to optimizing breeding and management strategies for dairy cattle but require the identification of traits that capture the most important biological processes involved in behavioral responses. These traits should be heritable, repeatable, and measured in noninvasive and cost-effective ways in many individuals from the breeding populations or related reference populations. Although behavior traits are heritable in dairy cattle populations, they are highly polygenic, with no known major genes influencing their phenotypic expression. Genetically selecting dairy cattle based on their behavior can be advantageous because of their relationship with other key traits such as animal health, welfare, and productive efficiency, as well as animal and handler safety. Trait definition and longitudinal data collection are still key challenges for breeding for behavioral responses in dairy cattle. However, the more recent developments and adoption of precision technologies in dairy farms provide avenues for more objective phenotyping and genetic selection of behavior traits. Furthermore, there is still a need to standardize phenotyping protocols for existing traits and develop guidelines for recording novel behavioral traits and integrating multiple data sources. This review gives an overview of the most common indicators of dairy cattle behavior, summarizes the main methods used for analyzing animal behavior in commercial settings, describes the genetic and genomic background of previously defined behavioral traits, and discusses strategies for breeding and improving behavior traits coupled with future opportunities for genetic selection for improved behavioral responses.

Artificial light at night (ALAN) can disrupt the natural behaviour, physiology, and circadian rhythms of organisms exposed to it, and therefore presents a significant and widespread ecological concern. ALAN typically comprises a wide range of wavelengths, and different wavelengths have different effects on circadian clocks. In the animals investigated thus far, short and middle wavelengths are intensely involved in synchronisation and entrainment, but we still have a poor understanding of how different wavelengths might affect behaviour when animals are exposed to ALAN, in particular whether some wavelengths are disproportionally detrimental. This experiment examined the direct and transgenerational effects of 10 different wavelength treatments of ALAN on behaviour in zebrafish (Danio rerio), a diurnally active model organism. Across a 10-day period, female zebrafish were exposed to either a monochromatic wavelength, white light ALAN, or to a control treatment, and the individual impacts of each treatment on locomotion and anxiety-like behaviours were examined both for solitary fish and fish in groups. We found the strongest impact at short wavelengths (365 to 470 nm), with individuals and groups of zebrafish showing more anxiety-like behaviour after fewer nights of ALAN exposure relative to the other wavelengths. Furthermore, F1 offspring born from ALAN-exposed mothers displayed less frequent movement and shorter movement distances despite never being exposed to ALAN themselves, regardless of the spectral treatment. Our results highlight both the specific and broad-spectrum potential for ALAN to cause disruption to locomotion in adult zebrafish and their offspring.

While transgenerational epigenetic inheritance has been extensively documented in plants, nematodes, and fruit flies, its existence in mammals remains controversial. Several factors have contributed to this debate, including the lack of a clear distinction between intergenerational and transgenerational epigenetic inheritance (TEI), the inconsistency of some studies, the potential confounding effects of in-utero vs. epigenetic factors, and, most importantly, the biological challenge of epigenetic reprogramming. Two waves of epigenetic reprogramming occur: in the primordial germ cells and the developing embryo after fertilization, characterized by global erasure of DNA methylation and remodelling of histone modifications. Consequently, TEI can only occur if specific genetic regions evade this reprogramming and persist through embryonic development. These challenges have revived the long-standing debate about the possibility of inheriting acquired traits, which has been strongly contested since the Lamarckian and Darwinian eras. As a result, coupled with the absence of universally accepted criteria for transgenerational epigenetic studies, a vast body of literature has emerged claiming evidence of TEI. Therefore, the goal of this study is to advocate for establishing fundamental criteria that must be met for a study to qualify as evidence of TEI. We identified five criteria based on the consensus of studies that critically evaluated TEI. To assess whether published original research papers adhere to these criteria, we examined 80 studies that either claimed or were cited as supporting TEI. The findings of this analysis underscore the widespread confusion in this field and highlight the urgent need for a unified scientific consensus on TEI requirements.

Paternal health and exposure to adverse environments in the period prior to conception have a profound impact on future generations. Adversities such as stress, diet, and toxicants influence offspring health. Emerging evidence indicates that epigenetic mechanisms including noncoding RNA, DNA methylation, and chromatin remodelling mediate these effects. Preclinical studies have contributed to advancing mechanistic understanding in the field; however, human research is limited and primarily observational. Here, we discuss the evidence linking paternal to offspring health and advocate for further research in this area, which may ultimately inform policy and healthcare guidelines to improve paternal preconception health and offspring outcomes.

To preclinically study the effectiveness of new antihypertensive drugs, various animal hypertension models are used. However, most of them do not correspond to primary hypertension, which develops in people with age. We used male Wistar rats of 4, 10, 12 and 18 months old. The animals were divided according to systolic blood pressure (SBP) into normotensive (SBP ≤ 114 mmHg) or hypertensive (SBP ≥ 115 mmHg). Within hypertensive animals, two cohorts were distinguished-with SBP below and above 125 mmHg. The animals received 100 µg/kg of taxifolin intraperitoneally for 7 days. A significant difference was shown between animals with SBP above and below 115 mmHg, as well as between cohorts of hypertensive animals with SBP above and below 125 mmHg within each age. The number of animals with elevated SBP increased with age both for clusters with an SBP above 115 mmHg and for cohorts with an SBP above 125 mmHg. Administration of taxifolin led to a significant decrease in the SBP only in hypertensive animals. A physiological model of age-related hypertension was obtained in male Wistar rats. It has been shown that hypertension develops and worsens with age. In preclinical studies, it should be taken into account that drugs may have different effects depending on the initial SBP of the animals.

Anisman, H., Doubad, D., Asokumar, A. & Matheson, K. Psychosocial and neurobiological aspects of the worldwide refugee crisis: From vulnerability to resilience. NEUROSCI BIOBEHAV REV, XXXX. Immigration occurs between countries either to obtain employment, for family reunification or to escape violence and other life-threatening conditions. Refugees and asylum seekers are often obligated to overcome a uniquely challenging set of circumstances prior to and during migration. Settlement following immigration may pose yet another set of stressors related to acculturation to the host country, as well as financial insecurity, discrimination, language barriers, and social isolation. Here we discuss the multiple consequences of immigration experiences, focusing on the health disturbances that frequently develop in adults and children. Aside from the psychosocial influences, immigration-related challenges may cause hormonal, inflammatory immune, and microbiota changes that favor psychological and physical illnesses. Some biological alterations are subject to modification by epigenetic changes, which have implications for intergenerational trauma transmission, as might disruptions in parenting behaviors and family dysfunction. Despite the hardships experienced, many immigrants and their families exhibit positive psychological adjustment after resettlement. We provide information to diminish the impacts associated with immigration and offer strength-based approaches that may foster resilience.

Early social isolation (SI) leads to various abnormalities in emotion and behavior during adulthood. However, the negative impact of SI on offspring remains unclear. This study has discovered that paternal early SI causes social memory deficits and anxiety-like behavior in F1 young adult mice, with alterations of myelin and synapses in the medial prefrontal cortex (mPFC). The 2-week SI in the F1 progeny exacerbates social memory impairment and hypomyelination in the mPFC. Furthermore, the down-regulation of miR-124, a key inhibitor of myelinogenesis, or over-expression of its target gene Nr4a1 in the mPFC of the F1 mice improves social interaction ability and enhances oligodendrocyte maturation and myelin formation. Mechanistically, elevated levels of miR-124 in the sperm of paternal SI mice are transmitted epigenetically to offspring, altering the expression levels of miR-124/Nr4a1/glucocorticoid receptors in mPFC oligodendrocytes. This, in turn, impedes the establishment of myelinogenesis-dependent social behavior. This study unveils a novel mechanism through which miR-124 mediates the intergenerational effects of early isolation stress, ultimately impairing the establishment of social behavior and neurodevelopment.

Epigenetic modifications, such as 5-methylcytosine (5mC), can sometimes be transmitted between generations, provoking speculation that epigenetic changes could play a role in adaptation and evolution. Here, we use experimental evolution to investigate how 5mC levels evolve in populations of biparental insect (Nicrophorus vespilloides) derived from a wild source population and maintained independently under different regimes of parental care in the lab. We show that 5mC levels in the transcribed regions of genes (gene bodies) diverge between populations that have been exposed to different levels of care for 30 generations. These changes in 5mC do not reflect changes in the levels of gene expression. However, the accumulation of 5mC within genes between populations is associated with reduced variability in gene expression within populations. Our results suggest that evolved change in 5mC could contribute to phenotypic evolution by influencing variability in gene expression in invertebrates.

Exercise has the unique aptitude to benefit overall health of body and brain. Evidence indicates that the effects of exercise can be saved in the epigenome for considerable time to elevate the threshold for various diseases. The action of exercise on epigenetic regulation seems central to building an "epigenetic memory" to influence long-term brain function and behavior. As an intrinsic bioenergetic process, exercise engages the function of the mitochondria and redox pathways to impinge upon molecular mechanisms that regulate synaptic plasticity and learning and memory. We discuss how the action of exercise uses mechanisms of bioenergetics to support a "epigenetic memory" with long-term implications for neural and behavioral plasticity. This information is crucial for directing the power of exercise to reduce the burden of neurological and psychiatric disorders.

Prenatal maternal stress (PMS) is known to shape the phenotype of the first generation offspring (F1) but according to some studies, it could also shape the phenotype of the offspring of the following generations. We previously showed in the Japanese quail that PMS increased the emotional reactivity of F1 offspring in relation to (i) a variation in the levels of some histone post-translational modification (H3K27me3) in their brains and (ii) a modulation of the hormonal composition of the eggs from which they hatched. Here, we wondered whether PMS could also influence the behaviour of the second (F2) and third (F3) generation offspring due to the persistence of the specific marks we identified. Using a principal component analysis, we found that PMS influenced F2 and F3 quail profiles with subtle differences between generations. It increased F2 neophobia, F3 fearfulness and F3 neophobia but only in females. Interestingly, we did not find any variations in the level of histone post-translational modification in F3 brains and we observed inconsistent modulations of androstenedione levels in F1 and F2 eggs. Although they may vary over generations, our results demonstrate that PMS can have phenotypical effects into the third generation.

Evolutionary biology provides a unifying theory for testing hypotheses about the relationship between hormones and person perception. Person perception usually receives attention from the perspective of sexual selection. However, because person perception is one trait in a suite regulated by hormones, univariate approaches are insufficient. In this Perspectives article, quantitative genetics is presented as an important but underutilized framework for testing evolutionary hypotheses within this literature. We note tacit assumptions within the current literature on psychiatric genetics, which imperil the interpretation of findings thus far. As regulators of a diverse manifold of traits, hormones mediate tradeoffs among an array of functions. Hormonal pleiotropy also provides the basis of correlational selection, a process whereby selection on one trait in a hormone-mediated suite generates selection on the others. This architecture provides the basis for conflicts between sexual and natural selection within hormone-mediated suites. Due to its role in person perception, psychiatric disorders, and reproductive physiology, the sex hormone estrogen is highlighted as an exemplar here. The implications of this framework for the evolution of person perception are discussed. Empirical quantification of selection on traits within hormone-mediated suites remains an important gap in this literature with great potential to illuminate the fundamental nature of psychiatric disorders.

Stress in early life can affect the progeny and increase the risk to develop psychiatric and cardiometabolic diseases across generations. The cross-generational effects of early life stress have been modeled in mice and demonstrated to be associated with epigenetic factors in the germline. While stress is known to affect gut microbial features, whether its effects can persist across life and be passed to the progeny is not well defined. Here we show that early postnatal stress in mice shifts the fecal microbial composition (binary Jaccard index) throughout life, including abundance of eight amplicon sequencing variants (ASVs). Further effects on fecal microbial composition, structure (weighted Jaccard index), and abundance of 16 ASVs are detected in the progeny across two generations. These effects are not accompanied by changes in bacterial metabolites in any generation. These results suggest that changes in the fecal microbial community induced by early life traumatic stress can be perpetuated from exposed parent to the offspring.

Several epidemiological, clinical and experimental studies in recent decades have shown the relationship between exposure to stressors during development and health outcomes later in life. The characterization of these susceptible phases, such as preconception, gestation, lactation and adolescence, and the understanding of factors that influence the risk of an adult individual for developing obesity, metabolic and cardiovascular diseases, is the focus of the DOHaD (Developmental Origins of Health and Disease) research line. In this sense, advancements in molecular biology techniques have contributed significantly to the understanding of the mechanisms underlying the observed phenotypes, their morphological and physiological alterations, having as a main driving factor the epigenetic modifications and their consequent modulation of gene expression. The present narrative review aimed to characterize the different susceptible phases of development and associated epigenetic modifications, and their implication in the development of non-communicable diseases. Additionally, we provide useful insights into interventions during development to counteract or prevent long-term programming for disease susceptibility.

Maternal care during the early postnatal period of altricial mammals is a key factor in the survival and adaptation of offspring to environmental conditions. Natural variations in maternal care and experimental manipulations with maternal-child relationships modeling early-life adversity (ELA) in laboratory rats and mice have a strong long-term influence on the physiology and behavior of offspring in rats and mice. This literature review is devoted to the latest research on the role of epigenetic mechanisms in these effects of ELA and mother-infant relationship, with a focus on the regulation of hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor. An important part of this review is dedicated to pharmacological interventions and epigenetic editing as tools for studying the causal role of epigenetic mechanisms in the development of physiological and behavioral profiles. A special section of the manuscript will discuss the translational potential of the discussed research.

Although the long-lasting effects of variation in early-life environment have been well documented across organisms, the underlying causal mechanisms are only recently starting to be unraveled. Yet understanding the underlying mechanisms of long-lasting effects can help us predict how organisms will respond to changing environments. Birds offer a great system in which to study developmental plasticity and its underlying mechanisms owing to the production of large external eggs and variation in developmental trajectories, combined with a long tradition of applied, physiological, ecological and evolutionary research. Epigenetic changes (such as DNA methylation) have been suggested to be a key mechanism mediating long-lasting effects of the early-life environment across taxa. More recently, changes in the early-life gut microbiome have been identified as another potential mediator of developmental plasticity. As a first step in understanding whether these mechanisms contribute to developmental plasticity in birds, this Review summarizes how changes in early-life environment (both prenatal and postnatal) influence epigenetic markers and the gut microbiome. The literature shows how both early-life biotic (such as resources and social environment) and abiotic (thermal environment and various anthropogenic stressors) factors modify epigenetic markers and the gut microbiome in birds, yet data concerning many other environmental factors are limited. The causal links of these modifications to lasting phenotypic changes are still scarce, but changes in the hypothalamic-pituitary-adrenal axis have been identified as one putative pathway. This Review identifies several knowledge gaps, including data on the long-term effects, stability of the molecular changes, and lack of diversity in the systems studied, and provides directions for future research.

Chronic stress and alcohol (ethanol) use are highly interrelated and can change an individual's behavior through molecular adaptations that do not change the DNA sequence, but instead change gene expression. A recent wealth of research has found that these nongenomic changes can be transmitted across generations, which could partially account for the "missing heritability" observed in genome-wide association studies of alcohol use disorder and other stress-related neuropsychiatric disorders. In this review, we summarize the molecular and behavioral outcomes of nongenomic inheritance of chronic stress and ethanol exposure and the germline mechanisms that could give rise to this heritability. In doing so, we outline the need for further research to: (1) Investigate individual germline mechanisms of paternal, maternal, and biparental nongenomic chronic stress- and ethanol-related inheritance; (2) Synthesize and dissect cross-generational chronic stress and ethanol exposure; (3) Determine cross-generational molecular outcomes of preconception ethanol exposure that contribute to alcohol-related disease risk, using cancer as an example. A detailed understanding of the cross-generational nongenomic effects of stress and/or ethanol will yield novel insight into the impact of ancestral perturbations on disease risk across generations and uncover actionable targets to improve human health.

Neurological diseases and neurotrauma manifest significant sex differences in prevalence, progression, outcome, and therapeutic responses. Genetic predisposition, sex hormones, inflammation, and environmental exposures are among many physiological and pathological factors that impact the sex disparity in neurological diseases. MicroRNAs (miRNAs) are a powerful class of gene expression regulator that are extensively involved in mediating biological pathways. Emerging evidence demonstrates that miRNAs play a crucial role in the sex dimorphism observed in various human diseases, including neurological diseases. Understanding the sex differences in miRNA expression and response is believed to have important implications for assessing the risk of neurological disease, defining therapeutic intervention strategies, and advancing both basic research and clinical investigations. However, there is limited research exploring the extent to which miRNAs contribute to the sex disparities observed in various neurological diseases. Here, we review the current state of knowledge related to the sexual dimorphism in miRNAs in neurological diseases and neurotrauma research. We also discuss how sex chromosomes may contribute to the miRNA sexual dimorphism phenomenon. We attempt to emphasize the significance of sexual dimorphism in miRNA biology in human diseases and to advocate a gender/sex-balanced science.

Stress is one of the prevalent factors influencing cognition. Several studies examined the effect of mild or chronic stress on cognition. However, most of these studies are limited to a few behavioral tests or the expression of selected RNA/proteins markers in a selected brain region.

This study examined the effect of restraint stress on learning, memory, cognition, and expression of transcripts in key learning centers. Male mice were divided into three groups (n = 6/group)-control group, stress group (adult stressed group; S), and F1 group (parental stressed group). Stress group mice were subjected to physical restraint stress for 2 h before light offset for 2 weeks. The F1 group comprised adult male mice born of stressed parents. All animals were subjected to different tests and were sacrificed at the end. Transcription levels of Brain-Derived Neurotrophic Factor (Bdnf), Tyrosine kinase (TrkB), Growth Associated Protein 43 (Gap-43), Neurogranin (Ng), cAMP Response Element-Binding Protein (Creb), Glycogen synthase kinase-3β (Gsk3β), Interleukine-1 (IL-1) and Tumour necrosis factor-α (Tnf-α) were studied.

Results show that both adult and parental stress negatively affect learning, memory and cognition, as reflected by taking longer time to achieve the task or showing reduced exploratory behavior. Expression of Bdnf, TrkB, Gsk3β and Ng was downregulated, while IL-1 and Tnf-α were upregulated in the brain's cortex, thalamus, and hippocampus region of stressed mice. These effects seem to be relatively less severe in the offspring of stressed parents.

The findings suggest that physical restraint stress can alter learning, memory, cognition, and expression of transcripts in key learning centers of brain.

The brain is built up during pregnancy. How it functions afterwards depends on how the expectant mother's diet nourishes it. Walnuts contain significant quantities of polyunsaturated fatty acids (PUFAs) and bioactive phytochemicals, which enhance brain health and function even with advancing age. This study examined the effects of a walnut-enriched diet (WED) on corticohippocampal histoarchitecture and gene expression in rat offspring.

Twenty-eight female adult Wistar rats (n= 7) averaging about 185 g in weight were used for this study. After mating, pregnant dams were split randomly into four groups: A (standard rat chow/control), B (WED from GD 0 - PND 21), C (WED from GD 0 - PND 1), D (WED from PND 1 - PND 21). Offspring of dams were sacrificed at adolescence (PND 35), with brain tissues of interest harvested for subsequent analyses.

We observed no significant correlates in litter size, body, and brain weights across the experimental groups. Histomorphology revealed no distortion in cellular layering and delineation of cells in the PFC and dentate gyrus of both control and WED groups. Nissl staining intensity was enhanced in the offspring of dams exposed to WED versus the control, indicating improved proteostasis. Upregulated mRNA expression of DNMT3a, H2Ax, OPA1, and BDNF was observed in cortical and hippocampal tissues of WEDexposed offspring compared with the control group.

A diet enriched with African walnuts during early development induced changes predictive of cognitive improvements and enhanced stress-response signalling, plasticity, and neural resilience in rat offspring.

Food and nutrition-related factors, including foods and nutrients consumed, dietary patterns, use of dietary supplements, adiposity, and exposure to food-related environmental contaminants, have the potential to impact semen quality and male and female fertility; obstetric, fetal, and birth outcomes; and the health of future generations, but gaps in evidence remain. On 9 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and the school's Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships between food, nutrition, and fertility. Topics addressed included male fertility, female fertility and gestation, and intergenerational effects. This meeting report summarizes the presentations and deliberations from the meeting. Regarding male fertility, a positive association exists with a healthy dietary pattern, with high-quality evidence for semen quality and lower quality evidence for clinical outcomes. Folic acid and zinc supplementation have been found to not impact male fertility. In females, body weight status and other nutrition-related factors are linked to nearly half of all ovulation disorders, a leading cause of female infertility. Females with obesity have worse fertility treatment, pregnancy-related, and birth outcomes. Environmental contaminants found in food, water, or its packaging, including lead, perfluorinated alkyl substances, phthalates, and phenols, adversely impact female reproductive outcomes. Epigenetic research has found that maternal and paternal dietary-related factors can impact outcomes for future generations. Priority evidence gaps identified by meeting participants relate to the effects of nutrition and dietary patterns on fertility, gaps in communication regarding fertility optimization through changes in nutritional and environmental exposures, and interventions impacting germ cell mechanisms through dietary effects. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and fertility.

Prenatal exposure to high-energy diets (HED) increases the susceptibility to behavioral alterations in the male offspring. We addressed whether prenatal HED primes the transgenerational inheritance of structural brain changes impacting anxiety/depression-like behavior in the offspring. For this, we used female Wistar rats exposed to a HED [cafeteria (CAF) diet, n = 6] or chow [control (CON) n = 6] during development. Anxiety and depression-like behavior were evaluated in filial 1 (F1), filial 2 (F2), and filial 3 (F3) male offspring using the open field (OFT), elevated plus maze, novelty suppressed feeding (NSFT), tail suspension (TST), and forced swimming tests. Structural brain changes were identified by deformation-based morphometry (DBM) and diffusion tensor imaging using ex vivo MRI. We found that the F1, F2, and F3 offspring exposed to CAF diet displayed higher anxious scores including longer feeding latency during the NSFT, and in the closed arms, only F1 offspring showed longer stay on edges during the OFT versus control offspring. DBM analysis revealed that CAF offspring exhibited altered volume in the cerebellum, hypothalamus, amygdala, and hippocampus preserved up to the F3 generation of anxious individuals. Also, F3 CAF anxious exhibited greater fractional anisotropy and axial diffusivity (AD) in the amygdala, greater apparent diffusion coefficient in the corpus callosum, and greater AD in the hippocampus with respect to the control. Our results suggest that prenatal and lactation exposure to HED programs the transgenerational inheritance of structural brain changes related to anxiety-like behavior in the male offspring.

While physiologic stress has long been known to impair mammalian reproductive capacity through hormonal dysregulation, mounting evidence now suggests that stress experienced prior to or during gestation may also negatively impact the health of future offspring. Rodent models of gestational physiologic stress can induce neurologic and behavioral changes that persist for up to three generations, suggesting that stress signals can induce lasting epigenetic changes in the germline. Treatment with glucocorticoid stress hormones is sufficient to recapitulate the transgenerational changes seen in physiologic stress models. These hormones are known to bind and activate the glucocorticoid receptor (GR), a ligand-inducible transcription factor, thus implicating GR-mediated signaling as a potential contributor to the transgenerational inheritance of stress-induced phenotypes. Here, we demonstrate dynamic spatiotemporal regulation of GR expression in the mouse germline, showing expression in the fetal oocyte as well as the perinatal and adult spermatogonia. Functionally, we find that fetal oocytes are intrinsically buffered against changes in GR signaling, as neither genetic deletion of GR nor GR agonism with dexamethasone altered the transcriptional landscape or the progression of fetal oocytes through meiosis. In contrast, our studies revealed that the male germline is susceptible to glucocorticoid-mediated signaling, specifically by regulating RNA splicing within the spermatogonia, although this does not abrogate fertility. Together, our work suggests a sexually dimorphic function for GR in the germline, and represents an important step towards understanding the mechanisms by which stress can modulate the transmission of genetic information through the germline.

Sex differences are found across brain regions, behaviors, and brain diseases. Sexual differentiation of the brain is initiated prenatally but it continues throughout life, as a result of the interaction of three major factors: gonadal hormones, sex chromosomes, and the environment. These factors are thought to act, in part, via epigenetic mechanisms which control chromatin and transcriptional states in brain cells. In this review, we discuss evidence that epigenetic mechanisms underlie sex-specific neurobehavioral changes during critical organizational periods, across the estrous cycle, and in response to diverse environments throughout life. We further identify future directions for the field that will provide novel mechanistic insights into brain sex differences, inform brain disease treatments and women's brain health in particular, and apply to people across genders.

Recent studies have identified a critical role of the diverse and dynamic microbiome in modulating various aspects of host physiology and intrinsic processes. However, the altered microbiome has also become a hallmark of cancer, which could influence the tumor microenvironment. Aberrations in epigenetic regulation of tumor suppressors, apoptotic genes, and oncogenes can accentuate breast cancer onset and progression. Interestingly, recent studies have established that the microbiota modulates the epigenetic mechanisms at global and gene-specific levels. While the mechanistic basis is unclear, the cross-talk between the microbiome and epigenetics influences breast cancer trajectory. Here, we review different epigenetic mechanisms of mammalian gene expression and summarize the host-associated microbiota distributed across the human body and their influence on cancer and other disease-related genes. Understanding this complex relationship between epigenetics and the microbiome holds promise for new insights into effective therapeutic strategies for breast cancer patients.

Dexamethasone is a stress hormone receptor agonist used widely in clinics. We and others previously showed that paternal administration of dexamethasone in mice affects the phenotype of their offspring. The substrate of intergenerational transmission of environmentally induced effects often involves changes in sperm RNA, yet other epigenetic modifications in the germline can be affected and are also plausible candidates. First, we tested the involvement of altered sperm RNAs in the transmission of dexamethasone induced phenotypes across generations. We did this by injecting sperm RNA into naïve fertilized oocytes, before performing metabolic and behavioral phenotyping of the offspring. We observed phenotypic changes in discordance with those found in offspring generated by in vitro fertilization using sperm from dexamethasone exposed males. Second, we investigated the effect of dexamethasone on chromatin accessibility using ATAC sequencing and found significant changes at specific genomic features and gene regulatory loci. Employing q-RT-PCR, we show altered expression of a gene in the tissue of offspring affected by accessibility changes in sperm. Third, we establish a correlation between specific DNA modifications and stress hormone receptor activity as a likely contributing factor influencing sperm accessibility. Finally, we independently investigated this dependency by genetically reducing thymine-DNA glycosylase levels and observing concomitant changes at the level of chromatin accessibility and stress hormone receptor activity.

Multiple lines of evidence suggest that paternal psychological stress contributes to an increased prevalence of neuropsychiatric and metabolic diseases in the progeny. While altered paternal care certainly plays a role in such transmitted disease risk, molecular factors in the germline might additionally be at play in humans. This is supported by findings on changes to the molecular make up of germ cells and suggests an epigenetic component in transmission. Several rodent studies demonstrate the correlation between paternal stress induced changes in epigenetic modifications and offspring phenotypic alterations, yet some intriguing cases also start to show mechanistic links in between sperm and the early embryo. In this review, we summarise efforts to understand the mechanism of intergenerational transmission from sperm to the early embryo. In particular, we highlight how stress alters epigenetic modifications in sperm and discuss the potential for these modifications to propagate modified molecular trajectories in the early embryo to give rise to aberrant phenotypes in adult offspring.

Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation in obsessive-compulsive disorder (OCD) has been reported, epigenetic changes in HPA axis-related genes have not been well studied in OCD. The present study investigated whether the epigenetic regulation of FK506-binding protein 51 gene (FKBP5) intron 7 is associated with OCD status in each sex. In addition, relationships among the DNA methylation levels of FKBP5 intron 7, OCD status and early-life trauma were explored.

A total of 267 patients with OCD and 201 controls aged between 18 and 40 years were recruited. Demographic and clinical assessment, FKBP5 rs1360780 genotyping, and pyrosequencing of FKBP5 intron 7 were conducted. DNA was extracted from peripheral blood leucocytes. First, multivariate analysis of covariance for differential DNA methylation levels between OCD patients and controls was conducted with adjustment for FKBP5 rs1360780 genotype, early-life trauma, depressive symptoms, and age as covariates in each sex. Next, path analysis was conducted to determine the mediation effects of DNA methylation levels of FKBP5 between early-life trauma and OCD status. In addition, sensitivity analyses for medication and lifetime major depression were also performed.

DNA methylation at the FKBP5 intron 7 CpG site was significantly lower in men with OCD, compared to controls (mean difference -1.33%, 95% CI -2.11 to -0.55, p < 0.001). The results remained significant for drug naïve or free subjects (mean difference -1.27%, 95% CI -2.18 to -0.37, p = 0.006, in men) and for subjects without lifetime major depressive disorder (mean difference -1.60%, 95% CI -2.54 to -0.66, p < 0.001, in men). The mediation effect of DNA methylation levels was not significant between early-life trauma and OCD status.

These findings suggest that epigenetic factors of HPA axis-related gene FKBP5 may play a role in the pathogenesis of OCD. Further studies are needed to determine how altered DNA methylation of FKBP5 intron 7 and HPA axis function are involved in OCD.

Changes in gene expression are involved in many brain functions. Epigenetic processes modulate gene expression by histone modification and DNA methylation or RNA-mediated processes, which is important for brain function. Consequently, epigenetic changes are also a part of brain diseases such as mental illness and addiction. Understanding the role of different factors on the brain epigenome may help us understand the function of the brain. This review discussed the effects of caffeine, lipids, addictive substances, physical activity, and pollutants on the epigenetic changes in the brain and their modulatory effects on brain function.

Understanding and treatment of antisocial behavior have improved through efforts to subtype individuals based on similar risk factors and outcomes. In particular, the presence of psychopathic traits is associated with distinct etiological factors and antisocial behavior that begins early in life, is aggressive, persistent, and less likely to normalize with traditional treatments, relative to individuals low on psychopathy or its childhood precursor, callous-unemotional (CU) traits. However, important distinctions can be made within individuals with CU/psychopathic traits according to the presence of elevated anxiety symptoms and/or adverse childhood experiences, known as secondary psychopathy/CU traits. This paper provides a broad and brief overview of theory and empirical literature supporting the existence of secondary psychopathy/CU variants as a distinct subtype of childhood antisocial behavior. It outlines the Emotionally Sensitive Child-Adverse Parenting Experiences-Allostatic (Over)Load (ESCAPE-AL) model for the developmental psychopathology of secondary psychopathic/CU traits and discusses research and theory supporting this perspective. Future research directions for testing this conceptual model and its implications for assessing and treating high-risk individuals with secondary CU/psychopathic traits are discussed.

Growing evidence suggests that epigenetic changes through various parental environmental factors alter the phenotypes of descendants in various organisms. Environmental factors, including exposure to chemicals, stress and abnormal nutrition, affect the epigenome in parental germ cells by different epigenetic mechanisms, such as DNA methylation, histone modification as well as small RNAs via metabolites. Some current remaining questions are the causal relationship between environment-induced epigenetic changes in germ cells and altered phenotypes of descendants, and the molecular basis of how the abnormal epigenetic changes escape reprogramming in germ cells. In this review, we introduce representative examples of intergenerational and transgenerational inheritance of phenotypic changes through parental environmental factors and the accompanied epigenetic and metabolic changes, with a focus on animal species. We also discuss the molecular mechanisms of epigenomic inheritance and their possible biological significance.

Early-life stress and ovarian hormones contribute to increased female vulnerability to cocaine addiction. Here, we reveal molecular substrates in the reward area, the nucleus accumbens, through which these female-specific factors affect immediate and conditioning responses to cocaine. We find shared involvement of X chromosome inactivation-related and estrogen signaling-related gene regulation in enhanced conditioning responses following early-life stress and during the low-estrogenic state in females. Low-estrogenic females respond to acute cocaine by opening neuronal chromatin enriched for the sites of ΔFosB, a transcription factor implicated in chronic cocaine response and addiction. Conversely, high-estrogenic females respond to cocaine by preferential chromatin closing, providing a mechanism for limiting cocaine-driven chromatin and synaptic plasticity. We find that physiological estrogen withdrawal, early-life stress, and absence of one X chromosome all nullify the protective effect of a high-estrogenic state on cocaine conditioning in females. Our findings offer a molecular framework to enable understanding of sex-specific neuronal mechanisms underlying cocaine use disorder.

While physiologic stress has long been known to impair mammalian reproductive capacity through hormonal dysregulation, mounting evidence now suggests that stress experienced prior to or during gestation may also negatively impact the health of future offspring. Rodent models of gestational physiologic stress can induce neurologic and behavioral changes that persist for up to three generations, suggesting that stress signals can induce lasting epigenetic changes in the germline. Treatment with glucocorticoid stress hormones is sufficient to recapitulate the transgenerational changes seen in physiologic stress models. These hormones are known to bind and activate the glucocorticoid receptor (GR), a ligand-inducible transcription factor, thus implicating GR-mediated signaling as a potential contributor to the transgenerational inheritance of stress-induced phenotypes. Here we demonstrate dynamic spatiotemporal regulation of GR expression in the mouse germline, showing expression in the fetal oocyte as well as the perinatal and adult spermatogonia. Functionally, we find that fetal oocytes are intrinsically buffered against changes in GR signaling, as neither genetic deletion of GR nor GR agonism with dexamethasone altered the transcriptional landscape or the progression of fetal oocytes through meiosis. In contrast, our studies revealed that the male germline is susceptible to glucocorticoid-mediated signaling, specifically by regulating RNA splicing within the spermatogonia, although this does not abrogate fertility. Together, our work suggests a sexually dimorphic function for GR in the germline, and represents an important step towards understanding the mechanisms by which stress can modulate the transmission of genetic information through the germline.

The field of molecular biology is advancing fast with new powerful technologies, sequencing methods and analysis software being developed constantly. Commonly used tools originally developed for research on humans and model species are now regularly used in ecological and evolutionary research. There is also a growing interest in the causes and consequences of epigenetic variation in natural populations. Studying ecological epigenetics is currently challenging, especially for vertebrate systems, because of the required technical expertise, complications with analyses and interpretation, and limitations in acquiring sufficiently high sample sizes. Importantly, neglecting the limitations of the experimental setup, technology and analyses may affect the reliability and reproducibility, and the extent to which unbiased conclusions can be drawn from these studies. Here, we provide a practical guide for researchers aiming to study DNA methylation variation in wild vertebrates. We review the technical aspects of epigenetic research, concentrating on DNA methylation using bisulfite sequencing, discuss the limitations and possible pitfalls, and how to overcome them through rigid and reproducible data analysis. This review provides a solid foundation for the proper design of epigenetic studies, a clear roadmap on the best practices for correct data analysis and a realistic view on the limitations for studying ecological epigenetics in vertebrates. This review will help researchers studying the ecological and evolutionary implications of epigenetic variation in wild populations.

Recent decades provide mounting evidence for the continual increase in global temperatures, now termed "global warming," to the point of drastic worldwide change in the climate. Climatic change is a long-term shift in temperatures and weather patterns, including increased frequency and intensity of extreme environmental events such as heat waves accompanied by extreme temperatures and high humidity. Climate change and global warming put several challenges to the livestock industry by directly affecting the animal's production, reproduction, health, and welfare. The broad impact of global warming, and in particular heat stress, on-farm animals' performance has been comprehensively studied. It has been estimated that the US livestock industry's loss caused by heat stress is up to $2.4 billion annually. However, the long-term intergenerational and transgenerational effects of climatic change and global warming on farm animals are sparse. Transgenerational effects, which are mediated by epigenetic mechanisms, can affect the animal's performance regardless of its immediate environment by altering its phenotypic expression to fit its ancestors' environment. In many animal species, environmental effects are epigenetically encoded within a narrow time interval during the organism's gametogenesis, and these epigenetic modifications can then be intergenerationally transmitted. Several epigenetic mechanisms mediate intergenerational transmission of environmental effects, typically in a parent-dependent manner. Therefore, exposure of the animal to an extreme climatic event and other environmental stressors during gametogenesis can undergo epigenetic stabilization in the germline and be passed to the offspring. As a result, the offspring might express a phenotype adjusted to fit the stressors experienced by their ancestors, regardless of their direct environment. The purpose of this perspective is to review current evidence for intergenerational and transgenerational transmission of environmental stress effects, specifically in the context of global warming and climate change, and to offer viewpoints on the possible impacts on the livestock industry.

Social behavior deficits are a common, debilitating consequence of traumatic brain injury and stroke, particularly when sustained during childhood. Numerous factors influence the manifestation of social problems after acquired brain injuries, raising the question of whether environmental manipulations can minimize or prevent such deficits. Here, we examine both clinical and preclinical evidence addressing this question, with a particular focus on environmental enrichment paradigms and differing housing conditions. We aimed to understand whether environmental manipulations can ameliorate injury-induced social behavior deficits. In summary, promising data from experimental models supports a beneficial role of environmental enrichment on social behavior. However, limited studies have considered social outcomes in the chronic setting, and few studies have addressed the social context specifically as an important component of the post-injury environment. Clinically, limited high-caliber evidence supports the use of specific interventions for social deficits after acquired brain injuries. An improved understanding of how the post-injury environment interacts with the injured brain, particularly during development, is needed to validate the implementation of rehabilitative interventions that involve manipulating an individuals' environment.

Necrotizing enterocolitis (NEC) is the leading cause of intestinal morbidity and mortality in neonates. A large body of work exists; however, the pathogenesis of NEC remains poorly understood. Numerous predictors have been implicated in the development of NEC, with relatively less emphasis on maternal factors. Utilizing human tissue plays a crucial role in enhancing our comprehension of the underlying mechanisms accountable for this devastating disease. In this review, we will discuss how maternal stress affects the pathogenesis of NEC and how changes in the intestinal microbiome can influence the development of NEC. We will also discuss the results of transcriptomics-based studies and analyze the gene expression changes in NEC tissues and other molecular targets associated with the pathogenesis of NEC.

Autism spectrum disorder (ASD) is the assorted uneven conditions of the human brain that lead to developmental disabilities. This cross-sectional study aimed to identify the substantial risk factors of ASD among children in Bangladesh. The data were collected using convenience sampling through a questionnaire filled up by the trained interviewers. Mann-Whitney U and Kruskal-Wallis H tests were applied as bivariate analysis, and generalized beta regression was performed to determine the significant risk factors of autism spectrum disorder. The odds ratio (OR) along with 95% confidence interval (CI) were the measuring parameters of the risk factors of ASD. The result revealed that later birth order children have more risk of ASD (OR = 1.13, CI: 1.014-1.264, p = 0.027) compared to the children whose birth order is first. Premature birth of the child (OR: 0.87, CI: 0.76-1.00, p = 0.05) and father's age (OR: 0.86, CI: 0.76-0.97, p = 0.020) substantially affects ASD. The maternal history of specific illness (diabetes, thyroiditis, and hypertension) during pregnancy also significantly affect ASD (OR: 1.34, CI: 1.14-1.61, p = 0.002). The results of this study would assist policymakers in taking necessary steps to reduce the incidence of this disorder by targeting the potential risk factors.

The social environment is one of the primary sources of challenging stimuli that can induce a stress response in animals. It comprises both short-term and stable interactions among conspecifics (including unrelated individuals, mates, potential mates and kin). Social stress is of unique interest in the field of stress research because (1) the social domain is arguably the most complex and fluctuating component of an animal's environment; (2) stress is socially transmissible; and (3) stress can be buffered by social partners. Thus, social interactions can be both the cause and cure of stress. Here, we review the history of social stress research, and discuss social stressors and their effects on organisms across early life and adulthood. We also consider cross-generational effects. We discuss the physiological mechanisms underpinning social stressors and stress responses, as well as the potential adaptive value of responses to social stressors. Finally, we identify outstanding challenges in social stress research, and propose a framework for addressing these in future work.