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Published in final edited form as: Eur J Neurosci. 2019 Oct 17;53(1):271–280. doi: 10.1111/ejn.14582

Paternal Transgenerational Epigenetic Mechanisms Mediating Stress Phenotypes of Offspring

Ashley M Cunningham 1, Deena M Walker 1, Eric J Nestler 1,*
PMCID: PMC7085959  NIHMSID: NIHMS1051688  PMID: 31549423

Abstract

Depression and anxiety risk are highly influenced by both genetic and environmental factors. Recently, it has been proposed that epigenetic mechanisms may also contribute to the transmission of both depression- and anxiety-related behaviors across multiple generations. This review highlights long-lasting epigenetic alterations observed in offspring of fathers, including some distinct effects on male and female offspring, in animal models. Available evidence emphasizes how both the developmental time point and the type of paternal stress (social vs asocial) influence the complex transmission patterns of these phenotypes to future generations. This research is critical in understanding the factors that influence risk for depression and anxiety disorders and has the potential to contribute to the development of innovative treatments that can more precisely target vulnerable populations.

Keywords: epigenetics, transgenerational stress, sperm

Graphical Abstract

graphic file with name nihms-1051688-f0001.jpg

• Males exposed to stress in early life or adulthood transmit stress phenotypes offspring with more robust phenotypes in males

• Stress type (social or asocial) and the timing of stress appear to impact behavioral and epigenetic transmission pattern

• Epigenetic changes are observed in both the gametes of fathers exposed to stress and their offspring

Graphical abstract created with BrioRender.com

1. Introduction

Mood and anxiety disorders represent the most common and costly psychiatric disorders. Major depressive disorder (MDD) in particular, has a lifetime prevalence of ~16% in the US population (Kessler et al., 2012), the leading cost of disability (Birnbaum et al., 2010), and has an estimated economic cost of $210.5 billion per year (Greenberg et al., 2015). It is clear that both genetic (Kendler et al., 2001; Eichler et al., 2010) and environmental (Agid et al., 1999; de Codt et al., 2016); (Mandelli et al., 2015) factors contribute to major depressive disorder. For example, twin studies suggest a heritability of about 37% with environmental factors having an influential role (Sullivan et al., 2000). However, studies attempting to identify genomic loci that are associated with increased risk for developing depression (Baselmans et al., 2019; Donaldson et al., 2016; Khandaker et al., 2018; Lemonde et al., 2003; Strobel et al., 2003; Wray et al., 2018) have very recently begun to recognize loci that achieve genome-wide significance but have required the analysis of tens or hundreds of thousands of individuals, and all loci identified to date exert miniscule effects on overall risk. Therefore, it is thought that there is a complex interplay between genetic and environmental factors, such as stress, that influence the onset of both depression and anxiety (McEwen et al., 2004). Preclinical models of major depressive disorder indicate that chronic stress exposure leads to both depression- and anxiety-like phenotypes in rodent models (Lezak et al., 2017). Interestingly, these phenotypes can be transmitted to male and female offspring in both the F1 and F2 generations following paternal exposure to chronic social stress during either adolescence or early adulthood (Franklin et al., 2011; Saavedra-Rodriguez & Feig et al., 2013). Recent studies have focused on understanding the complex mechanisms involved in the transmission of stress pathologies specifically in understanding how epigenetic mechanisms may contribute.

Epigenetics was first described by Waddington based on the observation that changes in phenotype did not always reflect changes in genetic deviation (Waddington, 1957). It has since evolved to be defined as transient or long-lasting heritable changes in the absence of modifications to the genetic code itself. Potential mechanisms of this regulation include DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), all of which produce downstream functional changes which may alter target gene transcription or alternative splicing in a given tissue, in the case of transgenerational transmission in sperm or egg cells. Importantly, these epigenetic mechanisms may contribute to individual differences in predisposition to depression and anxiety disorders (Hodes et al., 2017; Peña et al., 2018). Studies have posited that environmental changes can lead to long-lasting alterations in the epigenome which might act as an important message to relay heritable information to offspring across multiple generations through the germline (Manikkam et al., 2012; Skinner et al., 2013).

The earliest study regarding the influence of an individual’s experience on offspring phenotype across multiple generations exposed pregnant rat dams to a fungicide, vinclozolin, which resulted in disease phenotypes in male offspring including altered DNA methylation and sperm motility, fertility, and testicular apoptosis in both F2 and F3 offspring (Anway et al., 2005). These initial findings provided critical evidence that environmental stimuli may reprogram germ cells to impart important environmental information to subsequent generations. While this study was the first to show transgenerational transmission of a phenotype, several studies have identified key environmental stimuli which influence offspring phenotypes including but not limited to exposure to other toxins (Crews et al., 2007; Skinner et al., 2018), drugs of abuse (Szutorisz & Hurd et al. 2018; Vassoler et al., 2013), stress (Bale et al., 2014), and maternal behaviors (Meaney et al., 2001). Importantly, these studies highlight the need to differentiate between transmission that is intergenerational (context dependent) and transgenerational as both mechanisms can lead to alterations in offspring phenotype. Intergenerational or context dependent transmission occurs when gametes are exposed to a stimulus resulting in an altered phenotype of offspring. However, in transgenerational transmission, the phenotype must be observed in generations that were never exposed to the environmental stimulus. Therefore, paternal transmission of phenotypes must be observed in the F2 generation and maternal transmission of phenotypes must be observed in the F2 generation in non-pregnant females and the F3 generation in pregnant females in order to be considered transgenerational (Bale et al., 2015). Because of this, maternal lineage transgenerational studies can be expensive and time consuming. Despite this, studies have found that maternal stress is weakly associated with increased risk for development of a wide variety of disease phenotypes (Pena et al., 2014). However, those effects are beyond the scope of this review. Instead, the focus of this review will be on how the timing of paternal stress influences transmission patterns of both inter- and transgenerational transmission.

2. Transmission of Behavioral Phenotypes

2.1. Anxiety-Related Behaviors:

Studies examining paternal transmission of anxiety-like phenotypes indicate that the timing of paternal stress is important in the transmission of such phenotypes. For example, stress in early-life (Gapp et al., 2014; Gapp et al., 2018) but not in adolescence or adulthood (Manners et al., 2018) results in decreased baseline anxiety in the offspring (Table 1). Specifically, offspring from male mice who experience maternal separation which involves unpredictable maternal separation combined with unpredictable maternal stress (MSUS) from P1 – P14 show decreased anxiety-like phenotypes on multiple behavioral tests. Importantly, this effect was transmitted across multiple generations in F1 and F2 males (Gapp et al., 2014; Gapp et al., 2018) and F1–F3 females (Franklin et al., 2010). By contrast, fathers exposed to chronic variable (or unpredictable) stress in adolescence or adulthood produced offspring with no discernable baseline anxiety-related phenotypes in F1 or F2 male or female mice (Table 1) (Rodgers et al., 2013).

Table 1.

Behavioral effects of paternal stress in offspring.

Transmission Behavioral Test Patertal Stress Stress time Mating Generation Sex of Offspring Baseline or Stressed Behavioral Output Overview Reference
“Anxiety” Elevated-Plus-Maze Unpredictable Maternal Stress/Seperation early life natural F1 M Baseline shorter latency to first enter an open arm ↓ anxiety Gapp et al., 2014
Gapp et al., 2018
Chronic Social Defeat adulthood natural M Stressed: Submaximal Defeat decreased time in open arm ↑ anxiety Dietz et al., 2011
F
IVF M no effect no effect
F
Elevated Zero Maze Chronic Variable Stress adolescence natural F1 M Baseline no effect no effect Manners et al., 2018
F
Light Dark Box Unpredictable Maternal Stress/Seperation early life natural F1 M Baseline increased time in light zone ↓ anxiety Gapp et al., 2018
Gapp et al., 2014
F2
Chronic Variable Stress adolescence or adulthood F1 M no effect no effect Rodgers et al., 2013
F2 F
Marble Burrying Chronic Variable Stress adolescence natural F1 M Baseline no effect no effect Manners et al., 2018
F1 F
F2 M fewer marbles burned ↓, anxiety
F2 F no effect no effect
Open Field Unpredictable Maternal Stress/Seperation early life natural F1 M Baseline trend in decreased latency to center no effect Franklin et al., 2010
F2 M no effect no effect
F3
F2 F decrease latency to center ↓ anxiety
F3
Novel Environment Unpredictable Maternal Stress/Seperation early life natural F1 M Baseline decrease latency to unfamlilar area ↓ anxiety Franklin et al., 2010
F2 M no effect no effect
F3 M
F2 F decrease latency to unfamlilar area ↓ anxiety
F3 F
Chronic Social Defeat adulthood natural F1 M Stressed: Submaximal Defeat increased locomoter activity ↑ anxiety Dietz et al., 2011
F no effect no effect
IVF M
F
“Depression” Sucrose Preference Test Unpredictable Maternal Stress/Seperation early life natural F1 M Baseline decreased sucrose preference ↑ depression Franklin et al., 2010
F2 M no effect no effect
F3 M
F2 F
F3 F
Chronic Social Defeat adulthood natural F1 M Stressed: Submaximal Defeat trend in decreased sucrose preference no effect Dietz et al., 2011
F no effect no effect
IVF M
F
Forced Swim Test Unpredictable Maternal Stress/Seperation early life natural F1 M Baseline increased time floating ↑ depression Gapp et al., 2018
Gapp et al., 2014
Franklin et al., 2010
F2 Gapp et al., 2014
no effect no effect Franklin et al., 2010
F
F3 M increased time floating ↑ depression
F no effect no effect
Chronic Variable Stress adolescence natural F1 M Baseline no effect no effect Manners et al., 2018
F
Chronic Social Defeat adulthood natural F1 M Stressed: Submaximal Defeat decreased latency to immobility ↑ depression Dietz et al., 2011
F
IVF M
F
Tail Suspension Test Chronic Variable Stress adolescence or adulthood natural F1 M Baseline no effect no effect Rodgers et al., 2013
F
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Abbreviations: IVF=in vitro fertalization; M=male; F=female; ↑=increase in behavior; ↓= decrease in behavior

The type of stress may also be important for the transmission of such phenotypes, as a recent study from our laboratory indicates that adult males exposed to chronic social defeat stress (CSDS) produce offspring with enhanced anxiety-related phenotypes in both male and female F1 mice when exposed to sub-maximal defeat stress, a stressor that exposes male mice to repeated defeat episodes over one day. These behavioral effects were more pronounced in sons than daughters suggesting that male offspring are more susceptible to these pathologies (Dietz et al., 2011). Variations in experimental design likely contribute to differences observed in paternal transmission; examples include (among others) the type and duration of stress, time after stress and differences in sperm maturation during the stressors (for details see Table 1). However, it should be noted that both maternal separation and chronic social defeat stress are social stressors and these data provide intriguing evidence that social stress results in opposite effects on the transmission of anxiety-related behaviors depending on the stage of life in which the fathers are exposed (See Figure 1). More research is necessary to determine how these various factors influence the transmission of such phenotypes including if there are any stress-induced anxiety-related behavioral effects.

Figure 1.

Figure 1.

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A summary of how paternal stress alters behavioral outcomes of offspring rodents. (A) A schematic of developmental of male sex cells and mouse development. (B) Effects of paternal stress during either early life, adolescence, or adulthood on depression- and anxiety-related behaviors in offspring. Neonatal or adolescence stress results in decreased anxiety- like behaviors in offspring when fathers are exposed to either social or asocial stress. However, only social paternal stress results in increased depression- like behaviors in offspring. While little information is available regarding how paternal stress during adulthood (dotted line) alters baseline behavioral phenotypes in offspring, one study has found changed in offspring behavior in social stress paradigms.

2.2. Depression-Related Behaviors:

Studies examining paternal transmission of baseline depression-like behaviors have produced similar results to those observed in baseline anxiety-related behaviors in that the timing and type of stress may influence transmission of such phenotypes. Exposing fathers to maternal separation from P1 – P14 leads to consistent increased baseline depression-like behaviors in F1 male mice, whereas females show no effects (Table 1). Specifically, F1 males spend more time floating in a forced swim test and have decreased sucrose preference. These effects are not as consistent in subsequent generations where F2 males have shown both increases in depression-like behaviors (Gapp, et al. 2014) and no differences in such behaviors (Franklin et al., 2010). To our knowledge, only one study has investigated the effects of maternal separation on the F3 generation and found that male offspring display an increased baseline depression-like phenotype as indicated by increased time floating during a forced swim test (Franklin et al., 2010) (Table 1).

As with the transmission of anxiety-related behaviors, when paternal stress occurs later in life less robust depression-related phenotypes in offspring are observed. No discernable phenotypes are observed in F1 or F2 offspring of fathers exposed to chronic variable stress during adolescence or adulthood (Table 1). However, this may be specific to the type of stress, as our laboratory has found that exposure of the fathers to 10 days of chronic social defeat stress causes increased depression-like behavior in F1 male and female offspring with the phenotypes being more severe in male offspring (Table 1) (Dietz et al., 2011). This study also found that male offspring displayed increased stress reactivity: when the male offspring were exposed to sub-maximal social defeat stress, a stress that does not alter behavior in control animals, they exhibited increased social avoidance which might reflect anhedonia in rodent species (Nestler & Hyman et al., 2010).

Together, these data suggest that the timing of stress is important in influencing the transmission of both anxiety- and depression-like phenotypes to multiple generations (See Figure 1). Further research is necessary to determine if the type of stress (social vs asocial), timing of stress (postnatal vs adolescent vs adult) and duration of stress indeed influences the transmission of such baseline phenotypes to subsequent generations. It would be useful to expand the range of behavioral tests used to examine these behavioral phenotypes, as to our knowledge no study to date has utilized cognitive read outs. Additionally, it is critical to determine if the offspring are more sensitive to stress as anxiety and depression are often triggered by a traumatic or stressful experience in humans (Green et al., 2010).

3. Epigenetic Mechanisms Contributing to the Transmission of Paternal Stress Phenotypes

3.1. DNA Methylation:

Numerous studies have sought to identify epigenetic mechanisms that contribute to the transmission of phenotypes across multiple generations in rodent models. Most of these studies have focused on changes in ncRNAs in the sperm of stressed fathers (see below), however, one study identified changes in DNA methylation in the sperm of F1 males and brains of F2 offspring suggesting that DNA methylation might mediate the transmission of stress phenotypes to subsequent generations. DNA methylation is a process by which methyl groups are covalently added typically to cytosines, oftentimes in dinucleotide CpG sequences. This process influences gene expression by modifying the interactions of DNA with both chromatin proteins and specific transcription factors (Kuehner et al., 2019) and regulates both protein-coding and non-coding genes (Moore et al., 2013). The above study found that DNA methylation was altered in sperm and brain at the promoters of 3 loci previously associated with depression after exposure of mice to maternal separation from P1 – P14 (Franklin et al., 2010), a manipulation which alters anxiety- and depression-related behaviors in offspring (see Section 2 and Table 1). Specifically, methylation was increased at the promoter of methyl CpG binding protein 2 (Mecp2) and cannabinoid receptor 1 (Cnr1) and decreased at corticotrophin-releasing factor receptor 2 (Crhr2). Importantly, the methylation changes at Mecp2 and Crhr2 within the F1 sperm were reflected in the brains of female, but not male, F2 offspring (Franklin et al., 2010). Although these results may seem surprising, considering DNA modifications are almost completely reprogrammed during fertilization in mammals (Sasaki & Matsui et al., 2008), other studies have found similar alterations in DNA methylation in sperm following changes to the environment which are transferred to subsequent generations including but not limited to exposure to ancestral organ damage (Zeybel et al., 2012) and changes in diet (Terashima et al., 2015). Future work is required to prove causality, namely, to demonstrate that given DNA methylation changes in sperm are both necessary and sufficient to transmit paternal effects to offspring, and to understand the precise molecular mechanisms by which such changes program alterations within specific cell types in the brain. With these caveats, the experimental results, taken together, suggest that sperm are sensitive to paternal stress and may be capable of relaying information about the environment to future generations in a sex-specific manner through changes in DNA methylation.

3.2. Non-coding RNAs:

As mentioned above, the majority of studies investigating the epigenetic mechanisms mediating paternal transmission of stress phenotypes have focused on non-coding RNAs (ncRNAs). ncRNAs are a group of genetic regulators that contain short and long transcripts that do not code for proteins but play an important role in gene regulation. Specifically, microRNAs (miRNAs) are small ncRNAs (~22 nucleotides) which have emerged as epigenetic regulators with diverse effectors on gene regulation including chromatin remodeling (Wade et al., 2015), DNA methylation (Yao et al., 2019), both decreased (Carthew & Sontheimer et al., 2009) and increased mRNA translation (Fabian et al., 2010) and mRNA degradation (Bagga et al., 2005; Wu et al., 2006). Long ncRNAs (lncRNAs) include all ncRNAs longer than ~200 nucleotides and make up the largest portion of the non-coding transcriptome (Mercer et al., 2009). lncRNAs are involved in several biological and pathological processes, such as genomic imprinting and development (Geisler & Coller et al., 2013). Increasing evidence shows that ncRNAs are dysregulated in males following exposure to stress and recent studies show that certain of these changes can be transmitted across generations.

Studies have found that offspring from stressed males have altered miRNA expression independent of whether behavioral changes are observed, and the type of stressor experienced (social vs asocial). Fathers exposed to maternal separation from P1–P14 produce sons with dysregulated miRNA expression. Specifically, male offspring in both F1 and F2 generations show dysregulation of several miRNAs in their serum and hippocampus, however, there were no changes in miRNA expression in the F3 generation. Validation using qPCR identified five miRNAs upregulated in F1 MSUS sperm (miR-375–3p, miR-375–5p, miR-200b-3p, miR-672–5p and miR-466–5p). These miRNAs were also upregulated in the serum and hippocampus of adult F2 male offspring but no changes in miRNA expression were found in sperm (Gapp et al., 2014). A study by the same group found that lncRNAs are differentially regulated in sperm of stressed males following 2 weeks of maternal separation. Importantly, 47 dysregulated mRNAs and lncRNAs in sperm had correlated fold changes in expression in zygotes (Gapp et al., 2018). To our knowledge, only one study has explored if ncRNAs are dysregulated in daughters and this study found no epigenetic differences in female offspring despite changes in male offspring. Specifically, following two weeks of paternal MSUS in mice, no epigenetic changes were observed in female offspring in the F1 or F2 generations. However, both F1 and F2 male offspring had differentially expressed genes in the amygdala, a brain region known for its involvement in fear and emotion (Manners et al., 2018). These data support the behavioral effects many studies have reported in which males show more robust transmission patterns (see Section 2.1 and 2.2). Taken together, these results suggest that sperm cells undergo epigenetic alterations following stress through the dysregulation of ncRNA expression which can be transmitted to male offspring. It is important to note that more studies should be conducted to determine if there are truly no changes to ncRNA expression in female offspring.

Surprisingly, paternal stress later in life produced highly robust epigenetic alterations despite a lack of behavioral transmission (see Section 2). Following 6 weeks of chronic variable stress, miRNA expression was altered in the brains of both male and female offspring. Specifically, changes in miRNA expression were seen in F1 male and female offspring with predicted mRNA targets involved in chromatin regulation, DNA methylation and mRNA processing. Additionally, qPCR revealed changes in the expression of stress axis-related genes in the paraventricular nucleus of the hypothalamus, a stress regulated brain region, of both male and female offspring. Importantly, the offspring also showed blunted stress responses (Rodgers et al., 2013). These results are unsurprising as dysregulation of brain’s stress circuitry is a common feature across psychiatric diseases, with studies reporting both hyper- and hypoactivity of the hypothalamic-pituitary-adrenal stress axis (Bale & Epperson et al., 2015; Burke et al., 2005; Martin et al.,2010). These data suggest that ncRNA expression is altered in offspring following stress later in life, however, changes do not produce detectible behavioral differences in offspring.

4. Gamete Manipulation

Paternal transmission studies utilize the fact that most male rodents are not involved in offspring rearing, which allows observed phenotypes in offspring to be attributed to male gamete contribution. However, studies have reported altered maternal care when females are allowed to mate naturally with stressed males. Specifically, a recent study found that, when female mice were allowed to mate naturally with food restricted males, they demonstrated maternal masking via increased prenatal care as measured by food consumption during gestation and postnatal care (maternal contact with pups, nursing posture, and pup grooming) to their offspring which lead to no difference in depression- or anxiety-like phenotypes compared to control fathers. Importantly, the same study found that, when naive females were impregnated with sperm from food restricted fathers using embryo transfer, offspring showed decreased anxiety behaviors measured by decreased latency to enter the center of an open field arena and increased depression-like behaviors as measured by reduced sucrose consumption (Mashoodh et al., 2018). Studies such as this one suggests that maternal interaction with an afflicted father may lead to maternal masking and highlight the appeal in using gamete manipulation techniques to provide a less biased investigation of how male gametes contribute to the transmission of stress phenotypes across generations.

It is important to highlight that the type of gamete manipulation may be important in interpreting results about the mechanisms of stress transmission. It has been established that manipulations such as in vitro fertilization can lead to changes in the epigenome, with imprinted genes serving as one of the main targets of these alterations (Reik et al., 2001). Therefore, it is unsurprising that when sperm from males who have undergone 10 days of chronic social defeat stress in adulthood is used for in vitro fertilization very few depression or anxiety phenotypes are observed in offspring (Dietz et al., 2011). Although these data on the surface might suggest that epigenetic modifications in sperm are not causally related to the transmission of stress phenotypes or gene expression changes in offspring, many studies dispute this conclusion. Manipulation of zygotes that mimic epigenetic changes seen in sperm following stress suggests that these changes do contribute to transgenerational transmission of stress phenotypes. Microinjection of nine miRNAs into one-cell zygotes recapitulates a blunted stress response in offspring after brief restraint stress seen in previous studies using a chronic variable stress paradigm, thus demonstrating a direct role of sperm miRNAs in transgenerational inheritance. This result was not seen when a single miRNA was injected (Rodgers et al., 2015). Another study found that injection of small or long RNA fractions from the sperm of MSUS males into naïve fertilized oocytes alone was insufficient to reproduce phenotype changes in offspring risk-taking behaviors on the elevated plus maze observed in natural MSUS animals. However, injection of long but not small RNAs induced a tendency for increased time spent in the light zone of the light dark box, suggesting decreased anxiety-like phenotypes, similar to natural MSUS offspring. By contrast, injection of small RNAs resulted in a tendency for decreased time spent in the bright field, an increased anxiety phenotype. These results suggest that alterations in both small and long RNAs together mediate the transmission of stress phenotypes from father to offspring and injection of small or large RNAs alone results in different behavioral effects (Gapp et al., 2018). Further study is needed to determine exactly how lncRNAs and miRNAs interact with eachother to mediate transgenerational germline-dependent transfer mechanisms of stress phenotypes and gene expression changes. Although the use of gamete manipulation allows for in depth investigation into how epigenetic changes in sperm may be functionally related to changes in offspring, to our knowledge, no studies to date have used gamete manipulation to examine other epigenetic changes such as DNA methylation or histone modifications. As the field advances with molecular tools such as CRISPER, we may be able to not only use gamete manipulation to investigate the role of sperm in paternal transmission of stress phenotypes but also to develop a better understanding of the mechanisms involved in this complex process.

5. Conclusion

We are just beginning to understand the complex mechanisms by which germ cells such as sperm are able to relay information about the environment to progeny and how this may influence risk for depression and anxiety across multiple generations. This review has highlighted how epigenetic changes due to paternal stress might mediate the transmission of stress phenotypes across generations and points to several emerging themes. The first is that the developmental time point at which stress is experienced can greatly influence patterns of stress transmission. As sperm development occurs early in life (P1–30), this reproductive axis may be more sensitive to stress during this critical period (Bellve et al., 1977; Janca et al., 1986) and may, in part, explain the more robust transmission of behavioral phenotypes seen when stress is experienced early in life (See Figure 1). The second is that the type of paternal stress (social or nonsocial) stress that is experienced exerts a strong influence on the transmission pattern of behavioral changes observed in offspring. Importantly, social and nonsocial stressors likely involve different molecular pathways and neural circuits in the brain, as other studies have found (Koo et al., 2019). In addition, social stress and non-social stress have been shown to differentially impact depression-vs and anxiety-like behavior (Yoon et al., 2014). The third is that transmission of epigenetic changes appears to occur in a sex-specific manner with no study to date reporting both behavioral and epigenetic changes in female offspring. However, more research is needed in female offspring to more definitively assess this possibility. Although the field has made progress in understanding how paternal experience influences offspring, there remains a paucity of causal data directly linking epigenetic changes in germ cells to behavioral phenotypes in the offspring. There is also little insight into the molecular processes by which epigenetic changes in germ cells affect specific types of neurons in the brain and how those adaptations alter neural circuitry to create the abnormal behaviors. The field would benefit as well from further research into how epigenetic changes can be targeted for potential therapeutic approaches. Incorporation of results from human studies (van Steenwyk et al., 2018;Yehuda et al., 2014) with animal studies will be crucial as we move forward, as these investigations will be imperative for better understanding of individual factors that influence risk for psychiatric disorders such as major depressive disorder and applying this knowledge to novel therapeutic interventions.

Acknowledgements:

This work was supported by grants from the National Institutes of Mental Health [NIMH—P50MH096890 (EJN)], the National Institutes of Health [NIH- R01MH51399 (EJN)] NIDA K99 Pathway to Independence Award [DA042100 (DW)], R01MH51399 and Hope for Depression Research Foundation

Abbreviations:

Cnr1

cannabinoid receptor 1

Crhr2

corticotrophin-releasing factor receptor 2

CSDS

chronic social defeat stress

Mecp2

methyl CpG binding protein 2

MDD

major depressive disorder

MSUS

maternal separation combined with unpredictable maternal stress

Footnotes

Conflict of Interest Statement:

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data Accessibility Statement:

No data to share or make available.

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