The Role of Epigenetic Mechanisms in the Long-Term Effects of Early-Life Adversity and Mother-Infant Relationship on Physiology and Behavior of Offspring in Laboratory Rats and Mice

Abstract

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 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 early-life adversity and mother-infant relationship, with a focus on the regulation of hypothalamic-pituitary-adrenal (HPA) axis and brain derived neurotrophic factor (BDNF). 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.

Introduction

In line with the biological embedding theory, early-life experiences have the potential to induce enduring physiological and molecular alterations that become embedded in the biological systems, impacting outcomes like health, well-being, and behavior across the lifespan Hertzman (2012). In studies on humans, the close relationship of adverse early life conditions, mainly associated with the quality of parental care, with cognitive abilities (Kaplan et al., 2001; Nelson III et al., 2007), physical health (Burenkova et al., 2021; Poulton et al., 2002; Wickrama, Conger, & Abraham, 2005), and mental health (Kessler et al., 2010; Mullen, Martin, Anderson, Romans, & Herbison, 1996; Poulton et al., 2002; Wickrama et al., 2005) of adults has been revealed in empirical studies and further confirmed by multiple meta-analyses on cognitive abilities (Goodman, Freeman, & Chalmers, 2019), physical (Jakubowski, Cundiff, & Matthews, 2018) and mental health outcomes (LeMoult et al., 2020; McKay et al., 2022; Trotta, Murray, & Fisher, 2015). In experiments with laboratory animals, effects of early-life adversity (ELA), again related to the quality of parental care, on the future physiological (F. Champagne, Francis, Mar, & Meaney, 2003; Francis, Diorio, Plotsky, & Meaney, 2002) and behavioral (D. Champagne et al., 2008; F. Champagne et al., 2003; Francis, Diorio, Liu, & Meaney, 1999; Francis et al., 2002; Franklin et al., 2010) phenotypes were revealed in multiple rodent models, such as maternal deprivation or separation, variation in the level of maternal care, limited bedding and nesting, and others (Bonapersona et al., 2019; Duque-Quintero et al., 2022; Rocha, Wang, Avila-Quintero, Bloch, & Kaffman, 2021) (Figure 1). One of the underlying mechanisms for the long-term effects of early experience is epigenetic modifications of the genome of nervous cells, common to both humans (Anacker, O’Donnell, & Meaney, 2014; Labonté et al., 2012; Neves, Dinis-Oliveira, & Magalhaes, 2021; Romens, McDonald, Svaren, & Pollak, 2015; Suderman et al., 2014; Suderman et al., 2012; Turecki & Meaney, 2016; Yehuda et al., 2014; T. Zhang, Labonte, Wen, Turecki, & Meaney, 2013) and animals (Anacker et al., 2014; Suderman et al., 2012; Turecki & Meaney, 2016; T. Zhang et al., 2013).

Figure 1.

Simplified scheme of the long-term effects of early-life adversity and mother-infant relationship on physiology and behavior of offspring. Note. GRs = glucocorticoid receptors; DNAm = DNA methylation; HDACi = HDAC inhibitors; HPA axis = hypothalamic-pituitary-adrenal axis; LG-ABN = licking/grooming and arched-back nursing. Activating pathways are indicated by solid lines, inhibitory with dashed ones.

The field of epigenetics explores heritable¹, self-sustaining alterations in the transcriptional activity of the genome; these alterations occur without changes in the DNA sequence and persist even in the absence of the initial stimuli that triggered them (Ptashne, 2007; Vanyushin, 2014). Epigenetic modifications are involved at the stage of germ cell formation and the preimplantation stage of embryo development in the process of genomic imprinting (Li, 2002; Reik, Dean, & Walter, 2001). Neurogenesis and gliogenesis at all stages of ontogenesis, starting from the embryonic period, are controlled by epigenetic regulation (Hirabayashi & Gotoh, 2010; J. Hsieh & Gage, 2005). The molecular investigation of epigenetic mechanisms of activity-dependent processes of long-term plasticity in adult neurons at different stages of the ontogenetic development of an organism has provided novel insights into the interplay between the organism’s genotype and the environment in shaping the phenotype (Day & Sweatt, 2011; Kappeler & Meaney, 2010); this perspective aligns with Waddington’s concept of epigenetics (Waddington, 1940). It has become apparent that epigenetic modifications in neurons of the developing brain are a key mechanism in adapting the behavior of developing organism to future anticipated environmental variations, forming the so-called “predictive adaptive response” (Gluckman & Hanson, 2004). For example, high anxiety level can be considered an adaptive stress response in situations where the early environment signals a high-stress environment (Meaney, 2001; Meaney & Szyf, 2005), so an individual with a heightened stress response may be better equipped to cope with and respond to stressors in the future. This could contribute to increased survival in challenging conditions.

The most studied main types of epigenetic modifications that occur in response to environmental signals are DNA methylation and post-translational modifications of histones. Acetylation, as the most common and well-studied histone modification, is a key factor that affects chromatin structure and gene transcription, enabling the interaction of extracellular signals with the genome (Clayton, Hazzalin, & Mahadevan, 2006). DNA methylation and histone modifications can be interrelated processes: The suppression of transcription occurs through an increase in DNA methylation levels, which is accompanied by a decrease in acetylation levels through the activation of histone deacetylases (Z. Chen & Pikaard, 1997; Eden, Hashimshony, Keshet, Cedar, & Thorne, 1998; Jones et al., 1998).

This narrative literature review focuses on the role of epigenetic mechanisms in mediating the enduring impacts of early-life experiences, including those influenced by maternal care levels, on the physiological and behavioral profiles of laboratory rats and mice. The research sheds light on the translational potential of understanding epigenetic processes, paving the way for possible interventions, such as the implementation of histone deacetylase inhibitors and epigenome editing, to modify epigenetic marks and mitigate the long-term consequences of early-life adversity.

Maternal Care and Development of Behavioral and Physiological Phenotype of Laboratory Rodent Offspring

In humans, a close relationship has been found among cognitive abilities (Kaplan et al., 2001; Nelson III et al., 2007), physical health (Burenkova et al., 2021; Poulton et al., 2002; Wickrama et al., 2005), and mental health (Kessler et al., 2010; Mullen et al., 1996; Poulton et al., 2002; Wickrama et al., 2005) on one hand and adverse early life conditions on the other. In particular, dysfunctional family environment in childhood (physical and sexual abuse, psychological pressure, lack of parental care, divorce or death of parents) is often associated with the emergence of psychopathology² (depression, alcohol, and drug addiction, post-traumatic stress disorder, bipolar disorder, among others) (LeMoult et al., 2020; McKay et al., 2022; Trotta et al., 2015) and antisocial behavior (Barnow, Lucht, & Freyberger, 2001) in adulthood. Conversely, a positive psychological climate in the family and supportive early relationships can act as social buffering and help reduce the negative impact of unfavorable conditions on the child’s emotion regulation skills, positive affect, and self-esteem (Hostinar, Sullivan, & Gunnar, 2014).

During the early postnatal development of all altricial mammals, including humans, maternal control and care are crucial and play a pivotal role in the survival and adaptation of offspring to environmental conditions (Kotenkova, Meshkova, & Shutova, 1989; Kruchenkova, 2009). The quality of the child-maternal relationship determines the physical development of the offspring and their behavior (Bredy, Humpartzoomian, Cain, & Meaney, 2003; Caldji et al., 1998; Francis et al., 1999; D. Liu, Diorio, Day, Francis, & Meaney, 2000). Licking and grooming of altricial rodent pups by a dam in the early postnatal period is the main source of tactile stimulation that regulates their metabolism and is required to facilitate normative developmental processes (Kappeler & Meaney, 2010).

The model of natural variations in maternal care in rodents developed by M. J. Meaney and colleagues has contributed to a comprehensive study of the mechanisms of the long-term influence of maternal care on various aspects of offspring development. Observations of child-maternal relationships in lactating laboratory rats and mice in the first week of life showed that natural variations in maternal care take place (F. Champagne et al., 2003; Pedersen, Vadlamudi, Boccia, & Moy, 2011; Wei, David, Duman, Anisman, & Kaffman, 2010). Specifically, dams with a high level of maternal care, who lick and groom their pups more often and also characterized by longer duration of licking/grooming and arched-back nursing (LG-ABN), and dams with a low LG-ABN level can be identified (F. Champagne et al., 2003; Meaney, 2001; Pedersen et al., 2011; Wei et al., 2010). Despite the fact that differences in the quality of maternal care between females with high and low LG-ABN levels are observed only during the first postnatal week, they have a strong lifelong influence on the physiology and behavior in the offspring (F. Champagne, Diorio, Sharma, & Meaney, 2001). Particularly, offspring of mothers with high LG-ABN levels display high levels of their own maternal care compared to offspring of mothers with low LG-ABN levels (Francis et al., 1999), are less anxious in a new environment (Pedersen et al., 2011), are characterized by lower plasma corticosterone levels after stress exposure (D. Liu et al., 1997), and improved learning in models without significant exposure to stress: either spatial learning/memory in the Morris water maze (Bredy et al., 2003; Bredy, Zhang, Grant, Diorio, & Meaney, 2004; D. Liu et al., 2000) or social learning of food preferences (Lindeyer, Meaney, & Reader, 2013) with no available data for stress-related learning models, such as fear conditioning. In a cross-fostering experiment, females born by low-LG-ABN mothers but reared by high-LG-ABN females demonstrated a high-LG-ABN maternal profile similar to their foster mothers (Weaver et al., 2004). These results indicate an acquired, non-genetic nature of the manifestation of this behavior.

In addition to natural variations of maternal care, experimental manipulations with maternal-child relationships during the early postnatal period could also be critical for the future physiological and behavioral phenotype of the offspring. This has been shown in a number of studies using experimental models of offspring handling (Caldji, Francis, Sharma, Plotsky, & Meaney, 2000; Lesuis, van Hoek, Lucassen, & Krugers, 2017), deprivation (Llorente-Berzal et al., 2012) or separation (Burenkova, Aleksandrova, & Zaraiskaya, 2014a; Burenkova, Aleksandrova, & Zarayskaya, 2012, 2019; Caldji et al., 2000; Franklin et al., 2010) of offspring from the mother, maternal stress (Blaze & Roth, 2017), and others (Davis, Bolton, Hanson, & Guarraci, 2020). Handling (3–15 min separation of pups from the mother) usually has a favorable effect on the future emotional (level of anxiety assessed in the neophagia test, elevated plus maze, open field test, and others) and cognitive characteristics (performance on learning and memory tasks) of the offspring. The effects of this experimental procedure are expressed in a decrease in the level of anxiety (Caldji et al., 2000; Denenberg & Haltmeyer, 1967; S. Levine, 1956; Meerlo, Horvath, Nagy, Bohus, & Koolhaas, 1999) and an improvement in memory in adult offspring (Kosten, Lee, & Kim, 2007; S. Levine, 1956). These effects are probably caused by an increase in the level of maternal care induced by this procedure of short-term separation of offspring from the mother (M. Lee & Williams, 1974; D. Liu et al., 1997; Pryce, Bettschen, & Feldon, 2001; Smotherman, Brown, & Levine, 1977; Wei et al., 2010). On the opposite end of the spectrum are models of early-life adversity (ELA) that typically have negative effects on animals – the models of limited bedding and nesting (LBN), maternal separation (MS) or maternal deprivation (MD) in laboratory rats and mice offspring (Pryce et al., 2005; Tractenberg et al., 2016). The latter two models represent either a single 24 h episode (in the case of MD) or shorter multiple (in the case of MS, most commonly for 3 h, but generally very heterogeneous, from 15 to 480 min) episodes of isolation of offspring from the mother, and sometimes simultaneously from sibs and performed at different time points of the early postnatal period (Tractenberg et al., 2016). Deprivation or separation of the offspring from the mother can have a negative impact on the phenotype of the grown offspring. In particular, they lead to an increase in the level of anxiety tested at the behavioral and physiological levels (Aisa, Tordera, Lasheras, Del Rio, & Ramirez, 2008; Aisa, Tordera, Lasheras, Del Rio, & Ramirez, 2007; R. L. Huot, Plotsky, Lenox, & McNamara, 2002; Kalinichev, Easterling, Plotsky, & Holtzman, 2002), memory impairment (Aisa et al., 2009; Aisa et al., 2008; Aisa et al., 2007; R. L. Huot et al., 2002; Uysal Harzadın et al., 2005), preference for alcohol (Cruz, Quadros, Planeta, & Miczek, 2008; Rebecca L Huot, Thrivikraman, Meaney, & Plotsky, 2001) and cocaine (Moffett et al., 2006), or a decrease in the level of maternal care in adult offspring females (Lovic, Gonzalez, & Fleming, 2001).

The rearing of rat pups during the first week of life by a stressed female is another model of intervention in the mother-child relationship, leading to a change in the phenotype of the offspring. Females exposed to stress by providing limited nesting resources in an unfamiliar environment were characterized by a reduced level of maternal care and an increased proportion of adverse forms of pup-directed behaviors (stepping on, dropping during transport, dragging, actively rejection, rough handling, and neglect); adult females with a history of maltreatment later reproduced abusive behaviors toward their offspring (Roth, Lubin, Funk, & Sweatt, 2009).

The extensive dataset amassed on the impact of ELA on animal behavior facilitated subsequent systematic reviews and meta-analyses. A qualitative systematic review revealed that the deleterious effects of MS appear to be more consistent in certain behavioral phenotypes, such as depressive-like behavior and memory performance, while exhibiting less consistency in anxiety-like behavior (Tractenberg et al., 2016). Subsequent meta-analysis demonstrated that ELA leads to deficits in hippocampal-dependent learning assessed through Morris water maze and novel object recognition tests in adult rodents exposed to two models of ELA: MS and limited bedding and nesting (LBN) (Rocha et al., 2021). In another meta-analysis, Bonapersona et al. (2019) showed that ELA , encompassing maternal separation, maternal deprivation, LBN, and low LG-ABN levels, impairs non-stressful learning (Morris water maze with water temperature >26°C, object and social recognition), while promoting memory formation during stressful learning (Morris water maze with water temperature <24°C, fear conditioning, and shuttle box). Increased defensive behavior was observed in the elevated plus maze and open field test after MS according to the next meta-analysis (D. Wang, Levine, Avila-Quintero, Bloch, & Kaffman, 2020). Consistent with these findings, Bonapersona et al. (2019) demonstrated that ELA increases anxiety-like behavior (assessed in the elevated plus maze, open field test, forced swim test, light/dark box, and some other tests) and decreases social behavior. ELA, including maternal separation, maternal deprivation, LBN, and low LG-ABN levels, also significantly reduced reward responsiveness and social reward directed behaviors without affecting reward learning (Duque-Quintero et al., 2022).

Along with the effects of ELA on behavioral phenotypes of offspring, numerous physiological effects related to hypothalamic-pituitary-adrenal (HPA) axis functioning have been demonstrated as well. According to recent meta-analysis, it was displayed in a decrease in hippocampal volume, the number of dendritic branches, and dendritic length and suppresses neurogenesis in adulthood (Joëls, Kraaijenvanger, Sarabdjitsingh, & Bonapersona, 2022). Apparently, the hippocampus is one of the primary targets of exposure to stressors, which could be attributed to a high number of glucocorticoid receptors (GRs) that bind cortisol/corticosterone in this brain structure (Sanchez, Young, Plotsky, & Insel, 2000). In addition to enabling negative feedback in the regulation of HPA axis activity, this brain structure is also critically involved in cognitive functioning (Lisman et al., 2017) and, therefore, may play a role in establishing the associations between ELA and cognitive performance.

However, a question arises concerning the mechanisms that unite stress-induced changes in the functioning of the HPA axis with alterations in the brain and behavior. As comprehensively reviewed by Suri and Vaidya (2013), glucocorticoids alter expression and signaling of brain derived neurotrophic factor (BDNF), either through direct binding to putative glucocorticoid response elements (GREs) on the Bdnf gene promoter regions or via other transcription factors involved in Bdnf transcription. These mechanisms represent how the HPA axis activity influence neurobiological and behavioral stress-induced alterations, considering the pivotal role of BDNF in brain structural and functional plasticity, including hippocampal neurogenesis (H. Schmidt & Duman, 2007), synaptogenesis and spine formation (Yoshii & Constantine-Paton, 2010), and neuronal survival (Lipsky & Marini, 2007). Furthermore, the relationship between the HPA axis and BDNF is bidirectional, since BDNF can directly influence the HPA-axis regulation through alterations of corticotrophin‐releasing hormone (CRH) expression levels (Jeanneteau et al., 2012).

It should be noted that standard experimental batteries for testing the physical, somatosensory, or cognitive development of mice in the early postnatal period require isolation of the offspring from the mother for a period of 30 to 60 minutes. However, the long-term consequences of such procedures are practically not studied, which complicates the interpretation of the results of behavioral phenotyping of adult animals that had experienced testing in longitudinal experiments in the early postnatal period. In this regard, a model of daily intermediate length of 45-minute MS from the 3rd to the 6th postnatal day (PND) has been developed; this procedure was shown to induce stress in pups on both hormonal and behavioral levels (Burenkova, Averkina, Aleksandrova, & Zarayskaya, 2020) and impair olfactory discrimination learning task with imitation of maternal grooming as positive reinforcement at the PND8 (Burenkova et al., 2012) that can be explained by alterations in maternal behavior caused by MS (Burenkova et al., 2020). This early-life experience also negatively affected contextual fear memory formation in adult male offspring subjected to brief MS, though no effect on their emotionality tested in the open field test or elevated plus-maze test was observed (Burenkova et al., 2014a). In female adult offspring subjected to brief MS, this experience altered their maternal behavior (Burenkova et al., 2019).

Long-term modifications of behavior caused by early life events have been also identified in subsequent generations. Experimental evidence has been obtained for the transfer of properties of the behavioral phenotype through epigenetic inheritance in mammals: the offspring of mothers with high-LG-ABN maternal profile in two subsequent generations themselves demonstrate high-LG-ABN maternal profile compared to the offspring of mothers with low-LG-ABN maternal profile (Francis et al., 1999). Another example of an epigenetic exposure that leads to a change in the phenotype of animals over several generations is a model of unpredictable chronic MS combined with unpredictable maternal stress, consisting of either a 20-min restraint or a 5-min forced swim in cold water applied unpredictably and randomly during MS which took place daily for 3 hours from the PND1 to 14; this exposure induced depressive-like behaviors up to the third generation and in a complex gender-dependent manner (Franklin et al., 2010).

Experimental interventions in both natural variations of maternal care and models of ELA can potentially reverse the phenotypes of offspring. In the case of natural variations, this reversal can be achieved through cross-fostering, where the biological offspring of low-LG-ABN mothers reared by high-LG-ABN dams exhibit behavioral profiles similar to the offspring of high-LG-ABN mothers, and vice versa, specifically, in their maternal behavioral profiles and fearfulness in the open-field test of exploration (Francis et al., 1999), spatial learning (Bredy et al., 2003), or object recognition memory (Bredy et al., 2003). Additionally, environmental enrichment has been shown to counteract the negative effects of ELA. For instance, it can mitigate the impact of MS on both HPA activity and behavioral responses to stress (Francis et al., 2002), fearfulness in the open-field test of exploration (Berardo, Fabio, & Pautassi, 2016), anxiety in elevated plus-maze test (Dandi et al., 2018), spatial learning (Cordier et al., 2021; Dandi et al., 2018; Menezes, das Neves, Gonçalves, Benetti, & Mello-Carpes, 2020; Mohammadian, Najafi, & Miladi-Gorji, 2019), and object recognition (Menezes et al., 2020). This suggests that environmental influences can not only shape behavioral profiles but also reverse otherwise potentially deleterious outcomes.

Thus, the phenomenology of the effects of the mother-infant relationship on the subsequent physiological and behavioral profile of the offspring is currently well documented in laboratory rodents. As will be shown below, the HPA axis, in particular, the epigenetic mechanisms of the expression of GRs of the hippocampus, is one of the targets of effects of early-life experience.

Maternal Care Triggers Epigenetic Mechanisms of the Development of the Physiological and Behavioral Phenotype of Laboratory Rodents

The early postnatal period in immature rodents is marked by the presence of the so-called stress hyporesponsive period, SHRP (Schapiro, Geller, & Eiduson, 1962), which is analogous to such a period in children under the age of one year (Gunnar, Brodersen, Krueger, & Rigatuso, 1996; Larson, White, Cochran, Donzella, & Gunnar, 1998). In rats, it lasts from PND3 to 14 (Schapiro et al., 1962; Schoenfeld, Leathem, & Rabii, 1980), in mice, from PND1 to 12 (Cirulli, Santucci, Laviola, Alleva, & Levine, 1994; D’Amato et al., 1992; M. Schmidt, Oitzl, Levine, & de Kloet, 2002). This period is characterized by a reduced level of activity of the HPA system in response to stressors (Schapiro et al., 1962; Schoenfeld et al., 1980; Walker, Perrin, Vale, & Rivier, 1986). Its biological role is to protect the developing central nervous system from the negative effects of high concentrations of glucocorticoids released during stress (Sapolsky & Meaney, 1986). The existence of a period of low sensitivity to stress is suggestively based on the influence of maternal care, which suppresses the activity of the HPA system (De Kloet, Rosenfeld, Van Eekelen, Sutanto, & Levine, 1988; Suchecki, Rosenfeld, & Levine, 1993). This is substantiated by the fact that maternal deprivation is one of the few stressors, the impact of which during this period leads to the activation of the HPA system in pups, namely, to an increase in the blood level of corticosterone (Cirulli et al., 1994; D’Amato et al., 1992; Enthoven et al., 2010; Kuhn, Pauk, & Schanberg, 1990; McCormick, Kehoe, & Kovacs, 1998; Pihoker, Owens, Kuhn, Schanberg, & Nemeroff, 1993; Smith, Kim, van Oers, & Levine, 1997). Consequently, the activation of the HPA system in pups is regarded as one of the key mechanisms underlying the negative impact of maternal deprivation.

An important role in the regulation of the HPA system’s activity is played by GRs in the hippocampus: when corticosterone is released into the bloodstream, this activity is inhibited by the mechanism of negative feedback (Jacobson & Sapolsky, 1991). Adult offspring of high-LG-ABN mothers are characterized by a high expression of GRs, encoded by the Nr3c1 gene, in the hippocampus and, as a result, a more pronounced inhibition of the HPA system, i.e., its less pronounced activity under stress (Francis et al., 2002; Weaver et al., 2005). Manipulations with lactating females that lead to an increase in the level of LG-ABN (for example, handling of offspring) can cause a long-term increase in the expression of GRs in the hippocampus and a decrease in the activity level of the HPA system, in particular, a decrease in the level of corticosterone in blood plasma in response stress in adulthood (Avishai-Eliner, Eghbal-Ahmadi, Tabachnik, Brunson, & Baram, 2001; Francis et al., 1999). On the contrary, manipulations with lactating females that lead to a decrease in the level of LG-ABN, for example, separation of offspring from the mother, cause a decrease in the expression of GRs in the hippocampus (Francis et al., 2002; Ladd, Huot, Thrivikraman, Nemeroff, & Plotsky, 2004) and also an increase in the level of activation of the HPA system manifested in an increase in the adult plasma levels of corticosterone in response to stress (J. Chen et al., 2012; Kalinichev et al., 2002). The impact of maternal care level during the first week of offspring’s life on the enduring modification of HPA system functioning and the expression of hippocampal GRs is grounded in epigenetic mechanisms.

The availability of a DNA strand to various regulatory proteins, including transcription factors, determines the structure of chromatin, thus regulating gene expression (Vanyushin, 2014). The most well-known epigenetic modifications that occur in response to environmental influences are DNA methylation, post-translational modifications of histones, and gene silencing mediated by small RNAs, such as micro RNA (miRNA) and short interfering or silencing RNA (siRNA) (Vanyushin, 2014). In recent years, miRNA as an important regulator of gene expression has gained significant interest for their involvement in neural plasticity and diverse pathological processes (Allen & Dwivedi, 2020; McKibben & Dwivedi, 2021).

DNA methylation is known to cause transcription suppression of certain genes (Boyes & Bird, 1992; C. Hsieh, 1994). According to one of the hypotheses, methyl groups sterically hinder the binding of transcription factors to the DNA strand (Bird, 1986); according to another, methylation promotes the binding with DNA enzymes that suppress transcriptional activity (Bird, 2002). The main factor that determines the structure of chromatin is the state of amino acids at the N-terminus of H3 and H4 histones, i.e., those proteins that are the target of a number of reversible post-translational modifications that affect the structure of the nucleosome and gene transcription (Dorigo, Schalch, Bystricky, & Richmond, 2003; Luger, Mäder, Richmond, Sargent, & Richmond, 1997).

According to the “histone code” hypothesis (Strahl & Allis, 2000), the state of chromatin is dynamic. It is determined by a combination of post-translational modifications of various amino acid residues of histone proteins: acetylation (Sterner & Berger, 2000), phosphorylation (Nowak & Corces, 2004), methylation (Y. Zhang & Reinberg, 2001), ubiquitination (Osley, 2004; Sun & Allis, 2002), sumoylation (Nathan, Sterner, & Berger, 2003), propionylation and butyrylation (Y. Chen et al., 2007), glycosylation (Gugliucci, 1994; Liebich et al., 1993), biotinylation (Rodriguez-Melendez & Zempleni, 2003; Stanley, Griffin, & Zempleni, 2001), carbonylation (Wondrak, Cervantes-Laurean, Jacobson, & Jacobson, 2000), and ADP-ribosylation (Golderer & Gröbner, 1991). Acetylation, maybe the most studied histone modification, is a key factor influencing chromatin structure and gene transcription. It enables the interaction of extracellular signals with the genome (Clayton et al., 2006). In 1964, Allfrey et al. (Allfrey, Faulkner, & Mirsky, 1964) suggested that the level of histone acetylation correlates with the transcriptional activity of genes, with a decreased or increased level of histone acetylation, transcriptional activity is suppressed or activated, respectively. If histones are tightly bound to DNA, this prevents the DNA from interacting with other proteins, including the enzyme RNA polymerase required for transcription. For transcriptional activation, the chromatin structure must be changed. According to one hypothesis, the activation of transcription that occurs during histone acetylation (Z. Wang et al., 2008) is explained by the fact that these modifications decrease the positive charge of histones, due to which histones interact with negatively charged DNA (D. Lee, Hayes, Pruss, & Wolffe, 1993). Acetylation of the amino group of lysine at the N-terminus of the histone molecule neutralizes the positive charge of histones, whereas the affinity between histones and DNA decreases, which results in chromatin decondensation and increases the availability of DNA sites for transcription factors (D. Lee et al., 1993). According to an alternative hypothesis, transcription factors can recognize modified amino acids at the N-terminus of histone molecules and directly interact with them (Vettese-Dadey et al., 1996; Vitolo, Thiriet, & Hayes, 2000). Specific transcription coactivators are also capable of recognizing acetylated lysine residues and binding to acetylated histone “tails” (Dion, Altschuler, Wu, & Rando, 2005; Hong, Schroth, Matthews, Yau, & Bradbury, 1993). The above mechanisms underlie the long-term maintenance of not only stable genomic properties of individual cells but also their ensembles, which provide long-term changes in physiology and behavior (Korzus, Rosenfeld, & Mayford, 2004).

It was shown that in the pups raised by high- and low-LG-ABN mothers, the DNA of the GR promoter (exon 1₇) in the hippocampus is methylated differently: low and high levels of DNA methylation, correspondingly (Weaver et al., 2004). The levels of histone H3 acetylation in the same GR region of the hippocampus have the opposite trend: offspring of high- and low-LG-ABN mothers were characterized by high and low levels of histone acetylation, correspondingly (Weaver et al., 2004). These differences in the level of DNA methylation and histone acetylation in the brain of offspring appear after the first week of life and persist throughout the lifespan (Weaver et al., 2004; T. Zhang et al., 2013), potentially underlying the above-described emotional (Caldji et al., 2000; Francis et al., 1999; Weaver, Meaney, & Szyf, 2006) and cognitive (Bredy et al., 2003; Bredy et al., 2004; Lindeyer et al., 2013; D. Liu et al., 2000; Pedersen et al., 2011) profiles of adult animals. The long-term influence of the LG-ABN levels on hippocampal GRs expression is enabled through an increase in the expression of the transcription factor NGFI-A (nerve growth factor-inducible factor-A, also known as egr-1, krox-24, zenk, and zif-26) and its binding to exon 1₇ GR promoter (Weaver et al., 2007). It should be emphasized that although DNA methylation of the GR promoter of animals is transmitted across generations, it can also be reversed with cross-fostering, such as the biological offspring of low-LG-ABN mothers reared by high-LG-ABN dams resemble the offspring of high-LG-ABN mothers, and vice versa (Francis et al., 1999; Weaver et al., 2004). This suggests that environmental influences can not only program epigenetic and behavioral profiles but also reverse otherwise potentially negative outcomes.

In addition to the model of natural variations in maternal care, similar epigenetic effects have been shown in models of MS. MS increased DNA methylation levels within the exon 1₇ GR promoter region in the hippocampus of adult rats (Zhu et al., 2017) and mice (Kember et al., 2012; Kundakovic, Lim, Gudsnuk, & Champagne, 2013). The systematic review revealed a trend for a downregulation of GR mRNA expression and an increase in GR DNA methylation in response to MS (Tractenberg et al., 2016). Conversely, MS decreased the levels of histone acetylation in several studies. MS of rat pups from PND1 to 14 led to a decrease in the level of total (not associated with specific genes’ promoters) H3 and H4 histone acetylation in the mesolimbic structures, dorsal caudate putamen and nucleus accumbens core in adulthood (Tesone‐Coelho et al., 2015). Separation from the mother and siblings in the first two weeks of life reduced the level of total histone H4 acetylation at the PND21 in the forebrain neocortex of mice (A. Levine, Worrell, Zimnisky, & Schmauss, 2012). MD on PND9 in rats led to a decrease in histone H3 acetylation at lysine 9 in the ventral tegmental area (VTA) on PND14–21 (Shepard et al., 2018).

In the hippocampus, the levels of acetylated histones H3 and H4 were significantly reduced at the Bdnf gene promoter IV in the hippocampus of adult rats after MS (Seo et al., 2016). This and other studies thus show that the rearing environment in the first week of life affects the expression of the Bdnf gene, one of the key genes involved in neuronal plasticity (Yamada, Mizuno, & Nabeshima, 2002), through the epigenetic mechanisms. MS increased DNA methylation levels within the Bdnf IX promoter in the hippocampus of adult mice (Kundakovic et al., 2013). Nursing by a stressed female during the first week of life reduced Bdnf gene mRNA expression and increased the methylation level of the Bdnf gene promoter in the prefrontal cortex, both in the first week of life and in adult animals (Roth et al., 2009). Conversely, communal nursing, characterized by an increased level of maternal care received by offspring, led to an increase in the level of histone acetylation at the I, IV, VI, and VII promoters of the Bdnf gene (Branchi, Karpova, D’Andrea, Castren, & Alleva, 2011). The systematic review revealed a trend for an increase in Bdnf DNA methylation in response to MS (Tractenberg et al., 2016). In light of the previously mentioned interplay between the HPA axis and BDNF (Jeanneteau et al., 2012; Suri & Vaidya, 2013), these studies, along with research on GRs, provide evidence for the mutual reciprocal modulation of epigenetic molecular mechanisms that regulate stress and neuronal plasticity systems in the brain in response to alterations in mother-infant relationships in laboratory rodents.

It is important to note that the long-term impact of ELA in rats and humans is rooted in the same epigenetic mechanisms (Labonté et al., 2012; Romens et al., 2015; Suderman et al., 2014; Suderman et al., 2012; Turecki & Meaney, 2016; Yehuda et al., 2014). According to a systematic review published in 2016 by Turecki and Meaney, since the publication of the first data on the different levels of DNA methylation of the GR promoter (exon 1₇ GR promoter) in the hippocampus of the offspring of rats with different levels of maternal care, the number of studies on the effects of early-life experience, parental stress, and psychopathology on the methylation status of the GR had reached forty, of which 13 were carried out in animals and 27 in humans (Turecki & Meaney, 2016). Most of these studies determined the methylation status of exon 1₇ in rats and exon 1F in humans. Among the studies on the impact of ELA, an increase in the methylation level of these exons was shown in 89% of human studies and 70% of animal studies (Turecki & Meaney, 2016).

Thus, the rearing environment of altricial mammals, mediated by maternal care, plays a key role in the development of their phenotype, and epigenetic mechanisms might be essential “injectors” of the early environment under the “skin” of the pups. However, to establish a causal rather than merely correlational relationship between these two outcomes of ELA exposure – alteration of behavioral and epigenetic phenotype – experimental manipulation of the epigenetic profile is required, and the use of pharmacological agents that modulate the epigenetic mechanisms underlying these long-term negative consequences can serve to this purpose. Furthermore, it is of applied importance to correct the negative consequences caused by disturbances in mother-child relationships in the early postnatal period using pharmacological agents. Inhibitors of histone deacetylases (HDACs) and DNA methyltransferase (DNMT) inhibitors may serve as such agents.

Pharmacological Interventions and Epigenetic Editing as Tools for Studying the Role of Epigenetic Mechanisms in Nervous System Plasticity

HDACs are a family of enzymes consisting in humans of 18 HDAC enzymes (Seto & Yoshida, 2014) that catalyze acetyl groups removal from the lysine residues on both histone and nonhistone proteins (Seto & Yoshida, 2014). Some of these HDACs were proven to play a role in both physiological and pathological neuronal development and function (Guan et al., 2009; Kelly & Cowley, 2013; Parra, 2015; Reichert, Choukrallah, & Matthias, 2012). One of the methods of intervention in epigenetic mechanisms is HDAC inhibition, which leads to an increase in the level of histone acetylation in the brain and is accompanied by an increase in transcriptional activity (Sinn et al., 2007). The most widely used HDAC inhibitors block class I HDACs (trichostatin A, sodium butyrate, valproic acid, suberoylanilide hydroxamic acid (SAHA)), class II HDACs (TSA, sodium butyrate, and SAHA), or class IV HDACs (SAHA); each of them has a different degree of selectivity for HDACs isoforms (Grinkevich, 2014; Roth & Sweatt, 2009). The development of new, more specific inhibitors for each of the 18 existing types of HDAC is actively pursued in cancer research. However, these developments have not yet extended to the field covered in this review. Moreover, the differences in the effects of existing inhibitors in this context have yet to undergo careful examination, although some research has already demonstrated the varying effects of different HDAC inhibitors on learning and memory performance (Guan et al., 2009).

A large proportion of studies using HDAC inhibitors are devoted to the role of epigenetic mechanisms in the plasticity of the mature nervous system. For example, an increase in the level of histone acetylation in the brain caused by prolonged intraperitoneal administration of HDAC inhibitors (TSA, sodium valproate, sodium butyrate) triggers the processes of eye-dominant plasticity, which is usually observed only during the critical period of development of the visual system (Putignano et al., 2007; Vetencourt, Tiraboschi, Spolidoro, Castrén, & Maffei, 2011). In addition, restoration of visual functions is observed in adult animals with such a form of visual acuity impairment as amblyopia caused by prior monocular deprivation during the critical period of development of the visual system (Silingardi, Scali, Belluomini, & Pizzorusso, 2010). Another example of the plasticity of the mature nervous system is learning. The administration of HDAC inhibitors shortly before (from 30 min to 2 h) or immediately after training improves long-term memory and learning performance in a number of adult animal models: enhances memory for conditioned fear in mice and rats (Bredy & Barad, 2008; Guan et al., 2009; Levenson et al., 2004; Vecsey et al., 2007), facilitates memory in object recognition training in mice (Stefanko, Barrett, Ly, Reolon, & Wood, 2009), and potentiates the formation of long-term memory in passive avoidance task in chickens (Toropova, Anokhin, & Tiunova, 2014).

In the model of variation in the level of maternal care in rats, it should be noted that the reversibility of the epigenetic status acquired in the early postnatal period was experimentally shown in the adult offspring of low-LG-ABN mothers. Specifically, intracerebral (intraventricular) administration of TSA into the brains of adult offspring of low-LG-ABN mothers significantly reduced the level of DNA methylation of the GR promoter and increased the level of histone H3 acetylation in the region of the same promoter in the hippocampus to levels observed in the offspring of high-LG-ABN mothers (Weaver et al., 2004). In line with it, the level of corticosterone in the blood, normally elevated in the low-LG-ABN mothers in response to acute stress (immobilization for 20 min), decreased to the levels of the offspring of high-LG-ABN mothers (Weaver et al., 2004). In addition, the administration of TSA to adult offspring of low-LG-ABN mothers reduced anxiety levels in the open field test to the level observed in the offspring of high-LG-ABN mothers (Weaver et al., 2006).

In the model of MS, the administration of sodium butyrate to adult animals that underwent maternal separation (3 hours daily, PND1–14) increased total histone H3 acetylation levels in the hippocampus compared to saline administration (Albuquerque Filho et al., 2017). Furthermore, sodium butyrate restored object recognition memory in MS animals (Albuquerque Filho et al., 2017). This study also demonstrated an increase in BDNF levels in the hippocampus after the administration of sodium butyrate in the MS group but not in the non-MS group with a positive correlation was observed between BDNF levels and memory performance across all groups combined (Albuquerque Filho et al., 2017).

Studies of the effect of blockade of HDAC in the first week of life, which is a critical period for the development of the future epigenetic status of animals, are practically absent. It is important to note that the solvent commonly used to dissolve TSA, dimethyl sulfoxide (DMSO), is known to be toxic to the developing nervous system (Lobanov, Khokhlova, Suvorova, Zaraiskaya, & Murashev, 2008). In contrast, HDAC inhibitor sodium valproate does not pose this drawback, as it is readily soluble in saline. Studies have shown that its subcutaneous administration at a dose of 50 mg/kg on the mice PND1 significantly increases histone H3 acetylation levels in the brain and, at the same time, is well tolerated by them (Murray, Hien, de Vries, & Forger, 2009). This substance is also known as an anticonvulsant drug, the mechanism of action of which is attributed to the activation of the inhibitory GABAergic system, the suppression of the excitatory glutamatergic system, and the general decrease in brain metabolism when used in therapeutic doses. However, with the administration of smaller doses (such as 50 mg/kg), these effects are not observed (Johannessen & Johannessen, 2003). In our experiments, we showed that the blockade of histone deacetylases by sodium valproate, administered subcutaneously at a dose of 50 mg/kg on PND3–6 led to an improvement in olfactory discrimination learning task with imitation of maternal grooming as positive reinforcement impaired by MS procedure in a gender-dependent manner, i.e., in males, but not in females (Burenkova, Aleksandrova, & Zaraiskaya, 2014b). At the same time, the use of this scheme of administration of valproate did not lead to a violation of the physical, somatosensory development and social behavior of 129Sv mice in the nesting period (Burenkova, Aleksandrova, & Zarayskaya, 2015).

The results obtained indicate the possibility of further use of sodium valproate at the indicated dosage for experimental modulation of the level of histone acetylation in the developing brain (Burenkova et al., 2019). The long-term influence of the administration of histone deacetylase inhibitors on the physiological and behavioral phenotype of adult animals to correct those negative consequences of environmental influences in the early postnatal period that affect epigenetic molecular and cellular mechanisms remains poorly explored. The results obtained to date in adult males are showing that sodium valproate selectively increased the anxiety of adult male mice in open-field and elevated plus-maze tests (Burenkova et al., 2014a). At the same time, we revealed that 50 mg/kg sodium valproate injections prevented the reduction of the level of maternal nursing associated with licking-grooming and pup investigation induced by MS and pain from injections in offspring females later in adulthood (Burenkova et al., 2019). However, it appears that the positive effects of valproate might be constrained by a specific range of concentrations. To begin with, a single prenatal (on E10-E12, which approximately corresponds to the first trimester of human embryonic life) or multiple postnatal (in the range of PND0–14, which corresponds to the third trimester of human embryonic life) exposure of high valproate dosages (300–600 mg/kg) is widely utilized for modeling autism spectrum disorder since it recapitulates autism-related phenotypes, including deficits in social interactions (Elnahas et al., 2021; Kim et al., 2011; Moldrich et al., 2013). The mechanisms underlying these behavioral effects may involve elevated brain inflammatory cytokines, oxidative stress, histological neurodegeneration, and apoptosis (Elnahas et al., 2021). The effects of lower but still high postnatal valproate dosage are generally in line with the prenatal effects of valproate. Valproate injections on PND6–12 (150 mg/kg) decreased the interest in new social contacts on PND36 in rats (Gedzun et al., 2021). The injection of a dosage of 400 mg/kg to rat pups during the first week of life resulted in later maternal adverse behaviors toward their own pups in adulthood (Collins et al., 2022). Furthermore, valproate (200 mg/kg) administered on PND4–11 led to significant delays in weight gain and motor impairments in the nesting and adolescent period (Bath & Pimentel, 2017). Similarly, valproate injections on PND6–12 (150 mg/kg) led to a delay in early motor development and hyperactivity in the open field test on PND21 in rats (Gedzun et al., 2021).

A 400 mg/kg dose of another HDAC inhibitor, sodium butyrate, dissolved in a 5% sucrose solution and delivered orally before each maltreatment episode (exposure to stressed dams) on PND1–7 prevented the maltreatment-induced increase in methylation at Bdnf exon IX in the prefrontal cortex of male pups on PND8, though not in female pups (Doherty, Chajes, Reich, Duffy, & Roth, 2019). This outcome could be indicative of crosstalk between histone acetylation and DNA methylation levels, as demonstrated in earlier cell culture studies (Cervoni & Szyf, 2001). Decreased after MD on PND9 Bdnf mRNA levels were reversed 24 hours after a single injection of the selective class I HDAC inhibitor CI-994 (also known as N-acetyldinaline or tacedinaline; dissolved in 1% Tween80, which is considered not toxic) on PND14–21 (Shepard et al., 2018).

The second of the two most frequently utilized pharmacological tools in the study of epigenetic mechanisms related to ELA is the inhibition of DNA methyltransferase (DNMT). DNMTs constitute a family of enzymes, consisting in humans of five members, with DNMT1, DNMT3A, and DNMT3B being the primary ones; DNMT1 maintains existing DNA methylation patterns during DNA replication, whereas DNMT3A and DNMT3B are responsible for de novo DNA methylation (Lyko, 2018). Inhibition of DNMTs results in a decrease in DNA methylation, and commonly used inhibitors include zebularine, azacitidine, and decitabine (Weaver et al., 2017). Pertaining to the focus of this review, treatment with zebularine in adult animals reversed the effects of nursing by a stressed female during the first week of life in rats, leading to reduced Bdnf gene mRNA expression and increased DNA methylation of the Bdnf gene promoter in the prefrontal cortex (Roth et al., 2009). Similarly, zebularine rescued aberrations in maternal behavior caused by maltreatment exposure (LBN model), but its treatment resulted in an increase in DNA methylation levels of Bdnf exon IV and a decrease in its expression in the medial preoptic area (MPOA) of maltreated animals (Keller, Doherty, & Roth, 2019). Additionally, zebularine disturbed behavior in dams without a history of maltreatment, leading to higher levels of adverse behavior toward offspring compared to vehicle-treated controls (Keller et al., 2019). The negative behavioral effects of zebularine were also demonstrated in other studies, where it prevented memory consolidation (Lubin, Roth, & Sweatt, 2008; Miller & Sweatt, 2007). More precise mechanism of zebularine’s action still remains poorly understood, as it inhibits DNMT1 activity through intercalation into DNA during replication, potentially limiting its applicability in postmitotic neuronal cells. In contrast, the use of small molecule inhibitors that do not incorporate into DNA and act more as enzymatic DNMT inhibitors, such as RG108 (N-phthalyl-1-tryptophan) (Zheng, Wu, Chen, & Goodman, 2008), represent a more promising epigenetic tool, although it has not been tested for alleviating the effects of ELA yet.

Therefore, studies on the impact of HDACs and DNMTs inhibition during critical developmental periods and adulthood highlight their potential to reverse epigenetic changes associated with ELA. These inhibitors can be an important tool in understanding and manipulating epigenetic mechanisms in the context of brain development and function and in mitigating the consequences of early environmental influences on neural development. However, further study of the mechanisms of their action, as well as the examination of appropriate dosages and potential adverse effects, is warranted. Furthermore, an important caveat of using these inhibitors is their non-specific effects on particular genes or sequences. In other words, it is not possible to use HDAC inhibitors to target specific genes or loci, and this limitation could potentially restrict their therapeutic efficacy. This drawback can be addressed through the utilization of epigenome editing techniques.

Epigenome editing is a promising approach that involves the targeted modification of an epigenome at specific sites by employing molecules that bind to specific DNA sequences and modify them or adjacent histones. This approach is based on three different systems that can recognize nucleotide sequence: zinc-finger nucleases (ZFNs), transcription activator-like effectors (TALEs), and clustered regularly interspaced short palindromic repeats (CRISPR) interacting with dCas9 nucleases (Day, 2014). In this review, we will focus on CRISPR/dCas9-based approach as the most recent and effective one.

The traditional CRISPR/Cas9 system uses a guide RNA (gRNA) to target the Cas9 protein to specific DNA sequences, where the Cas9 induces double-strand breaks in the DNA. In contrast, CRISPR/dCas9 enables the targeting of specific genomic locations without inducing DNA breaks, as the Cas9 protein is altered to lack its endonuclease (cutting) activity, rendering it deactivated or ‘dead,’ for which the ‘d’ stands in its name (Whinn et al., 2019). Thus, CRISPR/dCas9 can be employed for the targeted modification of epigenetic marks, such as DNA methylation or histone modifications, without causing changes in the DNA sequence. For this purpose, CRISPR/dCas9 complex is fused with epigenetic modifying enzymes such as Tet1³ or DNMTs for the modulation of DNA methylation (X. Liu et al., 2016), or histone acetyltransferase (HAT) p300 or HDACs for the modulation of histone acetylation (Hilton et al., 2015).

In vivo, epigenome editing with CRISPR-dCas9 has already been validated on both molecular (X. Liu et al., 2016) and behavioral (Bohnsack et al., 2022) levels. X. Liu et al. (2016) demonstrated that targeted demethylation of the Bdnf promoter IV by dCas9-Tet1 injection into different regions of the same brain induced Bdnf gene expression in post-mitotic neurons. Bohnsack et al. (2022) used dCas9-p300 injection to the amygdala, which led to the attenuation of adult anxiety and excessive alcohol drinking in a rat model of adolescent alcohol exposure. No data on correction of the effects of ELA on the behavioral, physiological, or epigenetic profiles seem to be available currently.

Despite the obvious advantages of the method of epigenome editing, it also has some disadvantages that limit its widespread use. First, the necessity of precise viral injections to the brain can be challenging to carry out. Second, it can involve off-target effects – unintended modifications that occur at genomic loci other than the intended target site (X. H. Zhang, Tee, Wang, Huang, & Yang, 2015). Third, to be efficient, methylation requires prolonged high expression of dCas9-DNMT3A that declines rapidly after the termination of dCas9-DNMT3A expression (Sapozhnikov & Szyf, 2023). Four, DNMTs exhibit a non-specific activity, independent of targeting, that makes them unsuitable for precise epigenetic editing (Sapozhnikov & Szyf, 2023). Five, this technique is selective to the gene but not the position of acetylated histones. In conclusion, the use of epigenetic editing holds the potential to advance our comprehension of the causal connections between ELA and behavioral, physiological, as well as epigenetic profiles. However, significant improvements in this technique are necessary.

Translational Potential of Mother-Infant Relationship Models

An important result of the research discussed in this review is the fact that the target genes of the detected epigenetic modifications in human and animal brain cells can be similar and be controlled by the same epigenetic mechanisms (Turecki & Meaney, 2016). This indicates both the need for a wider range of studies of epigenetic modifications in developing brains and the possibility of using biological models of adverse early experiences as translational ones.

Translational research is a widely used concept whose meaning has been evolving since its introduction in the literature at the turn of the 21^st century as the process signifying the cycle of discoveries “from the bench to the bedside and back again” (Fort, Herr, Shaw, Gutzman, & Starren, 2017). In short, both the definition and the structure of translational research have evolved, reflecting the growing complexity and intensity of the field. Yet, the common notion of numerous various definitions is in attempting to identify and bridge a supposed gap between knowledge produced at the lab bench and its use at the clinical bedside, which needs to be closed to help society harvest the dividends of its support of and investments in scientific research (van der Laan & Boenink, 2015). The current consensus definition of translational research points to a hierarchical structure of interdisciplinary work, dissecting the continuous flow of translational research into five connected phases, T1-T0. Thus, the translational cycle includes (1) T1, where observations and ideas from basic research are verified through early testing in humans; (2) T2 involves the establishment of effectiveness of the basic finding in humans and formulating clinical guidelines; (3) T3 primarily focuses on implementation and dissemination research; (4) T4 focuses on outcomes and effectiveness in human subpopulations and populations; and (5) T0 covers research such as genome-wide association studies which wrap back around to basic research.

The research presented in this narrative review is mostly localized at the T1 phase of translation. Importantly, although most human studies are limited to observation and registration of association, model organism studies can create temporal sequences of events that are characteristic of developmental milestones across species. It is particularly relevant to studies of the impact of early life events on lifespan outcomes. Thus, with an eye to translational applications for human research and practice derivable from rodent studies, Bonapersona and colleagues (2019) conducted a multi-level (animals, outcomes, and experiments) large-scale (400+ independent experiments involving ~8600 animals) meta-analyses of the impact of aberrant maternal care on specific behavioral domains. Among numerous associations between aberrant maternal behavior and subsequent developmental outcomes, the authors stress the following as most interesting. First, they observed that aberrant maternal behavior has differential effects on memory by strengthening memory in stressogenic but hampering it in non-stressful situations. Second, faulty maternal care increases anxiety and decreases social behavior, especially in males. Importantly, in line with human work on cumulative stress (Suor, Sturge-Apple, Davies, Cicchetti, & Manning, 2015), the effects are amplified when rodents experience additional stressful life events (Daskalakis, Bagot, Parker, Vinkers, & de Kloet, 2013).

Moreover, in addition to literature summaries on the general effects of maternal care on subsequent development, there are targeted reviews aimed at evaluating the benefits of rodent models for advancing research on various aspects of human development and disease. Thus, Ham and colleagues (2023) conducted a cross-species review of rodents and humans on synchrony in parent-offspring social interactions across development. Concluding their review, the authors commented on both similar and distinct qualities of the developmental synchrony across the species, stressing that such comparative analyses can generate a deeper understanding of the mechanics of parent-offspring interactions and their typicality and atypicality and related lifespan consequences. The obvious targets for such translational investigations are offspring cries, physical touching, feeding behavior, and social interactions, among other complex behaviors.

To illustrate, altered methylation patterns of the Bdnf gene have been observed in human cord blood following high maternal bisphenol A, BPA, levels during pregnancy (Kundakovic et al., 2015). This result is aligned with the results of model studies in which developmental exposure to endocrine disruptors, such as BPA, results in drastic organismal changes driven by epigenetic mechanisms (Kundakovic & Champagne, 2011). Similarly, diet has been shown to be highly impactful on patterns of methylation in model organisms both during gestation (Reuter, Gupta, Park, Goel, & Aggarwal, 2011; Waterland & Jirtle, 2003) and outside (Milagro et al., 2009) of developmental periods. These findings have been paralleled by studies of severe dietary limitations as those during famine (Heijmans et al., 2008) in humans.

In general, model organisms provide a unique platform for understanding the epigenetic mechanics of fundamental processes unfolding in typical and atypical human development. Given the enormous corpora of the literature on the role of early life effects in the development of human and model organisms, careful comparative analyses similar to those presented by Ham and colleagues (2023) are needed. Findings from such analyses might permit the development of the interventions that might be evaluated at T2 of the translational cycle.

Conclusion

Research efforts in recent decades have focused on uncovering the epigenetic mechanisms underlying the development of physiological and behavioral phenotypes through the interaction of the organism with the environment in the early stages of the postnatal period. Maternal (parental) care is unique among other environmental factors as it determines the survival and adaptation of offspring to environmental conditions. Epigenetic modifications that occur in the neurons of the maturing brain in response to specific levels of parental care are apparently one of the key mechanisms on which this adaptation is based on.

An extremely important property of the detected epigenetic modifications is their reversibility (Weaver et al., 2004). The possibility of this reversibility underlies the importance of developing approaches that elucidate the mechanisms that trigger epigenetic modifications in the brain and mediate the influence of early developmental conditions. Given that a significant implication of “reversibility” is the potential for correction and “reprogramming” of the negative consequences of early-life experiences (Vaiserman, Voitenko, & Mekhova, 2011), further studies on precise techniques that modulate gene- and cell-specific levels of modified histones and DNA methylation are of utmost importance.