Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene

“Exposure of rat pups to stressed mothers during their first week of life increases DNAme at the BDNF locus in prefrontal cortex associated with decreased BDNF expression (Roth et al., 2009).”

“[26] Interestingly, all these studies refer to alterations in methylation levels as an influence by the extrinsic factors such as environment, food intake etc.”

“Accumulating evidence in murine studies suggests that psychological stress can dysregulate the DNA methylation pattern of multiple stress-related genes in the brain (Murgatroyd et al., 2009; Roth et al., 2009; Uchida et al., 2011; Roth, 2013).”

“BDNF DNA methylation was analyzed using the bisulfite pyrosequencing method as previously described (30, 32).”

“Exposure of infant rats to stressed caretakers that displayed abusive behaviour produced persisting changes in methylation of BDNF gene promoter in the adult prefrontal cortex (Roth et al., 2009).”

“This approach has proved to be useful for interrogating the methylation status of individual cytosine bases in DNA (32, 34, 36).”

“…suggest that negative earlylife experiences, including environmental adversity, reduced maternal care, and exposure to toxins, can induce epigenetic reprogramming and increase the susceptibility for the development of emotional dysregulation in adulthood (Roth et al., 2009;Weaver et al., 2004).”

“[91] used a limited nesting resource model to examine the effects of maternal maltreatment on the offspring’s epigenome.”

“In addition to the GC-GR and CRH-CRHR1 systems, molecules such as brain-derived neurotrophic factor (Roth et al., 2009; Suri et al., 2013) may also contribute to the effects of early-life stress on hippocampal structure and function.”

“For example, changes in methylation of both the genes for glucocorticoid receptors and BDNF have been associated with early-life trauma in human populations (McGowan et al. 2009; Roth et al. 2009).”

“Also, EL adversity from P1 to P7 by stress-abusive rat dams results in reduced brain-derived neurotrophic factor (BDNF) expression due to increased methylation at the BDNF exon IV promoter in the prefrontal cortex later in life (Roth et al., 2009).”

“…laboratory, early adversity can be associated with lifelong reductions of BDNF in frontal cortex and hippocampus (Post, 2007; Roceri et al., 2004; Roth et al., 2009), decreases in the set-point for neurogenesis (Gould and Tanapat, 1999), increases in inflammatory cytokines, and evidence of…”

“Early-life adversity has been shown to alter DNA methylation in the brain and increase the risk for psychiatric disorders later in life (Khulan et al., 2014; Labonté et al., 2012; Roth et al., 2009; Weaver et al., 2004).”

“BDNF expression could also be down-regulated by posttranscriptional processes or epigenetic mechanisms, such as DNA methylation or histone acetylation (Roth et al. 2009).”

“For example, factors such as maternal care and maltreatment (Weaver et al., 2004, 2007; Roth et al., 2009), fear conditioning (Miller and Sweatt, 2007; Lubin et al., 2008; Miller et al., 2010), stress (Roth et al., 2011), LTP (Levenson et al., 2006), and drug use (Anier et al., 2010; LaPlant et…”

“Female rat pups exposed to abusive care-giving in infancy engage in abusive caregiving toward their own offspring and F2 offspring of these F1 females have elevated levels of methylation within the BDNF promotor in the cortex and hippocampus (Roth et al., 2009).”

“Epigenetic modifications have been evaluated as potential mechanisms whereby stress affects expression of genes that encode for BDNF (Roth et al., 2009; Roth and Sweatt, 2010).”

“Through this kind of memory, the trait of altered maternal behaviour may be passed on to the subsequent generation [13,35,36] via, for example, a heritable pattern of hypermethylation of the gene encoding brain-derived neurotrophic factor (BDNF) [37].”

“In rodent models of early-life stress, increased methylation of BDNF promoter IV was found to be associated with decreased mRNA expression of BDNF in the prefrontal cortex (Ivy et al., 2008; Roth et al., 2009).”

“The pathway from stress experience via glucocorticoid stimulation to epigenetic modifications of BDNF and other important behavioural genes may be important for many stress-induced, long-term effects, such as those resulting from early maltreatment in humans (Roth, 2012; Roth et al., 2009).”

“In addition, maltreatment appears to span generations, with increased familial risk and family clustering that is replicated in rodent and NHP cross-fostering studies (Francis et al., 1999; Roth et al., 2009; Sanchez et al., 2010b).”

“BDNF is a neurotrophic factor involved in synaptic plasticity inducible by activity dependent processes and is highly epigenetically regulated (Roth et al., 2009; Tian et al., 2010).”

“…SI groups were performed using unpaired t-tests and comparisons between the experimental (AE and SI) and the control group (SC) were analyzed with a onesample t-test (hypothetical value set to 1.0) as commonly done in the field (e.g. Roth et al., 2009; Blaze and Roth, 2013; Debruin et al., 2014).”

“susceptibility to depression that is associated with early life stress (Roth et al. 2009).”

“In both rodents and nonhuman primates, lowquality maternal care leads to reduced nurturing in the next generation (Maestripieri, 2005; Roth et al., 2009).”

“Thus, epigenetic signatures and associated behaviors may be transmitted over multiple generations (Roth et al., 2009).”

“The term ‘neuroplasticity’ refers to ‘the ability of the nervous system to adapt its structural and functional organisation to altered circumstances arising from developmental or environmental (including traumatic) changes’ (Gould, 2007; Rutter, 2009).”

“These changes are transmitted to the female offspring which may lead to poor parental care and abusive behaviours that these maltreated females exhibit in toward their offspring (Roth et al., 2009).”

“Furthermore, adult rats exposed to early life stress have demonstrated reduced BDNF in the prefrontal cortex correlated with hypermethylation of the BDNF IV promoter region (Roth et al., 2009).”

“In addition, epigenetic modifications of the BDNF gene in response to stress, fear memory, and early maltreatment have also been studied in rats [Roth et al., 2009; Fuchikami et al., 2010; Roth et al., 2011] and humans [Lubin et al.”

“For example, pharmacological treatment has been shown to reverse the effects of earlier maternal abuse and neglect on DNA methylation in rat offspring (Roth et al., 2009; Tsankova et al., 2006; Weaver et al., 2005).”

“A number of studies have demonstrated the effect of in utero environment on multigenerational programming where DNA methylation changes occur in response to environmental exposures, particularly in response to early life stress and adversity [1–6].”

“However, the previous studies exploring the analogous region of rat BDNF found that DNA methylation controlled exon-specific transcription of the BDNF gene (Lubin et al., 2008; Roth et al., 2009).”

“Previous studies indicated that expression of the bdnf gene is regulated by epigenetic modification (Tsankova et al., 2006; Roth et al., 2009).”

“Rat pups raised by dams stressed for 30 min daily during the first postnatal week have significantly lower BDNF mRNA in PFC when adult.(82) This is associated with differential DNA methylation of an important regulatory region of the BDNF gene (exon IV).”

“Childhood adversity causes methylation changes in the genes encoding the glucocorticoid receptor (McGowan et al, 2009; Weaver et al, 2004) and the brain-derived neurotropic factor (Roth et al, 2009).”

“, ERS1 in the medial POA, brain-derived neurotrophic factor (BDNF) in the prefrontal cortex [PFC]), the direction of effect mirrors that observed in NR3C1, that is, exposure to ELS is associated with increased DNAm[35, 49] whereas in others, the effect is in the opposite direction (e.”

“2009) and abuse (Roth et al. 2009) modifying the genes expressing arginine vasopressin and brain-derived neurotropic factor, respectively.”

“netic modification of genes in response to early-life adversity affecting HPA regulation, including arginine vasopressin [92], FK506 binding protein 5 (FKBP5) [93], brain-derived neurotrophic factor (BDNF) [94], and glucocorticoid receptor (NR3C1) [95].”

“2010; Rowan 1925; Sharp 2005).”

“…plasticity (Levenson et al. 2006; Feng et al. 2010; Monsey et al. 2011; Meadows et al. 2015, 2016; Yu et al. 2015), and is modified in an experience-dependent manner (Miller and Sweatt 2007; Roth et al. 2009; Miller et al. 2010; Maddox and Schafe 2011; Day et al. 2013; Tognini et al. 2015).”

“Chronic social stress in mice decreases the expression of two specific BDNF transcripts (III and IV) in the hippocampus,(47) and maternal maltreatment decreases prefrontal cortex (PFC) BDNF mRNA expression in rats.(48) The BDNF expression alterations observed in chronic social stress in mice are mediated through incre…”

“Alternatively, choline supplementation may lead to long-term changes in gene expression through epigenetic regulation of gene promoter regions (73,74), such as was shown to occur for BDNF following early life stress (75).”

“Exposure of infant rats to stressed caretakers that displayed abusive behavior produced persisting changes in methylation of BDNF gene promoter in the adult prefrontal cortex (Roth et al. 2009).”

“…forms of behavioral experience, and this phenomenon generally occurs at genes that are known to control neuronal plasticity (Weaver et al., 2004, 2005; Miller and Sweatt, 2007; Lubin et al., 2008; Roth et al., 2009; Gupta et al., 2010; Miller et al., 2010; Guo et al., 2011a; Penner et al., 2011).”

“In a rat model of infant maltreatment, decreased BDNF levels were found to be programmed through an epigenetic mechanism (Roth et al., 2009).”

“By restricting a lactating dam’s bedding material in a novel arena, we can elicit adverse pup-directed caregiving behaviors, including stepping on, dragging, dropping, and actively avoiding pups (Roth and Sullivan, 2005; Roth et al., 2009; Blaze et al., 2013).”

“Studies in rats mimicking fragmented maternal care, maternal neglect, and early life psychosocial stress revealed cognitive and emotional dysfunctions and learning deficits in the offspring of ‘‘bad mothers’’ (Baram et al. 2012; Roth et al. 2009).”

“Many aspects of sensitization and cross sensitization effects appear to be mediated on the basis of long-lasting neurobiological alterations at the level of epigenetics (Berton et al., 2006; McGowan et al., 2009a, 2009b; Post, 2010a, 2010b; Roth et al., 2009; Tsankova et al., 2007).”

“The present study adds to the literature demonstrating that epigenetic modification of gene expression and resulting changes in phenotypic expression may be mediated via maternal care (Weaver et al., 2004; Roth et al., 2009).”

“Differential levels of DNA methylation of genes related to stress reactivity have already been associated with PTSD and early life stress [93-95].”

“see a possible exacerbation of bLRs’ anxiety-like behavior following MS stress exposure (Aisa et al., 2009; Franklin et al., 2010; Huot et al., 2001; Ladd et al., 2000; Roth et al., 2009).”

“Since then, other epigenetic modifications, such as modulations of promoters' methylation states of the brain-derived neurotrophic factor (BDNF) or of the arginine vasopressin, were linked to the pathophysiology of mood disorders (Murgatroyd et al., 2009; Roth et al., 2009).”

“BdnfpromoterDNAmethylationandcause lifelongchanges in Bdnf expression (20).”

“Early-life maltreatment of infant rats produced persistent changes in Bdnf DNA methylation that were passed to the next generation by maltreated mothers [73].”

“Translational work employing a rodent model of early-life maltreatment and trauma has demonstrated long-lasting epigeneticmediation of BDNF transcription (Roth et al., 2009).”

“Studies demonstrate altered DNA methylation of BDNF, reelin, and PP1 gene (all essential to the learning and memory process) following fear conditioning and hypermethylation of BDNF in rodents experiencing early-life adversity (Miller and Sweatt, 2007; Lubin et al., 2008; Roth et al., 2009).”

“…stress, social environment, environmental toxins, drugs, or childhood adversities produced persistent changes in methylation patterns of the promoters of several genes (Rampon et al. 2000; Bollati et al. 2007; Cheng et al. 2008; Roth et al. 2009; Devlin et al. 2010; Kang et al. 2013; Szyf, 2013).”

“To investigate the epigenetic regulation involved in decreased BDNF levels in the hippocampus of PS mice, we examined the DNAmethylation levels at CGIs of the Bdnf promoter [41, 42].”