Maternal separation alters serotonergic and HPA axis gene expression independent of separation duration in c57bl/6 mice

Own, Lawrence S.; Iqbal, Rimsha; Patel, Paresh D.

doi:10.1016/j.brainres.2013.03.032

Cited by 31 publications

(19 citation statements)

References 63 publications

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“…brain (1,28,32). Many of the components altered by ELS can play an important role in regulating vascular tone, senescence, and inflammation (14) and thus are possible mechanisms by which MSEW-induced superoxide in mouse aorta is orchestrated.…”

Section: Discussionmentioning

confidence: 99%

Early life stress in male mice induces superoxide production and endothelial dysfunction in adulthood

Burch

Musall

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Early life stress (ELS) is a risk for cardiovascular disease in adulthood although very little mechanistic insight is available. Because oxidative stress and endothelial dysfunction are major contributors to cardiovascular risk, we hypothesized that ELS induces endothelial dysfunction in adult male mice via increased superoxide production. Studies employed a mouse model of ELS, maternal separation with early weaning (MSEW), in which litters were separated from the dam for 4 h/day [postnatal days (PD) 2-5] and 8 h/day (PD6-16), and weaned at PD17. Control litters remained undisturbed until weaning at PD21. When compared with control mice, thoracic aortic rings from adult male MSEW mice displayed significant endothelial dysfunction that was reversed by the superoxide scavenger, polyethylene glycol-superoxide dismutase (PEG-SOD). PEG-SOD-inhibitable superoxide production by aortae from MSEW mice was significantly greater than observed in control aortae, although unaffected by nitric oxide synthase inhibition, suggesting that uncoupled nitric oxide synthase was not responsible for the accelerated superoxide production. Aortic SOD expression, plasma SOD activity, and total antioxidant activity were similar in MSEW and control mice, indicating unaltered antioxidant capacity in MSEW mice. Increased expression of the NADPH oxidase subunits, NOX2 and NOX4, was evident in the aortae of MSEW mice. Moreover, endothelial dysfunction and superoxide production in MSEW mice was reversed with the NADPH oxidase inhibitor, apocynin, indicating increased NADPH oxidase-dependent superoxide production and endothelial dysfunction. The finding that MSEW induces superoxide production and endothelial dysfunction in adult mice may provide a mechanistic link between ELS and adult cardiovascular disease risk.

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Section: Discussionmentioning

confidence: 99%

Early life stress in male mice induces superoxide production and endothelial dysfunction in adulthood

Burch

Musall

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…24, 25, 26 Environmentally-induced changes in SERT expression may partly account for the observed inconsistencies 27 but have been sparsely addressed in humans. Animal studies in various species provide first evidence that exposure to early adversity correlates with decreased SERT mRNA levels in the brain 28,29 (but also see Gardner et al 30 ) and in peripheral cells. 31 These long-term changes in SERT expression patterns may result from stable epigenetic modifications such as DNA methylation.…”

Section: Introductionmentioning

confidence: 94%

Effects of genetic and early environmental risk factors for depression on serotonin transporter expression and methylation profiles

et al. 2014

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The serotonin transporter (SERT) gene-linked polymorphic region (5-HTTLPR) has been implicated in moderating the link between life stress and depression. However, respective molecular pathways of gene–environment (GxE) interaction are largely unknown. Sustained alterations in SERT gene expression profiles, possibly mediated by epigenetic modifications, are a frequent correlate of depression and may thus constitute a putative mediator of GxE interaction. Here, we aimed to investigate joint effects of 5-HTTLPR and self-reported environmental adversity throughout the lifespan (prenatal, early and recent stress/trauma) on in vivo SERT mRNA expression in peripheral blood cells. To further evaluate whether environmentally induced changes in SERT expression are mediated by epigenetic modifications, we analyzed 83 CpG sites within a 799-bp promoter-associated CpG island of the SERT gene using the highly sensitive method of bisulfite pyrosequencing. Participants were 133 healthy young adults. Our findings show that both the 5-HTTLPR S allele and maternal prenatal stress/child maltreatment are associated with reduced in vivo SERT mRNA expression in an additive manner. Remarkably, individuals carrying both the genetic and the environmental risk factors exhibited 32.8% (prenatal stress) and 56.3% (child maltreatment) lower SERT mRNA levels compared with those without any risk factor. Our data further indicated that changes in SERT mRNA levels were unlikely to be mediated by DNA methylation profiles within the SERT CpG island. It is thus conceivable that the persistent changes in SERT expression may in turn relate to altered serotonergic functioning and possibly convey differential disease vulnerability associated with 5-HTTLPR and early adversity.

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“…Enhanced basal neuroendocrine reactivity has been reported in rats following maternal separation 19,20 while unaltered neuroendocrine activity has been widely reported in mouse models. 21,22 Similarly, rats display enhanced anxiety 23,24 and depression-like 19,25 behaviours after early stress. Mixed reports exist in mice, once again with unchanged behaviour in mouse models, 22,26, 27, 28, 29 although findings are varied.…”

Section: Factors Influencing the Effect Of Early Life Stressmentioning

confidence: 98%

“…21,22 Similarly, rats display enhanced anxiety 23,24 and depression-like 19,25 behaviours after early stress. Mixed reports exist in mice, once again with unchanged behaviour in mouse models, 22,26, 27, 28, 29 although findings are varied. As each of these factors ultimately influences the long-term sequelae of early adversity, it is likely that they also influence the way in which interventions alter changes in neurobiology.…”

Section: Factors Influencing the Effect Of Early Life Stressmentioning

confidence: 98%

“…Reduced serotonin receptor expression has been demonstrated in the prefrontal cortex, 56,57 hippocampus 56,57 and raphe nucleus 22,58 following early stress in animal models, indicating that adversity impairs serotonergic signalling. Reports also indicate that early stress influences dopaminergic signalling; decreased activity of the mesolimbic dopaminergic system has been demonstrated following separation, once again in line with depression-like behaviour.…”

Section: Early Life Stress Induces Changes In Neurobiologymentioning

confidence: 99%

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Modulation of early stress-induced neurobiological changes: a review of behavioural and pharmacological interventions in animal models

Harrison

Baune

2014

Transl Psychiatry

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Childhood adversity alters the predisposition to psychiatric disorders later in life. Those with psychiatric conditions and a history of early adversity exhibit a higher incidence of treatment resistance compared with individuals with no such history. Modulation of the influence early stress exerts over neurobiology may help to prevent the development of psychiatric disorders in some cases, while attenuating the extent of treatment resistance in those with established psychiatric disorders. This review aims to critically evaluate the ability of behavioural, environmental and pharmacologic interventions to modulate neurobiological changes induced by early stress in animal models. Databases were systematically searched to locate literature relevant to this review. Early adversity was defined as stress that resulted from manipulation of the mother–infant relationship. Analysis was restricted to animal models to enable characterisation of how a given intervention altered specific neurobiological changes induced by early stress. A wide variety of changes in neurobiology due to early stress are amenable to intervention. Behavioural interventions in childhood, exercise in adolescence and administration of epigenetic-modifying drugs throughout life appear to best modulate cellar and behavioural alterations induced by childhood adversity. Other pharmacotherapies, such as endocannabinoid system modulators, anti-inflammatories and antidepressants can also influence these neurobiological and behavioural changes that result from early stress, although findings are less consistent at present and require further investigation. Further work is required to examine the influence that behavioural interventions, exercise and epigenetic-modifying drugs exert over alterations that occur following childhood stress in human studies, before possible translational into clinical practice is possible.

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Maternal separation alters serotonergic and HPA axis gene expression independent of separation duration in c57bl/6 mice

Cited by 31 publications

References 63 publications

Early life stress in male mice induces superoxide production and endothelial dysfunction in adulthood

Early life stress in male mice induces superoxide production and endothelial dysfunction in adulthood

Effects of genetic and early environmental risk factors for depression on serotonin transporter expression and methylation profiles

Modulation of early stress-induced neurobiological changes: a review of behavioural and pharmacological interventions in animal models

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