Prenatal Restraint Stress is Associated with Demethylation of Corticotrophin Releasing Hormone (CRH) Promoter and Enhances CRH Transcriptional Responses to Stress in Adolescent Rats

Maternal stress can disturb normal fetal neurodevelopmental progress, and lead to negative behavioral and neuroendocrine consequences for the offspring. These effects may be related to alterations in the hypothalamic–pituitary–adrenal (HPA) axis. Early life events disrupting the function of the HPA axis may be associated with epigenetic modification. This study investigated the effect of maternal stress on the methylation rate of the corticotrophin-releasing hormone (CRH) promoter and HPA axis response to acute stress in the adolescent offspring of Sprague–Dawley rats. Pregnant dams were randomly assigned to two groups: restraint stress group and normal control group. Adolescent male and female offspring were used from each group. The results showed that prenatal stress is associated with the demethylation of the CRH promoter, and leads to anxiety-like behaviors in adolescent life stages, as well as hyper-responsiveness of the HPA axis. Together, these results imply that prenatal stress alters the normal HPA function, which may be via the epigenetic mechanism.     

Sex, stress, and mood disorders: at the intersection of adrenal and gonadal hormones

The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design.     

Glucocorticoids, prenatal stress and the programming of disease

An adverse foetal environment is associated with increased risk of cardiovascular, metabolic, neuroendocrine and psychological disorders in adulthood. Exposure to stress and its glucocorticoid hormone mediators may underpin this association. In humans and in animal models, prenatal stress, excess exogenous glucocorticoids or inhibition of 11β-hydroxysteroid dehydrogenase type 2 (HSD2; the placental barrier to maternal glucocorticoids) reduces birth weight and causes hyperglycemia, hypertension, increased HPA axis reactivity, and increased anxiety-related behaviour. Molecular mechanisms that underlie the ‘developmental programming’ effects of excess glucocorticoids/prenatal stress include epigenetic changes in target gene promoters. In the case of the intracellular glucocorticoid receptor (GR), this alters tissue-specific GR expression levels, which has persistent and profound effects on glucocorticoid signalling in certain tissues (e.g. brain, liver, and adipose). Crucially, changes in gene expression persist long after the initial challenge, predisposing the individual to disease in later life. Intriguingly, the effects of a challenged pregnancy appear to be transmitted possibly to one or two subsequent generations, suggesting that these epigenetic effects persist.     

QUANTITATIVE GENETIC MODELS FOR DEVELOPMENT,EPIGENETIC SELECTION,AND PHENOTYPIC EVOLUTION

Herein we describe a general multivariate quantitative genetic model that incorporates two potentially important developmental phenomena, maternal effects and epigenetic effects. Maternal and epigenetic effects are defined as partial regression coefficients and phenotypic variances are derived in terms of age-specific genetic and environmental variances. As a starting point, the traditional quantitative genetic model of additive gene effects and random environmental effects is cast in a developmental time framework. From this framework, we first extend a maternal effects model to include multiple developmental ages for the occurrence of maternal effects. An example of maternal effects occurring at multiple developmental ages is prenatal and postnatal maternal effects in mammals. Subsequently, a model of intrinsic and epigenetic effects in the absence of maternal effects is described. It is shown that genetic correlations can arise through epigenetic effects, and in the absence of other developmental effects, epigenetic effects are in general confounded with age-specific intrinsic genetic effects. Finally, the two effects are incorporated into the basic quantitative genetic model. For this more biologically realistic model combining maternal and epigenetic effects, it is shown that the phenotypic regressions of offspring on mother and offspring on father can be used in some cases to estimate simultaneously maternal effects and epigenetic effects.     

Prenatal exposure to maternal depression,neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses

Background: In animal models, variations in early maternal care are associated with differences in hypothalamic-pituitary-adrenal (HPA) stress response in the offspring, mediated via changes in the epigenetic regulation of glucocorticoid receptor (GR) gene (Nr3c1) expression. Objective: To study this in humans, relationships between prenatal exposure to maternal mood and the methylation status of a CpG-rich region in the promoter and exon 1F of the human GR gene (NR3C1) in newborns and HPA stress reactivity at age 3 months were examined. Methods: The methylation status of a CpG-rich region of the NR3C1 gene, including exon 1F, in genomic DNA from cord blood mononuclear cells was quantified by bisulfite pyrosequencing in infants of depressed mothers treated with a serotonin reuptake inhibitor antidepressant (SRI) (n=33), infants of depressed non treated mothers (n=13) and infants of non depressed/non treated mothers (n=36). To study the functional implications of the newborn methylation status of NR3C1 in newborns, HPA function was assessed at 3 months using salivary cortisol obtained before and following a non noxious stressor and at a late afternoon basal time. Results: Prenatal exposure to increased third trimester maternal depressed/anxious mood was associated with increased methylation of NR3C1 at a predicted NGFI-A binding site. Increased NR3C1 methylation at this site was also associated with increased salivary cortisol stress responses at 3 months, controlling for prenatal SRI exposure, postnatal age, and pre and postnatal maternal mood. Conclusions: Methylation status of the human NR3C1 gene in newborns is sensitive to prenatal maternal mood and may offer a potential epigenetic process that links antenatal maternal mood and altered HPA stress reactivity during infancy.     

Direct and dam-mediated effects of prenatal dexamethasone on emotionality, cognition and HPA axis in adult Wistar rats

Prenatal stress can affect foetal neurodevelopment and result in increased risk of depression in adulthood. It promotes increased maternal hypothalamo–pituitary–adrenal gland (HPA) secretion of glucocorticoid (GC), leading to increased foetal and maternal GC receptor activity. Prenatal GC receptor activity is also increased during prenatal treatment with dexamethasone (DEX), which is commonly prescribed as a prophylactic treatment of preterm delivery associated morbid symptoms. Here, we exposed pregnant Wistar rats to 0.1 mg/kg/d DEX during the last week of pregnancy and performed cross-fostering at birth. In the adult offspring we then studied the effects of prenatal DEX exposure per se and the effects of rearing by a dam exposed to prenatal DEX. Offspring were assessed in the following paradigms testing biobehavioural processes that are altered in depression: progressive ratio schedule of reinforcement (anhedonia), Porsolt forced swim test (behavioural despair), US pre-exposure active avoidance (learned helplessness), Morris water maze (spatial memory) and HPA axis activity (altered HPA function). Responsiveness to a physical stressor in terms of HPA activity was increased in male offspring exposed prenatally to DEX. Despite this increased HPA axis reactivity, we observed no alteration of the assessed behaviours in offspring exposed prenatally to DEX. We observed impairment in spatial memory in offspring reared by DEX exposed dams, independently of prenatal treatment. This study does not support the hypothesis that prenatal DEX exposure leads to depression-like symptoms in rats, despite the observed sex-specific programming effect on HPA axis. It does however emphasise the importance of rearing environment on adult cognitive performances.     

Growth and development of adipose tissue and gut and related endocrine status during early growth in the pig: impact of low birth weight

With genetic selection, the increase in litter size has led to higher variation in within-litter birth weights in pigs. This has been associated with a reduction in mean birth weights and a rise in the proportion of piglets weighing less than 1 kg at birth. Low birth weight pigs exhibit lower postnatal growth rates and feed efficiency, which may be explained by an inadequate digestion and/or nutrient use as a consequence of prenatal undernutrition. It is now documented that there is a relationship between birth weight and subsequent pattern of growth and development of tissues and organs. During the neonatal period, the rapid somatic growth is accompanied by tremendous anatomical, physiological and chemical composition changes. The present review focuses primarily on the influence of low birth weight on adipose tissue and the gastrointestinal tract growth and development during the suckling period. The importance of the somatotropic axis, insulin, thyroid hormones, glucocorticoids, epidermal growth factor and leptin in the regulation of these developmental processes is also considered.     

Prenatal alcohol exposure and fetal programming: effects on neuroendocrine and immune function

Alcohol abuse is known to result in clinical abnormalities of endocrine function and neuroendocrine regulation. However, most studies have been conducted on males. Only recently have studies begun to investigate the influence of alcohol on endocrine function in females and, more specifically, endocrine function during pregnancy. Alcohol-induced endocrine imbalances may contribute to the etiology of fetal alcohol syndrome. Alcohol crosses the placenta and can directly affect developing fetal cells and tissues. Alcohol-induced changes in maternal endocrine function can disrupt maternal-fetal hormonal interactions and affect the female's ability to maintain a successful pregnancy, thus indirectly affecting the fetus. In this review, we focus on the adverse effects of prenatal alcohol exposure on neuroendocrine and immune function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis and the concept of fetal programming. The HPA axis is highly susceptible to programming during fetal development. Early environmental experiences, including exposure to alcohol, can reprogram the HPA axis such that HPA tone is increased throughout life. We present data that demonstrate that maternal alcohol consumption increases HPA activity in both the maternal female and the offspring. Increased exposure to endogenous glucocorticoids throughout the lifespan can alter behavioral and physiologic responsiveness and increase vulnerability to illnesses or disorders later in life. Alterations in immune function may be one of the long-term consequences of fetal HPA programming. We discuss studies that demonstrate the adverse effects of alcohol on immune competence and the increased vulnerability of ethanol-exposed offspring to the immunosuppressive effects of stress. Fetal programming of HPA activity may underlie some of the long-term behavioral, cognitive, and immune deficits that are observed following prenatal alcohol exposure.     

The hierarchical relationships between the organs of the hypothalamo-hypophyseal-adrenal system (HHAS) in inflammation

The HPA axis is the major system of adaptation to the action of different stressors, including inflammatory agents. The glucocorticoids, the end product of HPA axis prevent the extension of inflammation. In this article we discuss the classic direct and feedback loops in the HPA axis during acute bacterial inflammation. On the basis of literary and own findings we put forward a speculation that different systemic cytokines released one by one during inflammation induce the appearance of new functional relations between the organs of HPA axis. Because of cytokines are involved in the modulation of hormonal sensitivity in the HPA axis the serious modification of direct as well as feedback relations is postulated. On the other hand cytokines and immune cells induce autocrine and paracrine production of cytokines in the HPA axis, that result in autonomization of pituitary and adrenals functions. So, the acute inflammation factors could be seen as "short-time" functional dominants of HPA axis functioning.     

Dexamethasone treatment supports age‐related maturation of the stress response in altricial nestling birds

In birds, the magnitude of the adrenocortical stress response can be down‐regulated during specific life‐history stages. Such modulation likely occurs when the effects of mounting robust corticosterone (Cort) elevations interfere with the normal progression of critical lifecycle activities (e.g. development, molt, migration, reproduction). The developmental hypothesis posits that altricial birds should display a ‘stress hyporesponsive period’ during the early post‐natal life stages, characterized by reduced adrenocortical stress responses compared to adult birds and a gradual age‐related increase. Such modulation would allow avoiding the potential deleterious effects that long‐term elevations of circulating Cort might exert on growth and development, when the physiological and behavioral abilities to cope with disturbance are limited. Two proximate hypotheses have been proposed to explain this age‐dependent pattern of Cort secretion. The ‘maturation hypothesis’ proposes a progressive age‐related growth, maturation and enhanced sensitivity to sensory input of the Hypothalamic‐Pituitary‐Adrenal (HPA) axis tissues, whereas the ‘negative feedback attenuation hypothesis’ proposes a gradual attenuation in the intensity of the negative feedback in the HPA axis. Here we tested these hypotheses by experimentally inducing negative feedback on the HPA axis via dexamethasone (DEX) treatment in nestling white storks Ciconia ciconia. Nestling age positively affected stress‐induced plasma Cort (STRESS‐Cort) levels during experimental handling and restraint, thus supporting the developmental hypothesis. DEX treatment significantly reduced STRESS‐Cort levels compared to saline (SAL) treatment, thus eliciting the expected negative feedback on the HPA axis. However, inter‐ and intra‐individual comparisons indicated no age effects on the intensity of the negative feedback exerted by DEX. Our results do not support the negative feedback attenuation hypothesis and suggest that progressive maturation of the HPA axis tissues is the proximate mechanism responsible for age‐related changes in the stress response during avian post‐natal development. We encourage further tests of the proposed proximate mechanisms during migration, breeding and molt.     

Early-life adversity and long-term neurobehavioral outcomes: epigenome as a bridge?

Accumulating evidence suggests that adversities at critical periods in early life, both pre- and postnatal, can lead to neuroendocrine perturbations, including hypothalamic-pituitary-adrenal axis dysregulation and inflammation persisting up to adulthood. This process, commonly referred to as biological embedding, may cause abnormal cognitive and behavioral functioning, including impaired learning, memory, and depressive- and anxiety-like behaviors, as well as neuropsychiatric outcomes in later life. Currently, the regulation of gene activity by epigenetic mechanisms is suggested to be a key player in mediating the link between adverse early-life events and adult neurobehavioral outcomes. Role of particular genes, including those encoding glucocorticoid receptor, brain-derived neurotrophic factor, as well as arginine vasopressin and corticotropin-releasing factor, has been demonstrated in triggering early adversity-associated pathological conditions. This review is focused on the results from human studies highlighting the causal role of epigenetic mechanisms in mediating the link between the adversity during early development, from prenatal stages through infancy, and adult neuropsychiatric outcomes. The modulation of epigenetic pathways involved in biological embedding may provide promising direction toward novel therapeutic strategies against neurological and cognitive dysfunctions in adult life.     

Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats

Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg·d caffeine from gestational days 11-20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in elucidating the developmental toxicity of caffeine and in exploring the fetal origin of adult HPA axis dysfunction and metabolic syndrome susceptibility for offspring with IUGR induced by caffeine.     

Developmental plasticity of HPA and fear responses in rats: a critical review of the maternal mediation hypothesis

Developmental plasticity of HPA and fear responses in rats has been proposed to be mediated by environment-dependent variation in active maternal care. Here, we review this maternal mediation hypothesis based on the postnatal manipulation literature and on our own recent research in rats. We show that developmental plasticity of HPA and fear responses in rats cannot be explained by a linear single-factor model based on environment-dependent variation in active maternal care. However, by adding environmental stress as a second factor to the model, we were able to explain the variation in HPA and fear responses induced by postnatal manipulations. In this two-factor model, active maternal care and environmental stress (as induced, e.g., by long maternal separations or maternal food restriction) exert independent, yet opposing, effects on HPA reactivity and fearfulness in the offspring. This accounts well for the finding that completely safe and stable, as well as, highly stressful maternal environments result in high HPA reactivity and fearfulness compared to moderately challenging maternal environments. Furthermore, it suggests that the downregulation of the HPA system in response to stressful maternal environments could reflect adaptive developmental plasticity based on the increasing costs of high stress reactivity with increasingly stressful conditions. By contrast, high levels of environmental stress induced by environmental adversity might constrain such adaptive plasticity, resulting in non-adaptive or even pathological outcomes. Alternatively, however, developmental plasticity of HPA and fear responses in rats might be a function of maternal HPA activation (e.g., levels of circulating maternal glucocorticoid hormones). Thus, implying a U-shaped relationship between maternal HPA activation and HPA reactivity and fearfulness in the offspring, increasing maternal HPA activation with increasing environmental adversity would explain the effects of postnatal manipulations equally well. This raises the possibility that variation in active maternal care is an epiphenomenon, rather than a causal factor in developmental plasticity of HPA and fear responses in rats. Developmental plasticity of HPA and fear responses in rats and other animals has important implications for the design of animal experiments and for the well-being of experimental animals, both of which depend on the exact underlying mechanism(s). Importantly, however, more naturalistic approaches are needed to elucidate the adaptive significance of environment-dependent variation of HPA reactivity and fearfulness in view of discriminating between effects reflecting adaptive plasticity, phenotypic mismatch and pathological outcomes, respectively.     

Prenatal stress alters circadian activity of hypothalamo-pituitary-adrenal axis and hippocampal corticosteroid receptors in adult rats of both gender.

Prenatal stress impairs activity of the hypothalamo-pituitary-adrenal (HPA) axis in response to stress in adult offspring. So far, very few data are available on the effects of prenatal stress on circadian functioning of the HPA axis. Here, we studied the effects of prenatal stress on the circadian rhythm of corticosterone secretion in male and female adult rats. To evaluate the effects of prenatal stress on various regulatory components of corticosterone secretion, we also assessed the diurnal fluctuation of adrenocorticotropin, total and free corticosterone levels, and hippocampal corticosteroid receptors. Finally, in the search of possible maternal factors, we studied the effects of repeated restraint stress on the pattern of corticosterone secretion in pregnant female rats. Results demonstrate that prenatal stress induced higher levels of total and free corticosterone secretion at the end of the light period in both males and females, and hypercorticism over the entire diurnal cycle in females. No diurnal fluctuation of adrenocorticotropin was observed in any group studied. The effects of prenatal stress on corticosterone secretion could be mediated, at least in part, by a reduction in corticosteroid receptors at specific times of day. Results also show that prepartal stress alters the pattern of corticosterone secretion in pregnant females. Those data indicate that prenatally stressed rats exhibit an altered temporal functioning of the HPA axis, which, taken together with their abnormal response to stress, reinforces the idea of a general homeostatic dysfunction in those animals.     

The prototypic antidepressant drug, imipramine, but not Hypericum perforatum (St. John's Wort), reduces HPA-axis function in the rat.

Dysregulation in corticotropin-releasing hormone (CRH) secretion in the hypothalamus-pituitary-adrenal (HPA) axis may be involved in the etiology of major depressive disorder (MDD). Chronic therapy with standard antidepressant drugs, such as imipramine, can downregulate HPA axis function, indicating that the HPA axis may be an important target for antidepressant action. We tested several doses of a standardized commercial preparation of Hypericum perforatum plant extract (popularly known as St. John's Wort), a medicinal herb used for treating mild depressive symptoms, to determine whether it also modulated HPA axis function. Chronic imipramine treatment (daily injections for 8 weeks) of male Sprague-Dawley rats significantly downregulated circulating plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone compared to animals treated with saline. However, chronic St. John's Wort treatment (daily gavage for 8 weeks) had no effect on plasma ACTH or corticosterone, even at the highest doses tested. Our results confirm previous findings that imipramine may have significant peripheral HPA axis-mediated effects. However, our data does not support any role for H. perforatum in modulation of HPA axis function, suggesting that alternative pathways may be involved in mediating its antidepressant effects.     

Plasticity in the adrenocortical response of a free-living vertebrate: the role of pre- and post-natal developmental stress

Optimal functioning of the hypothalamo–pituitary–adrenal (HPA) axis is paramount to maximizing fitness in vertebrates. Research in laboratory mammals has suggested that maternally-induced stress can cause significant variation in the responsiveness of an offspring's HPA axis involving both pre- and post-natal developmental mechanisms. However, very little is known regarding effects of maternal stress on the variability of offspring adrenocortical functioning in free-living vertebrates. Here we use an experimental approach that independently lowers the quality of both the pre- and post-natal developmental environment to examine programming and plasticity in the responsiveness of the HPA axis in fledglings of a free-living passerine, the European starling (Sturnus vulgaris). We found that mimicking a hormonal signal of poor maternal condition via an experimental pre-natal increase in yolk corticosterone decreased the subsequent responsiveness of the HPA axis in fledglings. Conversely, decreasing the quality of the post-natal developmental environment (by decreasing maternal provisioning capability via a maternal feather-clipping manipulation) increased subsequent responsiveness of the HPA axis in fledglings, apparently through direct effects on nestling body condition. The plasticity of these responses was sex-specific with smaller female offspring showing the largest increase in HPA reactivity. We suggest that pre-natal, corticosterone-induced, plasticity in the HPA axis may be a ‘predictive adaptive response’ (PAR): a form of adaptive developmental plasticity where the advantage of the induced phenotype is manifested in a future life-history stage. Further, we introduce a new term to define the condition-driven post-natal plasticity of the HPA axis to an unpredictable post-natal environment, namely a ‘reactive adaptive response’ (RAR). This study confirms that the quality of both the pre- and post-natal developmental environment can be a significant source of variation in the responsiveness of the HPA axis, and provides a frame-work for examining ecologically-relevant sources of stress-induced programming and plasticity in this endocrine system in a free-living vertebrate, respectively.     

Sustained Action of Developmental Ethanol Exposure on the Cortisol Response to Stress in Zebrafish Larvae and Adults

Background

Ethanol exposure during pregnancy is one of the leading causes of preventable birth defects, leading to a range of symptoms collectively known as fetal alcohol spectrum disorder. More moderate levels of prenatal ethanol exposure lead to a range of behavioural deficits including aggression, poor social interaction, poor cognitive performance and increased likelihood of addiction in later life. Current theories suggest that adaptation in the hypothalamo-pituitary-adrenal (HPA) axis and neuroendocrine systems contributes to mood alterations underlying behavioural deficits and vulnerability to addiction. In using zebrafish (Danio rerio), the aim is to determine whether developmental ethanol exposure provokes changes in the hypothalamo-pituitary-interrenal (HPI) axis (the teleost equivalent of the HPA), as it does in mammalian models, therefore opening the possibilities of using zebrafish to elucidate the mechanisms involved, and to test novel therapeutics to alleviate deleterious symptoms.

Results and Conclusions

The results showed that developmental exposure to ambient ethanol, 20mM-50mM 1-9 days post fertilisation, had immediate effects on the HPI, markedly reducing the cortisol response to air exposure stress, as measured by whole body cortisol content. This effect was sustained in adults 6 months later. Morphology, growth and locomotor activity of the animals were unaffected, suggesting a specific action of ethanol on the HPI. In this respect the data are consistent with mammalian results, although they contrast with the higher corticosteroid stress response reported in rats after developmental ethanol exposure. The mechanisms that underlie the specific sensitivity of the HPI to ethanol require elucidation.     

Frequency of Infant Stroking Reported by Mothers Moderates the Effect of Prenatal Depression on Infant Behavioural and Physiological Outcomes

Animal studies find that prenatal stress is associated with increased physiological and emotional reactivity later in life, mediated via fetal programming of the HPA axis through decreased glucocorticoid receptor (GR) gene expression. Post-natal behaviours, notably licking and grooming in rats, cause decreased behavioural indices of fear and reduced HPA axis reactivity mediated via increased GR gene expression. Post-natal maternal behaviours may therefore be expected to modify prenatal effects, but this has not previously been examined in humans. We examined whether, according to self-report, maternal stroking over the first weeks of life modified associations between prenatal depression and physiological and behavioral outcomes in infancy, hence mimicking effects of rodent licking and grooming. From a general population sample of 1233 first time mothers recruited at 20 weeks gestation we drew a stratified random sample of 316 for assessment at 32 weeks based on reported inter-partner psychological abuse, a risk to child development. Of these 271 provided data at 5, 9 and 29 weeks post delivery. Mothers reported how often they stroked their babies at 5 and 9 weeks. At 29 weeks vagal withdrawal to a stressor, a measure of physiological adaptability, and maternal reported negative emotionality were assessed. There was a significant interaction between prenatal depression and maternal stroking in the prediction of vagal reactivity to a stressor (p = .01), and maternal reports of infant anger proneness (p = .007) and fear (p = .043). Increasing maternal depression was associated with decreasing physiological adaptability, and with increasing negative emotionality, only in the presence of low maternal stroking. These initial findings in humans indicate that maternal stroking in infancy, as reported by mothers, has effects strongly resembling the effects of observed maternal behaviours in animals, pointing to future studies of the epigenetic, physiological and behavioral effects of maternal stroking.     

Detrimental effects of chronic hypothalamic—pituitary—adrenal axis activation

Increasing evidence suggests that the detrimental effects of glucocorticoid (GC) hypersecretion occur by activation of the hypothalamic-pituitary-adrenal (HPA) axis in several human pathologies, including obesity, Alzheimer's disease, AIDS dementia, and depression. The different patterns of response by the HPA axis during chronic activation are an important consideration in selecting an animal model to assess HPA axis function in a particular disorder. This article will discuss how chronic HPA axis activation and GC hypersecretion affect hippocampal function and contribute to the development of obesity. In the brain, the hippocampus has the highest concentration of GC receptors. Chronic stress or corticosterone treatment induces neuropathological alterations, such as dendritic atrophy in hippocampal neurons, which are paralleled by cognitive deficits. Excitatory amino acid (EAA) neurotransmission has been implicated in chronic HPA axis activation. EAAs play a major role in neuroendocrine regulation. Hippocampal dendritic atrophy may involve alterations in EAA transporter function, and decreased EAA transporter function may also contribute to chronic HPA axis activation. Understanding the molecular mechanisms of HPA axis activation will likely advance the development of therapeutic interventions for conditions in which GC levels are chronically elevated.