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Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: Possible implications for behaviour
Abstract
Glucocorticoids may underlie the association between low birth weight and adult disorders such as hypertension, type 2 diabetes and affective dysfunction. We investigated the behavioural and molecular consequences of two paradigms of prenatal dexamethasone administration in rats. Rats received dexamethasone (100 microg/kg per day) throughout pregnancy (DEX1-3), in the last third of pregnancy only (DEX3) or vehicle. Both dexamethasone treatments reduced birth weight, only DEX1-3 offspring had reduced body weight in adulthood. In adult offspring, both prenatal dexamethasone paradigms reduced exploratory behaviour in an open field. In contrast, only DEX3 reduced exploration in an elevated plus-maze and impaired behavioural responses and learning in a forced-swim test. This behavioural inhibition may reflect increased baseline corticotrophin-releasing hormone mRNA levels (30% higher) in the central nucleus of the amygdala in both dexamethasone-exposed groups. Adult DEX3 offspring also showed increased corticotrophin-releasing hormone mRNA with unaltered glucocorticoid receptor mRNA in the hypothalamic paraventricular nucleus and reduced hippocampal glucocorticoid- and mineralocorticoid receptor mRNA expression, suggesting reduced hippocampal sensitivity to glucocorticoid suppression of the stress axis. In contrast, DEX1-3 rats had no changes in hippocampal corticosteroid receptors, but showed increased mRNA levels for both receptors in the basolateral nucleus of the amygdala. From this data we suggest that prenatal glucocorticoid exposure programs behavioural inhibition perhaps via increased amygdalar corticotrophin-releasing hormone levels, while DEX3 also impairs coping and learning in aversive situations, possibly via altered hippocampal corticosteroid receptor levels. Overexposure to glucocorticoids, especially late in gestation, may explain the link between reduced early growth and adult affective dysfunction.
... Only one study reported an increased weight at the time of harvesting, a study of NHP using a multiple-day high DM dose. 14 While 16 reported a decrease in body weight in those exposed to ACSs, herein DM was used in 13/16 [15][16][17][18][19][20][21][22][23][24][25][26][27] and BM only in 3/16. [28][29][30] Furthermore, only 10.9% (7/64) reported on the brain weight or volume at the time of harvesting wherein 57.1% (4/7) reported a decrease of brain weight after the exposure of ACS. ...
... [28][29][30] Furthermore, only 10.9% (7/64) reported on the brain weight or volume at the time of harvesting wherein 57.1% (4/7) reported a decrease of brain weight after the exposure of ACS. 17,[30][31][32] Outcome assessment Neuropathology was the commonest outcome reported, either alone (28.1%, 18/64) Table 3. ...
... In rats, prenatal DM exposure resulted in more anxiety-like behavior, 22,31,45 sex-specific alterations in motor activity and sexual behavior, 15,59 and impaired spatial memory. 17,20 While in mice, maternal administration of ACS resulted in delayed development and impaired motoric function in the offspring. 68 Even a single course of ACS resulted in affecting anxiety, memory, and socialization behaviors. ...
Antenatal corticosteroids (ACSs) are recommended to all women at risk for preterm delivery; currently, there is controversy about the subsequent long-term neurocognitive sequelae. This systematic review summarizes the long-term neurodevelopmental outcomes after ACS therapy in animal models.
An electronic search strategy incorporating MeSH and keywords was performed using all known literature databases and in accordance with PRISMA guidance (PROSPERO CRD42019119663).
Of the 669 studies identified, eventually 64 were included. The majority of studies utilized dexamethasone at relative high dosages and primarily involved rodents. There was a high risk of bias, mostly due to lack of randomization, allocation concealment, and blinding. The main outcomes reported on was neuropathological, particularly glucocorticoid receptor expression and neuron densities, and neurobehavior. Overall there was an upregulation of glucocorticoid receptors with lower neuron densities and a dysregulation of the dopaminergic and serotonergic systems. This coincided with various adverse neurobehavioral outcomes.
In animal models, ACSs consistently lead to deleterious long-term neurocognitive effects. This may be due to the specific agents, i.e., dexamethasone, or the repetitive/higher total dosing used. ACS administration varied significantly between studies and there was a high risk of bias. Future research should be standardized in well-characterized models.
... Maternal hormone signalling plays an important role in shaping the hormonal environment of developing embryos 18,[20][21][22] . It is influenced by environmental cues perceived by mothers, such as the nutritional quality of the environment, risk, or social stability, which in turn can influence offspring growth, gene expression, and behaviour 18,[23][24][25] . In mammals, embryos can be influenced by maternal hormones via the placental blood stream during the entire gestation period 26 . ...
... A key candidate mechanism for modulating social phenotype in dependence of maternal and early social cues is the activity of the vertebrate 'stress axis' (i.e., the hypothalamic-pituitary-adrenal/interrenal axis 25,31 ) with glucocorticoid (GC) hormones as major signalling hormones 32 . GCs and glucocorticoid receptors (GRs) facilitate social behaviour of vertebrates in multiple ways 28 . ...
Mothers can influence offspring phenotype through egg-mediated maternal effects, which can be influenced by cues mothers obtain from their environment during offspring production. Developing embryos use these components but have mechanisms to alter maternal signals. Here we aimed to understand the role of mothers and embryos in how maternal effects might shape offspring social phenotype. In the cooperatively breeding fish Neolamprologus pulcher different social phenotypes develop in large and small social groups differing in predation risk and social complexity. We manipulated the maternal social environment of N. pulcher females during egg laying by allocating them either to a small or a large social group. We compared egg mass and clutch size and the concentration of corticosteroid metabolites between social environments, and between fertilized and unfertilized eggs to investigate how embryos deal with maternal signalling. Mothers in small groups produced larger clutches but neither laid smaller eggs nor bestowed eggs differently with corticosteroids. Fertilized eggs scored lower on a principal component representing three corticosteroid metabolites, namely 11-deoxycortisol, cortisone, and 11-deoxycorticosterone. We did not detect egg-mediated maternal effects induced by the maternal social environment. We discuss that divergent social phenotypes induced by different group sizes may be triggered by own offspring experience.
... This has been proposed as one way by which maternal stress effects are passed to the offspring (Thomas et al., 2018). A support to this suggestion is from a study in which pregnant rats that were treated with a synthetic glucocorticoid produced offspring with characteristics similar to rats that were exposed to prenatal stress (Welberg et al., 2001). In addition, removal of maternal adrenal gland relieves some of the stress effects in the offspring (Barbazanges et al., 1996). ...
... This process of gene expression is regulated at different levels; during the process of DNA copying, transport of the transcript to the cytoplasm, during and after protein synthesis, as well as epigenetically (Guerra et al., 2015) and by a wide range of external factors like environment (oxygen levels, temperature, humidity, daylight cycles, and nutrients etc.), internal signals such as stress hypoxia, nutrients, inflammation and even genetic non-coding RNAs (Dhama et al., 2019). Epigenetic modifications to the DNA include DNA methylation, genomic imprinting, histone modifications, and non-coding RNAs (Wei et al., 2017). These processes influence the accessibility of the gene to transcription factors by affecting the packaging of DNA and the structure of chromatin, thus "switching on or off " the genes (Larochelle et al., 2018). ...
Even though studies have shown that prenatal maternal stress is associated with increased reactivity of the HPA axis, the association between prenatal maternal stress and fetal glucocorticoid exposure is complex and most likely dependent on unidentified and poorly understood variables including nature and timing of prenatal insults. The precise mechanisms in which prenatal maternal stress influence neuroendocrine signaling between the maternal-placental-fetal interface are still unclear. The aim of this review article is to bring comprehensive basic concepts about prenatal maternal stress and mechanisms of transmission of maternal stress to the fetus. This review covers recent studies showing associations between maternal stress and alterations in offspring aggressive behavior, as well as the possible pathways for the “transmission” of maternal stress to the fetus: (1) maternal-fetal HPA axis dysregulation; (2) intrauterine environment disruption due to variations in uterine artery flow; (3) epigenetic modifications of genes implicated in aggressive behavior. Here, we present evidence for the phenomenon of intergenerational and transgenerational transmission, to better understands the mechanism(s) of transmission from parent to offspring. We discuss studies showing associations between maternal stress and alterations in offspring taking note of neuroendocrine, brain architecture and epigenetic changes that may suggest risk for aggressive behavior. We highlight animal and human studies that focus on intergenerational transmission following exposure to stress from a biological mechanistic point of view, and maternal stress-induced epigenetic modifications that have potential to impact on aggressive behavior in later generations.
... In this regard, prospective animal-and retrospective human studies have revealed that antenatal glucocorticoid administration in late gestation can lead to lifelong alterations on brain structures and functionality and may produce long-lasting modifications in the maturation of the hypothalamic-pituitary-adrenal (HPA) axis (Heim et al., 1997;French et al., 1999French et al., , 2004Sloboda et al., 2005;de Vries et al., 2007;Charil et al., 2010;Fowden and Forhead, 2015). Indeed, exposure to glucocorticoids during pregnancy, reducing negative-feedback on HPA axis, increases cortisol release in the progeny (Alexander et al., 2012): this leads to a slower recovery from stressors, reducing coping strategy in aversive situations (Welberg et al., 2001;Plescia et al., 2013). This evidence represents a key issue in the therapeutic administration of antenatal corticosteroids, which are commonly used when at risk of preterm delivery to ensure the survival of the preterm infant (Singh et al., 2012). ...
... Indeed, the behavioral outcomes here observed are supported by the results from plasma corticosterone level assessment in non-shock-induced conditions. Specifically, prenatally exposed adolescent offspring showed an increase in non-shock-induced plasma corticosterone levels, in line with findings in rodents and non-human primates (Welberg et al., 2001;de Vries et al., 2007;Rakers et al., 2017). It has been shown previously that differences in HPA axis activity are associated with differences in locomotor activity in response to novelty (Gancarz et al., 2012). ...
The perinatal window is a critical developmental time when abnormal gestational stimuli may alter the development of the stress system that, in turn, influences behavioral and physiological responses in the newborns. Individual differences in stress reactivity are also determined by variations in maternal care, resulting from environmental manipulations. Despite glucocorticoids are the primary programming factor for the offspring’s stress response, therapeutic corticosteroids are commonly used during late gestation to prevent preterm negative outcomes, exposing the offspring to potentially aberrant stress reactivity later in life. Thus, in this study, we investigated the consequences of one daily s.c. injection of corticosterone (25 mg/kg), from gestational day (GD) 14–16, and its interaction with offspring early handling, consisting in a brief 15-min maternal separation until weaning, on: (i) maternal behavior; and (ii) behavioral reactivity, emotional state and depressive-like behavior in the adolescent offspring. Corticosterone plasma levels, under non-shock- and shock-induced conditions, were also assessed. Our results show that gestational exposure to corticosterone was associated with diminished maternal care, impaired behavioral reactivity, increased emotional state and depressive-like behavior in the offspring, associated with an aberrant corticosterone response. The early handling procedure, which resulted in increased maternal care, was able to counteract the detrimental effects induced by gestational corticosterone exposure both in the behavioral- and neurochemical parameters examined. These findings highlight the potentially detrimental consequences of targeting the stress system during pregnancy as a vulnerability factor for the occurrence of emotional and affective distress in the adolescent offspring. Maternal extra-care proves to be a protective strategy that confers resiliency and restores homeostasis.
... However, this decrease is region-specific (Fenoglio et al., 2004;Zoli et al., 1990) and thus, may not show on western blots sampling tissue from the entire hippocampus. Interestingly, different prenatal administration paradigms using dexamethasone have surprisingly very different outcomes in postnatal hippocampal expression of CRH and GR (Welberg et al., 2001). ...
... CRH; cf. (Welberg et al., 2001)). Thus, further studies are warranted to assess hypothalamic slice preparations for CRH expression and potential circuit excitability differences. ...
Background:
The objective of this study was to determine whether prenatal exposure to betamethasone alters hippocampal expression of corticotropin-releasing hormone (CRH) and resultant hippocampal circuit excitability.
Methods:
Real time (RT)-PCR and western blots were used to determine CRH mRNA and protein expression levels, respectively, in hippocampal extracts of two-week old rat pups prenatally primed with betamethasone or saline on gestational day 15. The data were compared to changes in epileptiform activity induced by kainic acid (KA) or depletion of [Mg2+]0 in combined hippocampus-entorhinal cortex slices.
Results:
RT-PCR analysis showed 3-fold increased levels of CRH mRNA in hippocampal extracts from prenatally betamethasone-primed pups compared to saline controls (p < 0.05), but no changes in mRNA expression of CRH receptors (1 and 2). Changes in CRH protein isoform ratio in hippocampal extracts suggest 30 % increase in mature CRH levels in betamethasone-primed hippocampi (p < 0.05). No changes in mRNA expression in CRH feedback loop associated genes, GR and FKBP51, were found. Compared to saline-exposed pups, slices from betamethasone-primed pups had faster onset of epileptiform-like activity (inter-ictal discharges and seizure-like-events) after bath application of 4 μM KA (p < 0.05) suggesting a "more hyperexcitable" state. The epileptiform-like activity after KA application was significantly reduced following bath application of a CRH R2 antagonist (p < 0.05) but CRH R1 antagonist had no effect (p > 0.05). Also in the low-Mg2+-induced epileptiform activity, there was increased excitability, in the form of enhanced inter-ictal discharges, in slices from betamethasone primed compared to saline exposed rat pups (p < 0.05).
Conclusions:
Our study suggests a possible mechanistic link to prenatal betamethasone priming-induced increase in postnatal hippocampal excitability that involves enhanced expression of CRH acting at CRH R2. This is important in regards to the links between prenatal stress/corticosteroid-exposure and syndromes, such as epilepsy, autism spectrum disorders and other psychiatric disorders associated with neuronal hyperexcitability.
... For instance, it was found that rat offspring experiencing GC overexposure (0.1 mg/kg.day dexamethasone) during late pregnancy showed enhanced CRH mRNA expression in PVN, accompanied by reduced hippocampal GR and MR mRNA expression, suggesting an impairment of negative feedback regulation of HPA axis (Welberg et al. 2001). However, another study found GC overexposure during middle to late pregnancy (0.2 mg/ kg.day dexamethasone on gestational days 9-20) led to the low basal activity of the HPA axis in rat offspring, characterized by reduced concentrations of blood adrenocorticotropic hormone and GCs, as well as decreased CRH and arginine vasopressin (AVP) in the hypothalamus. ...
New human life begins in the uterus in a period of both extreme plasticity and sensitivity to environmental disturbances. The fetal stage is also a vital period for central nervous system development, with experiences at this point profoundly and permanently shaping brain structure and function. As such, some brain disorders may originate in utero. Glucocorticoids, a class of essential stress hormones, play indispensable roles in fetal development, but overexposure may have lasting impacts on the brain. In this review, we summarize data from recent clinical and non-clinical studies regarding alterations in fetal brains due to prenatal glucocorticoid overexposure that are associated with nervous system disorders. We discuss relevant changes to brain structure and cellular functions and explore the underlying molecular mechanisms. In addition, we summarize factors that may cause differential outcomes between varying brain regions, and outline clinically feasible intervention strategies that are expected to minimize negative consequences arising from fetal glucocorticoid overexposure. Finally, we highlight the need for experimental evidence aided by new technologies to clearly determine the effects of excessive prenatal glucocorticoid exposure. This review consolidates diverse findings to help researchers better understand the relationship between the prenatal glucocorticoid overexposure and the effects it has on various fetal brain regions, promoting further development of critical intervention strategies.
... It is also unclear whether the increase in cortisol synthase expression induced by intrauterine inflammation is a transient change or a change that persists into the neonatal period and early childhood. Furthermore, since fetal stress in utero varies, the changes in the reactivity of the HPA axis in response to various stressors such as hypoxia, undernutrition, maternal alcohol and drug consumption, and prenatal glucocorticoid administration [46][47][48][49][50] need to be investigated in the future. ...
Context
Intrauterine inflammation, a representative stressor for the fetus, has been shown to alter the hypothalamus–pituitary–adrenal (HPA) axis reactivity in preterm fetuses and increase postnatal cortisol production. However, the mechanism of this alteration has not yet been elucidated.
Objective
We aimed to clarify the effects of endotoxin-induced intrauterine inflammation on the HPA axis of periviable sheep fetuses.
Methods
Fetal sheep (0.63 term) were divided into 2 groups: (1) the endotoxin group, in which the endotoxin was injected into the amniotic fluid; and (2) the control group, in which the saline solution was injected instead. A corticotropin-releasing hormone (CRH) challenge test was performed on the third day after injection to evaluate the cortisol-producing capacity of each group. Gene expression levels in the fetal adrenal glands of each group were analyzed by RNA-seq.
Results
The cortisol levels were significantly higher in the endotoxin group than in the control group after CRH challenge (P = .02). There were no significant differences in the responsiveness of adrenocorticotropin and cortisone between the 2 groups. Gene expression levels of the following enzymes involved in cortisol synthesis were significantly elevated in the endotoxin group: cytochrome P450 family (CYP) 11 subfamily A member 1 (log2FC 1.75), CYP 17 subfamily A member 1 (log2FC 3.41), 3β-hydroxysteroid dehydrogenase type I (log2FC 1.13), steroidogenic acute regulatory protein (log2FC 1.09), and CYP 21 (log2FC 0.89).
Conclusion
Periviable fetuses exposed to inflammation in utero have altered the responsiveness of the HPA axis with increased expression of enzymes involved in cortisol synthesis in the adrenal gland.
... It is unclear how greater axonal myelination (i.e., higher QA) relates to decreased coactivation in this circuitry, but structural and functional alterations at the mPFC associated with maternal mental health and early life stress have been consistently reported (Posner et al., 2016;Thijssen et al., 2017). Like the paralimbic regions, rich expression of glucocorticoid receptors in the mPFC could render them vulnerable to potentially adverse effects of dysregulated maternal stress hormones (Humphreys et al., 2020;Welberg et al., 2001). While specific mechanisms linking intrauterine endocrine dysfunction to fetal brain endophenotypes and then to their socio-cognitive and affective long-term phenotypes are unknown, recent human and animal studies converge on the role of widespread epigenetic modification, specifically DNA methylation, in response to prenatal stress (Braun et al., 2020;Cao-Lei et al., 2020;Provençal and Binder, 2015;Talge et al., 2007). ...
In utero exposure to maternal stress, anxiety, and depression has been associated with reduced cortical thickness (CT), and CT changes, in turn, to adverse neuropsychiatric outcomes. Here, we investigated global and regional (G/RCT) changes associated with fetal exposure to maternal psychological distress in 265 brain MRI studies from 177 healthy fetuses of low-risk pregnant women. GCT was measured from cortical gray matter (CGM) voxels; RCT was estimated from 82 cortical regions. GCT and RCT in 87% of regions strongly correlated with GA. Fetal exposure was most strongly associated with RCT in the parahippocampal region, ventromedial prefrontal cortex, and supramarginal gyrus suggesting that cortical alterations commonly associated with prenatal exposure could emerge in-utero. However, we note that while regional fetal brain involvement conformed to patterns observed in newborns and children exposed to prenatal maternal psychological distress, the reported associations did not survive multiple comparisons correction. This could be because the effects are more subtle in this early developmental window or because majority of the pregnant women in our study did not experience high levels of maternal distress. It is our hope that the current findings will spur future hypothesis-driven studies that include a full spectrum of maternal mental health scores.
... Lower second-trimester cortisol levels are consistent with what has been observed among women diagnosed with posttraumatic stress disorder and has been interpreted as potentially related to a lifetime of exposure to increased stress due to repeated discriminatory experiences (120). Not only is cortisol essential for fetal growth and development, but findings indicate that lower cortisol levels in later stages of pregnancy are associated with decreased fetal growth among those who develop schizophrenia (105,(121)(122)(123). Black women may also be more sensitive to the effects of stress hormones during pregnancy, with some findings suggesting that smaller increases in stress hormones produce poor birth outcomes, such as preterm delivery, among these pregnancies (124). ...
Importance
Reducing the duration of untreated psychosis (DUP) is essential to improving outcomes for people with first-episode psychosis (FEP). Current US approaches are insufficient to reduce DUP to international standards of less than 90 days.
Objective
To determine whether population-based electronic screening in addition to standard targeted clinician education increases early detection of psychosis and decreases DUP, compared with clinician education alone.
Design, Setting, and Participants
This cluster randomized clinical trial included individuals aged 12 to 30 years presenting for services between March 2015 and September 2017 at participating sites that included community mental health clinics and school support and special education services. Eligible participants were referred to the Early Diagnosis and Preventative Treatment (EDAPT) Clinic. Data analyses were performed in September and October 2019 for the primary and secondary analyses, with the exploratory subgroup analyses completed in May 2021.
Interventions
All sites in both groups received targeted education about early psychosis for health care professionals. In the active screening group, clients also completed the Prodromal Questionnaire–Brief using tablets at intake; referrals were based on those scores and clinical judgment. In the group receiving treatment as usual (TAU), referrals were based on clinical judgment alone.
Main Outcomes and Measures
Primary outcomes included DUP, defined as the period from full psychosis onset to the date of the EDAPT diagnostic telephone interview, and the number of individuals identified with FEP or a psychosis spectrum disorder. Exploratory analyses examined differences by site type, completion rates between conditions, and days from service entry to telephone interview.
Results
Twenty-four sites agreed to participate, and 12 sites were randomized to either the active screening or TAU group. However, only 10 community clinics and 4 school sites were able to fully implement population screening and were included in the final analysis. The total potentially eligible population size within each study group was similar, with 2432 individuals entering at active screening group sites and 2455 at TAU group sites. A total of 303 diagnostic telephone interviews were completed (178 [58.7%] female individuals; mean [SD] age, 17.09 years [4.57]). Active screening sites reported a significantly higher detection rate of psychosis spectrum disorders (136 cases [5.6%], relative to 65 [2.6%]; P < .001) and referred a higher proportion of individuals with FEP and DUP less than 90 days (13 cases, relative to 4; odds ratio, 0.30; 95% CI, 0.10-0.93; P = .03). There was no difference in mean (SD) DUP between groups (active screening group, 239.0 days [207.4]; TAU group 262.3 days [170.2]).
Conclusions and Relevance
In this cluster trial, population-based technology-enhanced screening across community settings detected more than twice as many individuals with psychosis spectrum disorders compared with clinical judgment alone but did not reduce DUP. Screening could identify people undetected in US mental health services. Significant DUP reduction may require interventions to reduce time to the first mental health contact.
Trial Registration
ClinicalTrials.gov Identifier: NCT02841956
... Perinatal GC can also affect long-term behavior. Prenatal GC treatment leads to anxiety during adulthood in rats (Nagano et al., 2008;Welberg et al., 2001). Together with other studies, the development of anxiety due to perinatal GC treatment has been associated with alterations in the amygdala region of the brain (Nagano et al., 2008;Welberg et al., 2000;. ...
Early-life environmental factors can have persistent effects on physiological functions by altering developmental procedures in various organisms. Recent experimental and epidemiological studies now further support the idea that developmental programming is also present in mammals, including humans, influencing long-term health. Although the mechanism of programming is still largely under investigation, the role of endocrine glucocorticoids in developmental programming is gaining interest. Studies found that perinatal glucocorticoids have a persistent effect on multiple functions of the body, including metabolic, behavioral, and immune functions, in adulthood. Several mechanisms have been proposed to play a role in long-term programming. In this review, recent findings on this topic are summarized and the potential biological rationale behind this phenomenon is discussed.
... In animal models, rats with prenatal and perinatal malnutrition showed chronic increases in systolic pressure and heart rate during adulthood [21][22][23][24][25], and an increased neuronal tone of the sympathetic peripheral system [26]. Therefore, protein and calorie food restrictions in pregnant dams result in hypertensive adult offspring [27,28] through mechanisms that include altered hypothalamic programming [19,26,29], sustaining the significant role of nutritional programming on the neural and endocrine control of the cardiovascular system. Indeed, an increase in the activity and excitability of neurons in the hypothalamic paraventricular nucleus (PVN) has been described in some animal models of hypertension, which are closely related to an increase in sympathetic impulse. ...
A crucial etiological component in fetal programming is early nutrition. Indeed, early undernutrition may cause a chronic increase in blood pressure and cardiovascular diseases, including stroke and heart failure. In this regard, current evidence has sustained several pathological mechanisms involving changes in central and peripheral targets. In the present review, we summarize the neuroendocrine and neuroplastic modifications that underlie maladaptive mechanisms related to chronic hypertension programming after early undernutrition. First, we analyzed the role of glucocorticoids on the mechanism of long-term programming of hypertension. Secondly, we discussed the pathological plastic changes at the paraventricular nucleus of the hypothalamus that contribute to the development of chronic hypertension in animal models of prenatal undernutrition, dissecting the neural network that reciprocally communicates this nucleus with the locus coeruleus. Finally, we propose an integrated and updated view of the main neuroendocrine and central circuital alterations that support the occurrence of chronic increases of blood pressure in prenatally undernourished animals.
... Letters indicate significant groups, p < 0.05. paraventricular nucleus (Welberg et al., 2001), which mimics the situation we observed, namely high MR and low crh expression in the brain in GRKO tadpoles. Other studies in mammalian models have shown that progesterone can reduce avp levels (Crofton et al., 1985;Watanabe et al., 1997), which again is consistent with the high progesterone levels and low avp expression in GRKO tadpoles. ...
Blood glucocorticoid levels are regulated by the hypothalamo-pituitary-adrenal/interrenal axis (HPA axis in mammals, HPI axis in amphibians), and negative feedback by glucocorticoid signaling is a key player in that regulation. Glucocorticoid and mineralocorticoid receptors (GR and MR) mediate negative feedback in mammals, but little is known about nuclear receptor-mediated feedback in amphibians. Because amphibians have only one corticosteroidogenic cell type responsible for glucocorticoid and mineralocorticoid production, we hypothesized that GR knockout (GRKO) tadpoles have elevated levels of glucocorticoids and mineralocorticoids as well as axis components regulating their production. We also examined the response to stress and potential for increased aldosterone signaling in GRKO tadpoles. We found that GRKO tadpoles have severe hyperactivity of the HPI axis, namely high mRNA expression levels of pomc, cyp17a1, cyp21a2, cyp11b2, and star, and high tissue content of corticosterone, aldosterone, 17-hydroxyprogesterone, 21-deoxycortisol, and progesterone. Such aberrant HPI activity was accompanied by reduced survival after acute temperature shock and shaking stress. Like mammalian models of HPA hyperactivity, GRKO tadpoles have high MR mRNA expression levels in brain, kidney, heart, and skin and high levels of the inflammatory cytokine tnf-α and the profibrotic factor tgf-β in kidneys. This study showed GR is critical for negative feedback to the amphibian HPI axis and for survival from acute stressors. This study also showed GRKO tadpoles exhibit altered expression/overproduction of regulators of salt-water homeostasis and associated biomarkers of kidney disease.
... 7 In animal models, exposure to ACS has been shown to result in detrimental long-term neurocognitive and neurobehavioral effects, 8 including anxiety-like behavior, [9][10][11][12] delayed motor development, 13,14 and impaired spatial memory. 15,16 In a systematic review of animal fetuses, ACS exposure most commonly altered glucocorticoid receptors in the hippocampus and hypothalamus with coincident neurocognitive sequelae. 8 Several studies have assessed the long-term neurological implications of ACS on preterm infants. ...
The objective of this study was to synthesize the body of knowledge on the association between ACS exposure for risk of preterm birth and brain development in infants ultimately born late preterm and term. Three databases and eight conference proceedings were systematically searched (1972–2021). Selection criteria included ACS administration for risk of preterm delivery, cohort of late preterm and term infants, and assessment of brain development. Data on study characteristics, ACS administration, and neurological outcomes were extracted and qualitatively synthesized according to themes. Neurological outcomes of the included studies (n = 27) were grouped into four themes. The most common adverse outcomes were reduced neonatal head circumference, structural cortical differences on MRI, increased prevalence of psychiatric problems, and increased risk of neurodevelopmental delays in ACS-exposed late preterm and term infants. Our scoping review demonstrated that ACS exposure for risk of preterm delivery may have important neurological implications in infants ultimately born late preterm and term. Given that the existing research is at serious risk for bias, further research that accounts for confounders such as preterm labor, maternal stress, and the number of ACS courses is needed to better establish the long-term neurological effects of ACS on late preterm and term infants. Due to the difficulty in predicting preterm birth, approximately 40% of fetuses exposed to antenatal corticosteroids (ACS) are born at term (≥37 weeks’ gestation).This scoping review summarizes the knowledge on the association between ACS exposure for risk of preterm birth and brain development in late preterm and term infants.The majority of studies reported that ACS exposure was associated with adverse brain development outcomes across various domains, such as reduced neonatal head circumference, cortical differences on MRI, and increased prevalence of psychiatric problems and neurodevelopmental delays in late preterm and term infants. Due to the difficulty in predicting preterm birth, approximately 40% of fetuses exposed to antenatal corticosteroids (ACS) are born at term (≥37 weeks’ gestation). This scoping review summarizes the knowledge on the association between ACS exposure for risk of preterm birth and brain development in late preterm and term infants. The majority of studies reported that ACS exposure was associated with adverse brain development outcomes across various domains, such as reduced neonatal head circumference, cortical differences on MRI, and increased prevalence of psychiatric problems and neurodevelopmental delays in late preterm and term infants.
... This literature shares a focus on violence exposure rather than individual victimization, emphasizing the role of stress as a likely channel between violence and newborn health. 3 Animal experiments have tested the effects of in utero stress (Schneider, 1992;Schneider et al., 1992;Weinstock, 2008;Welberg et al., 2001), and the biological processes point to similar impacts on humans. Cortisol and adrenaline mediate this response; because fetuses are exposed to their mothers' stress hormones, transient high maternal stress in a sensitive period can impact fetal development. ...
This paper examines the relationship between maternal exposure to violence during pregnancy and newborn birthweight. The identification strategy exploits variation in the timing of exposure and in the geographic location of expectant mothers across Colombian municipalities. Exposure to violence in early pregnancy had a large negative impact on birthweight, primarily for boys, and the effect was mitigated by their mothers' education. Girls' birthweight was affected mainly by shocks in later stages of gestation. Furthermore, their mothers were more likely to engage in potentially harmful behaviors during the pregnancy. This evidence exposes the importance of parental responses in shaping the effect of exposure to violence on newborn health.
... Although, using rodents and flight animals for pain-assessment is criticized due to a lack of translational ability to humans [13][14][15]. Additionally, toxicology studies in pigs have also been used to investigate fetal programming, [16] antipsychotic drugs [17,18] for mental disorders like schizophrenia or addiction to drugs [19]. Furthermore, environmental enrichment is known to have a positive influence on early life stage in regard of sensory, social, cognitive and motor functions in rats [20,21]. ...
Background: The Open Field test is a common tool to measure anxiety and behavioral changes in rodents. However, scientific findings of rodent experiments may not translate adequately to humans and it has been shown that larger animal models might perform better in that regard. As a result, the number of published studies involving the Open Field test in domestic pig models is increasing.
Objective: The aim of our review was to investigate the Open Field set-ups in published studies as well as similarity between performance and parameters published.
Results: Following the PRISMA guidelines for reviews we selected 69 studies for data extraction in this systematic review. We were able to determine specific set-up conditions such as size, duration and daytime for most of the included studies and found a high variability within these test specifiers.
Conclusion: Results indicate a non-uniform performance of set-up including size, timing, parameters and additional combined tests such as the novel object test. We would like to point out the need for standardization of Open Field test for pigs in order to improve result, comparability and reduce inconsistencies.
... Lower second-trimester cortisol levels are consistent with what has been observed among women diagnosed with posttraumatic stress disorder and has been interpreted as potentially related to a lifetime of exposure to increased stress due to repeated discriminatory experiences (120). Not only is cortisol essential for fetal growth and development, but findings indicate that lower cortisol levels in later stages of pregnancy are associated with decreased fetal growth among those who develop schizophrenia (105,(121)(122)(123). Black women may also be more sensitive to the effects of stress hormones during pregnancy, with some findings suggesting that smaller increases in stress hormones produce poor birth outcomes, such as preterm delivery, among these pregnancies (124). ...
The authors examine U.S.-based evidence that connects characteristics of the social environment with outcomes across the psychosis continuum, from psychotic experiences to schizophrenia. The notion that inequitable social and economic systems of society significantly influence psychosis risk through proxies, such as racial minority and immigrant statuses, has been studied more extensively in European countries. While there are existing international reviews of social determinants of psychosis, none to the authors' knowledge focus on factors in the U.S. context specifically-an omission that leaves domestic treatment development and prevention efforts incomplete and underinformed. In this review, the authors first describe how a legacy of structural racism in the United States has shaped the social gradient, highlighting consequential racial inequities in environmental conditions. The authors offer a hypothesized model linking structural racism with psychosis risk through interwoven intermediary factors based on existing theoretical models and a review of the literature. Neighborhood factors, cumulative trauma and stress, and prenatal and perinatal complications were three key areas selected for review because they reflect social and environmental conditions that may affect psychosis risk through a common pathway shaped by structural racism. The authors describe evidence showing that Black and Latino people in the United States suffer disproportionately from risk factors within these three key areas, in large part as a result of racial discrimination and social disadvantage. This broad focus on individual and community factors is intended to provide a consolidated space to review this growing body of research and to guide continued inquiries into social determinants of psychosis in U.S. contexts.
... It would suggest that physical features and behaviors in offspring of prenatally stressed mothers result from permanent alterations in the structure and function of the offspring's brain and other organs, in part through maternal cortisol's impact on the fetus' developing hypothalamic-pituitary-adrenal (HPA) axis. Because a linear relationship exists between maternal and fetal cortisol levels, relatively small increases in maternal cortisol resulting from anxiety or stress can double fetal concentrations (Gitau et al. 1998), resulting in significant structural and functional changes in, for example, the hippocampus (Avishai-Eliner et al. 2002;Hayashi et al. 1998;Kawamura et al. 2006;Welberg et al. 2001;Ong et al. 2019;Qiu et al. 2013;Wang et al. 2019) and amygdala (Jones et al. 2019;Ong et al. 2019;Soe et al. 2018;Wen et al. 2017). The placenta is the passageway between mother and fetus. ...
Global climate change is resulting in more frequent, and increasingly severe, natural disasters that affect large populations. Disasters have a measurable effect on the physical and mental health of citizens, including pregnant women. In addition to increasing the pregnant woman’s risk of postpartum depression, prenatal (and perhaps even preconception) exposure to population-level disasters appears to program the unborn child in ways that could compromise long-term well-being. Although there are many options for dealing with stress in individual women going through punctual life events, such as the death of a family member, such individual-level interventions could not feasibly be applied to hundreds or thousands of perinatal women in the wake of a natural disaster that disrupts the functioning of an entire community.
... Third, maternal stress may lead to downregulation of placental 11β-HSD2, enabling greater amounts of maternal cortisol to reach the fetus (Benediktsson et al., 1997;Howland et al., 2017). Similar to upregulated placental CRH, elevated levels of maternal cortisol circulating in the fetal compartment may alter the programming of the HPA axis in a sex-dependent manner (Cottrell and Seckl, 2009;Giesbrecht et al., 2016;Carpenter et al., 2017), primarily by altering the abundance or sensitivity of GRs (Welberg et al., 2001;Noorlander et al., 2006). Sex-dependent shifts in the activity, balance, and programming of GRs along the HPA axis during fetal development may result in postnatal dysregulation of key physiological systems Rash et al., 2016), laying the foundation for sex differences in disease development later in life (de Kloet et al., 1998;Reynolds, 2013). ...
Stress is broadly defined as the non-specific biological response to changes in homeostatic demands and is mediated by the evolutionarily conserved neuroendocrine networks of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Activation of these networks results in transient release of glucocorticoids (cortisol) and catecholamines (epinephrine) into circulation, as well as activation of sympathetic fibers innervating end organs. These interventions thus regulate numerous physiological processes, including energy metabolism, cardiovascular physiology, and immunity, thereby adapting to cope with the perceived stressors. The developmental trajectory of the stress-axis is influenced by a number of factors, including the gut microbiome, which is the community of microbes that colonizes the gastrointestinal tract immediately following birth. The gut microbiome communicates with the brain through the production of metabolites and microbially derived signals, which are essential to human stress response network development. Ecological perturbations to the gut microbiome during early life may result in the alteration of signals implicated in developmental programming during this critical window, predisposing individuals to numerous diseases later in life. The vulnerability of stress response networks to maladaptive development has been exemplified through animal models determining a causal role for gut microbial ecosystems in HPA axis activity, stress reactivity, and brain development. In this review, we explore the evolutionary significance of the stress-axis system for health maintenance and review recent findings that connect early-life microbiome disturbances to alterations in the development of stress response networks.
... Signals from the central nervous system in the form of chemical signals or electrical potential are sent to the HPA axis signifying the release of corticotrophin releasing hormone (CRH). The CRH in turn stimulates biosynthesis and release of adrenocorticotrophic hormone that triggers the production of glucocorticoids (cortisol) which are the stress response markers (Welberg et al., 2001). ...
Exposure to violence (ETV) has been linked to epigenomics mechanisms such as DNA methylation (DNAm). We used epigenetic profiling of blood collected from 32 African American young adult males who lived in Washington DC to determine if changes in DNAm at CpG sites affiliated with nervous and immune system were associated with exposure to violence. Pathway analysis of differentially methylated regions comparing high and low ETV groups revealed an enrichment of gene sets annotated to nervous system and immune ontologies. Many of these genes are known to interact with each other which suggests DNAm alters gene function in the nervous and immune system in response to ETV. Using data from a unique age group, young African American adult males, we provide evidence that lifetime ETV could impact DNA methylation in genes impacted at Central Nervous System and Immune Function sites.
Method
Methylation analysis was performed on DNA collected from the blood of participants classified with either high or low lifetime ETV. Illumina®MethylationEPIC Beadchips (∼850k CpG sites) were processed on the iScan System to examine whole-genome methylation differences. Differentially methylated CpG-sites between high (n=19) and low (n=13) groups were identified using linear regression with violence and substance abuse as model covariates. Gene ontology analysis was used to identify enrichment categories from probes annotated to the nearest gene.
Results
A total of 595 probes (279 hypermethylated; 316 hypomethylated) annotated to 383 genes were considered differentially methylated in association with ETV. Males with high ETV showed elevated methylation in several signaling pathways were most impacted at Central Nervous System and Immune Function sites. Eight candidate genes were identified that play important biological roles in stress response to violence with HDAC4 (10%), NR4A3 (11%), NR4A2 (12%), DSCAML1(12%), and ELAVL3 (13%) exhibiting higher levels in the low ETV group and DLGAP1 (10%), SHANK2 (10%), and NRG1(11%) having increased methylation in the high ETV group. These findings suggest that individuals subjected to high ETV may be at risk for poor health outcomes that have not been reported previously.
... It has been suggested that fetal programming of brain connectivity in utero occurs primarily through endocrine and inflammatory mediators that pass through the placenta and fetal blood-brain barrier and precipitate developmental cascades via direct signaling or by modifying the availability and activity of critical neural growth factors and hormones (Buss et al., 2012b). For example, there is evidence that unusually high concentrations of glucocorticoids modify the trajectories of brain development both by binding directly to regions dense in glucocorticoid receptors (including the amygdala and PFC) and initiating local changes (Welberg et al., 2001), as well as by modulating the activity of proteins that facilitate neuronal differentiation and determine cell fates (Kumamaru et al., 2008;Lussier et al., 2009;Shimizu et al., 2010). However, it is unclear whether the influences of these potential mechanisms are "by design" (i.e., adaptive processes that will benefit the developing fetus postnatally) or are byproducts of other biological tradeoffs that negatively affect fetal development. ...
Stressful experiences are linked to neurodevelopment. There is growing interest in the role of stress in the connectivity between the amygdala and medial prefrontal cortex (mPFC), a circuit that subserves automatic emotion regulation. However, the specific timing and mechanisms that underlie the association between stress and amygdala-mPFC connectivity are unclear. Many factors, including variations in fetal exposure to maternal stress, appear to affect early developing brain circuitry. However, few studies have examined the associations of stress and amygdala-mPFC connectivity in early life, when the brain is most plastic and sensitive to environmental influence. In this longitudinal pilot study, we characterized the association between prenatal stress and amygdala-mPFC connectivity in young infants (approximately age 5 weeks). A final sample of 33 women who provided data on preconception and prenatal stress during their pregnancy returned with their offspring for a magnetic resonance imaging scan session, which enabled us to characterize amygdala-mPFC structural and functional connectivity as a function of prenatal stress. Increased prenatal stress was associated with decreased functional connectivity and increased structural connectivity between the amygdala and mPFC. These results provide insight into the influence of prenatal maternal stress on the early development of this critical regulatory circuitry.
... Different opinions exist on the relationship between rearing and anxiety. Some researchers, such as Broderick et al. showed the increase of rearing as a sign of a decrease in anxiety [20], whereas Wellberg et al. considered it to be a sign of increased anxiety [21]. Dielenberg et al. [22] and McGregor et al. [23] demonstrated that an increase in rearing is accompanied by enhanced blood pressure and decreased locomotor activity in rats. ...
Background: The use of herbal products is increased among people wordwide. Regarding lacking evidence on the use of herbal medication in children, this study was aimed to determine the effects of Echinacea Purpurea extract on anxiety-like behavior in neonatal rats. Materials and Methods: Forty male Wister strain pups in four groups received i.p injections of E. Purpurea extract (40, 80, and 250 mg/kg) or saline on 5th to 9th postnatal days. All pups were examined for anxiety test on the 22nd postnatal day in the elevated plus-maze test. During the test, parameters include percentage of open arm time (%OAT), percentage of open arm entry (%OAE), head dipping, rearing and locomotor activity have been measured. Results: In the present study, administration of 40, 80 and 250mg/kg doses of the E. Purpurea extract revealed a significant decrease in the %OAT compared to saline group (P<0.01). The E. Purpurea extract decreased head dipping parameters (P<0.01) and increased rearing parameters (P<0.01). E. Purpurea did not significantly change the locomotor activity.Conclusions: The results of present study showed that postnatal administration of E. Purpurea extract increases anxiety in neonatal rats comparing to control group. [GMJ.2017;6(1):52-60]
... In ovo CORT treatment elevated the circulating levels of CORT in hatch time in chickens [81] and at 8 weeks old in Japanese quail [82]. Similar results were reported in rats, revealing that exposure of CORT during gestation period inhibited fetal growth rate in mice [83,84] and permanently increased the plasma CORT levels in adult rats [85,86]. ...
Exposure to excess Glucocorticoids (GCs) during embryonic development influences offspring physiology and behaviors and induces change in Hypothalamic-Pituitary-Adrenal (HPA) axis genes expression and serotonergic system in mammals. Whether prenatal corticosterone (CORT) exposure induces similar effects in avian species remains unclear. In the present study, we injected low (0.2 µg) and high (1 µg) doses of CORT in ovo before incubation and detected changes in aggressive behavior, Tonic Immobility (TI), HPA axis and 5-hydroxytryptamine (serotonin) (5-HT) system gene expression on post hatch chickens of different ages. High dose of CORT significantly (P<0.05) suppressed growth rate, increased the frequency of aggressive behaviors, which was associated with elevated plasma CORT concentration. Likewise, in ovo injection of CORT significantly (P<0.05) increased Tonic Immobility (TI) duration both in chickens from low and high doses of CORT treatments compared to control. In addition, administration of CORT significantly (P<0.05) up-regulated mRNA expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) whereas it down-regulated 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and mineralocorticoid receptor (MR) mRNA expression in the hypothalamus. No significant differences were seen in Glucocorticoid Receptor (GR) and 20-hydroxysteroid dehydrogenase (20-HSD) mRNA levels upon CORT treatment. Moreover, CORT exposure significantly (P<0.05) increased hypothalamic 5-hydroxytryptamine (serotonin) receptor 1A (5-HTR1A) mRNA expression, but not 5-HT receptor 1B (5-HTR1B). In ovo administration of CORT may programs the aggressive behaviors in the chicken through alterations of HPA axis and 5-HT system.
... Accordingly, consistent evidence has demonstrated that the experience of serious stressful life events during pregnancy has been associated with the development of psychotic symptoms later in life and increased incidence of schizophrenia in the offspring [62,63]. It is assumed that these consequences may originate from sustained exposure to maternal glucocorticoids that interfere with the development and maturation of the fetal brain circuits [64]. Moreover, excessive glucocorticoids may induce an overall "sensitization" of the fetal brain to their action, potentially determining an exaggerated response to subsequent exposure to stress. ...
Stress exposure represents a major environmental risk factor for schizophrenia and other psychiatric disorders, as it plays a pivotal role in the etiology as well as in the manifestation of disease symptomatology. It may be inferred that pharmacological treatments must be able to modulate the behavioral, functional, and molecular alterations produced by stress exposure to achieve significant clinical outcomes. This review aims at examining existing clinical and preclinical evidence that supports the ability of atypical antipsychotic drugs (AAPDs) to modulate stress-related alterations. Indeed, while the pharmacodynamic differences between AAPDs have been extensively characterized, less is known on their ability to regulate downstream mechanisms that are critical for functional recovery and patient stabilization. We will discuss stress-related mechanisms, spanning from neuroendocrine function to inflammation and neuronal plasticity, which are relevant for the manifestation of schizophrenic symptomatology, and we will discuss if and how AAPDs may interfere with such mechanisms. Considering the impact of stress in everyday life, we believe that a better understanding of the potential effects of AAPDs on stress-related mechanisms may provide novel and important insights for improving therapeutic strategies aimed at promoting coping mechanisms and enhancing the quality of life of patients affected by psychiatric disorders.
... The differences could be explained by the type of stressor used. Low birth weight can be due to maternal glucocorticoids released during stress, as was demonstrated by the administration of dexamethasone during the last third of gestation (Welberg et al., 2001). The increased concentration of maternal glucocorticoids could alter glucose transport to fetuses, as prenatal stress causes a decrease in the expression of placental GLUT1, GLUT3 and GLUT4 glucose transporters (Knipp et al., 1999;Mairesse et al., 2007;O'Donnel et al., 2009), thus resulting in low birth weight. ...
Prenatal stress causes learning and spatial memory deficits in adulthood by modifying hippocampal function. The dorsal hippocampus contains serotonergic and noradrenergic neuron terminals, which are related to cognitive processes. It is currently unknown whether prenatal stress modifies serotonin (5-HT) and noradrenaline (NA) content and their release in the hippocampus during cognitive performance. Therefore, we measured these variables in the dorsal hippocampus of prenatally stressed males during spatial learning and memory tests. Cognitive tests were performed in 3-month-old control and prenatally stressed male rats in the Morris Water Maze (MWM). After cognitive tests, the dorsal hippocampus was dissected to quantify 5-HT and NA content. In other males, 5-HT and NA release in the dorsal hippocampus was assessed by microdialysis, before and after cognitive tests. Prenatally stressed males showed longer latencies to reach the platform, compared to control animals. Hippocampal 5-HT content decreased during learning and memory tasks in both groups, while NA content was not modified in prenatally stressed males neither before, nor after learning and memory tests. 5-HT and NA release were significantly lower in prenatally stressed animals during spatial learning and memory tasks. Corticosterone response was greater in prenatally stressed animals compared to controls. These results show that cognitive disruption caused by prenatal stress is related to decreased 5-HT and NA release, and to higher adrenal axis response in prenatally stressed animals.
... Placental CRF plays a crucial role in regulating the fetal HPA axis [124,126]. In rodent studies, the reduced HPA axis sensitivity and anxiety-like behaviors in offspring of dams with overactive HPA axis during pregnancy was in part explained by an attenuated hippocampal GR expression [127,128]. Also immune activity and psychosocial stress causes elevated glucocorticoid levels [129]. Maternal psychosocial stress is known to long-term modify the offspring HPA axis activity epigenetically towards increased stress sensitivity [130] and suicide risk [131,132]. ...
Obesity and diabetes is a worldwide public health problem among women of reproductive age. This narrative review highlights recent epidemiological studies regarding associations of maternal obesity and diabetes with neurodevelopmental and psychiatric disorders in offspring, and provides an overview of plausible underlying mechanisms and challenges for future human studies. A comprehensive search strategy selected terms that corresponded to the domains of interest (maternal obesity, different types of diabetes, offspring cognitive functions and neuropsychiatric disorders). The databases searched for articles published between January 2010 and April 2019 were PubMed, Web of Science and CINAHL. Evidence from epidemiological studies strongly suggests that maternal pre-pregnancy obesity is associated with increased risks for autism spectrum disorder, attention-deficit hyperactivity disorder and cognitive dysfunction with modest effect sizes, and that maternal diabetes is associated with the risk of the former two disorders. The influence of maternal obesity on other psychiatric disorders is less well studied, but there are reports of associations with increased risks for offspring depression, anxiety, schizophrenia and eating disorders, at modest effect sizes. It remains unclear whether these associations are due to intrauterine mechanisms or explained by confounding family-based sociodemographic, lifestyle and genetic factors. The plausible underlying mechanisms have been explored primarily in animal models, and are yet to be further investigated in human studies.
... Exposure to increased glucocorticoids may thus have specific effects depending on the developmental stage. In fact studies in mice have shown that dexamethasone administration either throughout pregnancy (20-21 days for Mus musculus) or in the last week have different effects that can also be observed at the behavioral level [71]. ...
A number of prenatal experiences are associated with adverse outcomes after birth, ranging from cardiovascular problems to psychiatric disease. Prenatal stress is associated with neurodevelopmental alterations that persist after birth and manifest at the behavioral level, for example, increased fearfulness, and at the physiological one, that is, brain structural and functional changes. Understanding the mechanisms that drive these lasting effects may help in preventing long-term negative outcomes of prenatal stress. Elevated glucocorticoid signaling in utero may be one of the key mediators of prenatal stress effects on the offspring. In this review, we summarize how prenatal glucocorticoids may impact the activity of the fetal hypothalamic–pituitary–adrenal (HPA) axis, disrupt neurodevelopmental processes and alter the epigenetic landscape of the fetus. We also discuss the need to take into consideration the interaction of these processes with the offspring’s genetic landscape.
... MD also causes a long lasting decrease in GR and MR expression in the hippocampus of the pups that were separated from dams (Henry, Kabbaj, Simon, Moal, & Maccari, 1994). This change in GR/MR expression can disrupt further HPA axis negative regulation, leading to changes in the structure and function of hippocampus (Oomen et al., 2011;Welberg, Seckl, & Holmes, 2001). ...
The brain is both central in orchestrating the response to stress, and, a very sensitive target when such response is not controlled. In fact, stress has long been associated with the onset and/or exacerbation of several neuropsychiatric disorders such as anxiety, depression, and drug addiction. The hippocampus is a key brain region involved in the response to stress, not only due to its anatomical connections with the hypothalamic-pituitary-adrenal axis but also as a major target of stress mediators. The hippocampal dentate gyrus (DG)-CA3 circuit, composed of DG granule cells axons (mossy fibers) synapsing onto CA3 pyramidal cells, plays an essential role in memory encoding and retrieval, functions that are vulnerable to stress. Although naturally
excitatory, this circuit is under the inhibitory control of GABAergic interneurons that maintain the excitation/inhibition balance. One subgroup of such interneurons produces neuropeptide Y (NPY), which has emerged as a promising endogenous stress “resilience molecule” due to its anxiolytic and anti-epileptic properties. Here we examine
existing evidence that reveals a potential role for hilar NPY+ interneurons in mediating stress-induced changes in hippocampal function. We will focus specifically on rodent models of early life stress (ELS), defined as adverse conditions during the early postnatal period that can have profound consequences for neurodevelopment.
Collectively, these findings suggest that the long-lasting effects of ELS might stem from the loss of GABAergic NPY+ cells, which then can lead to reduced inhibition in the DG-CA3 pathway. Such change might then lead to hyperexcitability and concomitant hippocampal-dependent behavioral deficits.
... MD also causes a long lasting decrease in GR and MR expression in the hippocampus of the pups that were separated from dams (Henry, Kabbaj, Simon, Moal, & Maccari, 1994). This change in GR/MR expression can disrupt further HPA axis negative regulation, leading to changes in the structure and function of hippocampus (Oomen et al., 2011;Welberg, Seckl, & Holmes, 2001). ...
The brain is both central in orchestrating the response to stress, and, a very sensitive target when such response is not controlled. In fact, stress has long been associated with the onset and/or exacerbation of several neuropsychiatric disorders such as anxiety, depression, and drug addiction. The hippocampus is a key brain region involved in the response to stress, not only due to its anatomical connections with the hypothalamic‐pituitary‐adrenal axis but also as a major target of stress mediators. The hippocampal dentate gyrus (DG)‐CA3 circuit, composed of DG granule cells axons (mossy fibers) synapsing onto CA3 pyramidal cells, plays an essential role in memory encoding and retrieval, functions that are vulnerable to stress. Although naturally excitatory, this circuit is under the inhibitory control of GABAergic interneurons that maintain the excitation/inhibition balance. One subgroup of such interneurons produces neuropeptide Y (NPY), which has emerged as a promising endogenous stress “resilience molecule” due to its anxiolytic and anti‐epileptic properties. Here we examine existing evidence that reveals a potential role for hilar NPY+ interneurons in mediating stress‐induced changes in hippocampal function. We will focus specifically on rodent models of early life stress (ELS), defined as adverse conditions during the early postnatal period that can have profound consequences for neurodevelopment. Collectively, these findings suggest that the long‐lasting effects of ELS might stem from the loss of GABAergic NPY+ cells, which then can lead to reduced inhibition in the DG‐CA3 pathway. Such change might then lead to hyperexcitability and concomitant hippocampal‐dependent behavioral deficits.
... We obtained data on lipids only from three separate publications (SI 12.2). Dexamethasone treatment during the last week of gestation did not modify triglycerides or HDL-C in adult offspring (Buhl et al., 2007;Cleasby et al., 2003a;Mark et al., 2014;Tsai et al., 2019;Welberg et al., 2001). ...
Background:
Numerous rodent studies have evaluated the effects of maternal stress (MS) on later in life susceptibility to Metabolic Syndrome (MetS) intermediate phenotypes with varying results. The aim of this study was to quantitatively synthesize the available data on the effects of MS on offspring obesity, estimated indirectly by body mass (BM), body fat (BF) and plasma leptin; systolic blood pressure (SBP); plasma glucose (and insulin) and blood lipid concentrations.
Methods:
Literature was screened and summary estimates of the effect of MS outcomes were calculated by using random-effects models. Data on the effects of exogenous corticosteroid administration (or inhibition of 11β-HSD2) during pregnancy in rodents was analysed separately to characterize the direct phenotypic effects of prenatal corticosteroid excess (PCE).
Results:
We conducted 14 separate meta-analyses and synthesized relevant data on outcomes scarcely reported in literature. Both MS and PCE were associated with low birth weight without rapid catch-up growth resulting in decreased body mass later in life. Our analysis also revealed significant and contradictory effects on offspring adiposity. Little evidence was found for effects on glucose metabolism and blood lipids. We identified increased SBP in offspring exposed to PCE; however, there is not enough data to draw any conclusion about effects of MS on SBP.
Conclusions:
Neonatal weight proved to be decreased in offspring prenatally exposed to stress or corticosteroids, but laboratory rodents in the absence of a challenging environment did not show catch-up growth. The available evidence is inconclusive regarding the effect on adiposity revealing clear methodological and knowledge gaps. This meta-analysis also confirmed a significant positive association between PCE and SBP. Nevertheless, additional studies should address the association with MS.
... Exposure to AG was found to be associated with higher blood pressure in adulthood in several animal species [21][22][23]. Seckl et al. reported that prenatal glucocorticoid exposure permanently increases basal plasma corticosterone levels because it induces permanent reductions in the hippocampal density of both glucocorticoid receptors and mineralocorticoid receptors, which attenuate the feedback sensitivity of the HPA axis [10,24]. In addition, they suggested that "HPA programming" occurs relatively frequently after prenatal environmental challenges and may act in part via alterations in placental 11HSD2 activity [8,25]. ...
Background:
Developmental changes in the hypothalamus-pituitary-adrenal (HPA) axis during infancy have been reported in term infants, but those in preterm infants have yet to be elucidated. If developmental changes in the HPA axis of preterm infants are modulated by any factors, it may affect their future health. Few studies have examined the lasting consequences of antenatal glucocorticoids on the development of the HPA axis.
Methods:
We measured pre- and post-palivizumab vaccination salivary cortisol values in two conforming periods of three-months intervals during infancy, and compared cortisol values and the response of cortisol secretion between groups with and without antenatal glucocorticoid (AG) therapy.
Results:
Although the strength of the response of cortisol secretion to palivizumab fell age-dependently (until late infancy) in the Non-AG group, the opposite pattern was exhibited in the AG group. The changes of the delta cortisol values between the 2 groups were significant.
Conclusions:
This study suggests that the HPA axis of preterm infants whose mothers receive AG therapy may be upregulated during infancy, possibly leading to long lasting health problems.
Prenatal stress programmes long-lasting neuroendocrine and behavioural changes in the offspring. Often this programming is maladaptive and sex specific. For example, using a rat model of maternal social stress in late pregnancy, we have demonstrated that adult prenatally stressed male, but not prenatally stressed female offspring display heightened anxiety-like behaviour, whereas both sexes show hyperactive hypothalamo–pituitary–adrenal (HPA) axis responses to stress. Here, we review the current knowledge of the mechanisms underpinning dysregulated HPA axis responses, including evidence supporting a role for reduced neurosteroid-mediated GABAergic inhibitory signalling in the brains of prenatally stressed offspring. How maternal psychosocial stress is signalled from the mother to the fetuses is unclear. Direct transfer of maternal glucocorticoids to the fetuses is often considered to mediate the programming effects of maternal stress on the offspring. However, protective mechanisms including attenuated maternal stress responses and placental 11β-hydroxysteroid dehydrogenase-2 (which inactivates glucocorticoids) should limit materno-fetal glucocorticoid transfer during pregnancy. Moreover, a lack of correlation between maternal stress, circulating maternal glucocorticoid levels and circulating fetal glucocorticoid levels is reported in several studies and across different species. Therefore, here we interrogate the evidence for a role for maternal glucocorticoids in mediating the effects of maternal stress on the offspring and consider the evidence for alternative mechanisms, including an indirect role for glucocorticoids and the contribution of changes in the placenta in signalling the stress status of the mother to the fetus.
During the past several decades there has been increasing attention to the risks of exposure to endocrine disrupting chemicals, agents that mimic or block the effects of endogenous hormones. Previous research demonstrates that there may be critical periods of development where factors such as prenatal stress and endocrine disrupting chemical exposure can result in endocrine system dysregulation which manifests both immediately and later in life. This review describes the types of common endocrine disrupting chemicals and routes of exposure, the structure and functions of the hypothalamic-pituitary-adrenal axis and its role in the physiological response to stress, and highlights the current evidence showing that endocrine disrupting chemicals may alter normal hypothalamic-pituitary-adrenal axis functions. These topics are unified upon discussion of evidence indicating that prenatal endocrine disrupting chemical exposure has many of the same effects as prenatal stress on the hypothalamic-pituitary-adrenal axis, leading to long-term dysregulation of the axis and subsequent alterations in physiological responses to stress. We further suggest that prenatal endocrine disrupting chemical exposure in combination with prenatal stress may result in additive, if not synergistic effects on the hypothalamic-pituitary-adrenal axis-mediated stress response. Finally, we discuss vulnerable populations at an elevated risk for dual stress and endocrine disrupting chemical exposure and emphasize critical areas for future research.
Development of the brain and the emergence of the mind constitute some of the most important concerns of contemporary biology. Disturbances during fetal life may have profound implications for a child's future neurological and psychological development, which can in turn impact society. The new edition of this highly respected work presents a comprehensive review of the basic mechanisms of brain development and the pathophysiology of disorders of the infant brain, written by a team of distinguished neuroscientists, neonatologists, and neuropediatricians. The book follows the main milestones of brain development, from formation of the neural tube and wiring of the neurons in the brain. Neurotrophic factors, neurotransmitters, glial cell biology, cerebral circulation development of sensory functions are all described in detail. Furthermore, there are more philosophical chapters on the evolution of the brain and the emergence of consciousness. Clinical considerations are highlighted where relevant.
Development of the brain and the emergence of the mind constitute some of the most important concerns of contemporary biology. Disturbances during fetal life may have profound implications for a child's future neurological and psychological development, which can in turn impact society. The new edition of this highly respected work presents a comprehensive review of the basic mechanisms of brain development and the pathophysiology of disorders of the infant brain, written by a team of distinguished neuroscientists, neonatologists, and neuropediatricians. The book follows the main milestones of brain development, from formation of the neural tube and wiring of the neurons in the brain. Neurotrophic factors, neurotransmitters, glial cell biology, cerebral circulation development of sensory functions are all described in detail. Furthermore, there are more philosophical chapters on the evolution of the brain and the emergence of consciousness. Clinical considerations are highlighted where relevant.
Development of the brain and the emergence of the mind constitute some of the most important concerns of contemporary biology. Disturbances during fetal life may have profound implications for a child's future neurological and psychological development, which can in turn impact society. The new edition of this highly respected work presents a comprehensive review of the basic mechanisms of brain development and the pathophysiology of disorders of the infant brain, written by a team of distinguished neuroscientists, neonatologists, and neuropediatricians. The book follows the main milestones of brain development, from formation of the neural tube and wiring of the neurons in the brain. Neurotrophic factors, neurotransmitters, glial cell biology, cerebral circulation development of sensory functions are all described in detail. Furthermore, there are more philosophical chapters on the evolution of the brain and the emergence of consciousness. Clinical considerations are highlighted where relevant.
Fetal programming is the concept that maternal stressors during critical periods of fetal development can alter offspring phenotypes postnatally. Excess glucocorticoids can interact with the fetus to effect genetic and epigenetic changes implicated in adverse developmental outcomes. The present study investigates how chronic exposure to the synthetic glucocorticoid dexamethasone during late gestation alters the expression of genes related to behavior in brain areas relevant to the regulation and function of the hypothalamic–pituitary–adrenal axis. Pregnant Wistar Kyoto rats received subcutaneous injections of dexamethasone (100 μg/kg) daily from gestational day 15–21 or vehicle only as sham controls. The amygdala and paraventricular nucleus (PVN) were micro-punched to extract mRNA for reverse transcription and quantitative polymerase chain reaction for the analysis of the expression of specific genes. In the PVN, the expression of the glucocorticoid receptor NR3C1 was downregulated in female rats in response to programming. The expression of CACNA1C encoding the Cav1.2 pore subunit of L-type voltage-gated calcium channels was downregulated in male and female rats prenatally exposed to dexamethasone. Collectively, the results suggest that prenatal exposure to elevated levels of glucocorticoids plays a role in the dysregulation of the hypothalamic–pituitary–adrenal axis and potentially learning and memory by altering the expression of specific genes within the amygdala and PVN.
p>The first study compared three tests of central HPAA function in a group of low birthweight men aged 60-69 years from Hertfordshire, UK. There were no differences in the free cortisol response to awakening or ACTH and cortisol responses during a 100μg corticotrophin-releasing hormone (CRH) test, but low birthweight men had significantly smaller pituitary-adrenal responses during a dexamethasone-suppressed CRH test. While these findings do not explain the HPAA abnormalities associated with low birthweight in previous studies, they provide further evidence of dysregulation of the HPAA in men who were small at birth.
In further analysis of the data, blood pressure, glucose tolerance and plasma lipid concentrations were not related to these measures of central HPAA activity, despite significant positive correlations with morning cortisol concentrations. These data suggest that other mechanisms, for example altered glucocorticoid metabolism, are responsible for elevating circulating cortisol concentrations in men with cardiovascular risk factors.
The second study explored cortisol and blood pressure responses to a series of psychological stress tests in a group of young men and women from Adelaide, Australia. Cortisol responses were not related to size at birth in either sex, but in women there was a significant inverse relationship between birthweight and blood pressure reactivity. This study provides the first human evidence that haemodynamic responses to psychological stress may be programmed antenatally, suggesting a potential mechanism linking reduced fetal growth with raised blood pressure and cardiovascular disease in later life.
In summary, this research does not support the idea that the HPAA is upregulated centrally in low birthweight individuals, but adds to the evidence that the activity of the axis may be influenced by factors affecting fetal growth. The work presented in this thesis has added complexity to the role of the HPAA in the fetal origins of adult disease, and confirms that this is likely to remain an exciting area of research in years to come.</p
The glucocorticosteroid, or glucocorticoid (GC), system is largely conserved across vertebrates and plays a central role in numerous vital physiological processes including bone development, immunomodulation, and modification of glucose metabolism and the induction of stress-related behaviours. As a result of their wide-ranging actions, synthetic GCs are widely prescribed for numerous human and veterinary therapeutic purposes and consequently have been detected extensively within the aquatic environment. Synthetic GCs designed for humans are pharmacologically active in non-mammalian vertebrates, including fish, however they are generally detected in surface waters at low (ng/L) concentrations. In this review, we assess the potential environmental risk of synthetic GCs to fish by comparing available experimental data and effect levels in fish with those in mammals. We found the majority of compounds were predicted to have insignificant risk to fish, however some compounds were predicted to be of moderate and high risk to fish, although the dataset of compounds used for this analysis was small. Given the common mode of action and high level of inter-species target conservation exhibited amongst the GCs, we also give due consideration to the potential for mixture effects, which may be particularly significant when considering the potential for environmental impact from this class of pharmaceuticals. Finally, we also provide recommendations for further research to more fully understand the potential environmental impact of this relatively understudied group of commonly prescribed human and veterinary drugs.
Exposure to challenging experiences during development, such as reduced parental care and food availability, can have profound effects on the adult phenotype with far-ranging consequences for individual performance. Traditionally, such early-life adversities have been assumed to lead to detrimental consequences for health and survival. Growing empirical evidence, however, pin point that early-life stress exposure can also promote adaptive coping mechanisms of resistance and resilience, and have beneficial long-lasting effects. Developmental timing, type, and severity of early-life stress exposure are hypothesized to be key features underlying subsequent phenotypic outcomes. In this book chapter, we provide an overview of the main molecular mechanisms and signals that may be driving the emergence of subsequent stress vulnerability or resilience. We focus on the actions of glucocorticoid hormones in shaping adult physiological stress responses, and in organizing key cellular and molecular mechanisms underlying senescence and life-history evolution, including telomeres, oxidative stress, and epigenetics. Finally, we critically appraise and identify gaps in our current knowledge and provide directions for future research.
In this paper, we present a transdisciplinary framework and testable hypotheses regarding the process of fetal programming of energy homeostasis brain circuitry. Our model proposes that key aspects of energy homeostasis brain circuitry already are functional by the time of birth (with substantial interindividual variation); that this phenotypic variation at birth is an important determinant of subsequent susceptibility for energy imbalance and childhood obesity risk; and that this brain circuitry exhibits developmental plasticity, in that it is influenced by conditions during intrauterine life, particularly maternal–placental–fetal endocrine, immune/inflammatory, and metabolic processes and their upstream determinants. We review evidence that supports the scientific premise for each element of this formulation, identify future research directions, particularly recent advances that may facilitate a better quantification of the ontogeny of energy homeostasis brain networks, highlight animal and in vitro-based approaches that may better address the determinants of interindividual variation in energy homeostasis brain networks, and discuss the implications of this formulation for the development of strategies targeted towards the primary prevention of childhood obesity.
Exposure to prenatal stress (PNS) can lead to long-lasting neurobiological and behavioral consequences for the offspring, which may enhance the susceptibility for mental disorders. The hypothalamus-pituitary-adrenal (HPA) axis and the immune system are two major factors involved in the stress response. Here, we performed a systematic review and meta-analysis of rodent studies that investigated the effects of PNS exposure on the HPA axis and inflammatory cytokines in adult offspring. Our analysis shows that animals exposed to PNS display a consistent increase in peripheral corticosterone (CORT) levels and central corticotrophin-releasing hormone (CRH), while decreased levels of its receptor 2 (CRHR2). Meta-regression revealed that sex and duration of PNS protocol are covariates that moderate these results. There was no significant effect of PNS in glucocorticoid receptor (GR), CRH receptor 1 (CRHR1), pro- and anti-inflammatory cytokines. Our findings suggest that PNS exposure elicits long-lasting effects on the HPA axis function, providing an important tool to investigate in preclinical settings key pathological aspects related to early-life stress exposure. Furthermore, researchers should be aware of the mixed outcomes of PNS on inflammatory markers in the adult brain.
The prenatal stress during pregnancy has a wide variety of negative effects on the offspring behaviors. As such, in the present study the effect of prenatal immobilization stress was investigated on the brain BDNF level, spatial memory, anxiety and depression-like behavior in the F1 generation female NMRI mice. Twenty female pregnant mice were randomly allocated to stress and control groups (n = 10/group). The stress group was placed in PVC cylinders (2.5 cm in diameter and 20 cm in length) for one hour/day until the 15th day of pregnancy. The female F1 offspring was nursed by their mothers until reaching 25–30 g (9–10 weeks) which was tested for spatial memory, anxiety and depressive-like behavior using Barnes Maze, elevated plus-maze and forced swimming test, respectively. Also, the brain BDNF level was assessed by the ELISA method. Mice that underwent prenatal restraint stress exhibited impaired spatial memory in the Barnes Maze, which the time and distance to achieve the target hole and the number of errors in the female adult offspring increased than the control group. In the elevated plus-maze, the animals that underwent prenatal restraint stress spent less time in the open arms of the maze and reduced entering the open arms, compared to the control group. In addition, stress caused a significant decrease in swim time and a significant increase in float time for the female adult offspring compared to the control group. The brain BDNF concentration also decreased significantly in the stress group compared to the control group. This data suggests that prenatal stress may impair spatial memory and induce anxiety and depressive-like behavior in the adult offspring female mice via reducing brain BDNF.
Congenital toxoplasmosis is a widespread worldwide disease producing varying degrees of damage to the fetus including ocular and neurological impairment. However, the underlying mechanisms are not yet clear. Therefore, the current study aimed to investigate the progress of congenital cerebral toxoplasmosis in experimentally infected offspring animal model at different age groups till become adults. To fulfill this aim, the offspring of Me49 T. gondii infected pregnant mice were divided into groups; embryo, infant, young and adult phases. Blood and brain samples were collected for further hormonal and histopathological studies and immunohistochemical staining of glial fibrillary acidic protein (GFAP) and synaptophysin (SYN). Our results showed several encephalitic changes in the infected groups ranging from gliosis to reduced cortical cell number and fibrinoid degeneration of the brain. We showed increased expression of GFAP and SYN indicating activation of astrocytes and modification of the synaptic function, respectively. These changes started intrauterine following congenital infection and increased progressively afterward. Moreover, infected mice had elevated corticosterone levels. In conclusion, the current study provided new evidences for the cellular changes especially in the infected embryo and highlighted the role of GFAP and SYN that may be used as indicators for T. gondii-related neuropathy.
Fetal programming describes the relationship between the influence of exogenous and endogenous factors in sensitive phases of fetal development and cell growth and organ development, ultimately resulting in a persistent postnatal change in organ and tissue function. Errors in this process can be associated with the appearance of diseases in later life. Suboptimal intrauterine conditions such as maternal malnutrition, hypoxia, psychological stress, or glucocorticoid (GC) exposure during pregnancy can have lasting effects on fetal development and are often associated with a reduction in birth weight. The possible spectrum of late effects is wide ranging. Antenatal GC treatment appears to be associated with gender-specific fetal growth restriction as well as structural and functional changes in the placenta that can potentially affect health later in life. While female fetuses seem to have a rather continuous sensitivity to GC, possibly in the sense of a preferential survival strategy to ensure reproductive ability with preservation of species, in male fetuses, the placenta seems to develop, at least temporarily, a resistance to GC after GC exposure. The gender-specific sensitivity to GC is probably caused by a different GR (glucocorticoid receptors) distribution pattern, expression, and/or interaction and influenced by treatment with GC. An improved understanding of the placenta-mediated signaling pathways that contribute to fetal programming will be critical in efforts to develop interventional strategies for high-risk groups.
Objective:
Prenatal stress (PS) contributes to depression-like behavior in the offspring. PDLIM5 is involved in the onset of mental disorders. This study is to investigate the role and mechanism of PDLIM5 in depression-like behavior of PS offspring rats.
Methods:
PS model was used to analyze the effects of different treatments to PS offspring rats with different sex, including PDLIM5, PDLIM5 shRNA and 5-aza-2' -deoxycytidine (5-azaD). The depression-like behavior was assessed by the sucrose preference test (SPT) and forced swimming test (FST). The mRNA and protein expression levels of PDLIM5 in the hippocampus of PS offspring rats were detected by qRT-PCR and western blot, respectively. The methylation of PDLIM5 promoter were analyzed by bisulfite sequencing.
Results:
Our data revealed that PS offspring rats showed a significant decrease in sucrose preference and a prolonged immobility time. Injection of PDLIM5 significantly improved the depression-like behavior in PS offspring rats, whereas administration of PDLIM5 shRNA aggravated it. In addition, PDLIM5 expression was decreased at the mRNA and protein levels, and the methylation level of PDLIM5 promoter was increased in hippocampus of PS male but not female offspring rats. Furthermore, microinjection of 5-azaD improved the PS induced depression-like behavior in offspring rats. Moreover, in male PS offspring rats, microinjection of 5-azaD reversed the effect of PS on PDLIM5 expression and promoter methylation.
Conclusion:
PDLIM5 can significantly improve the depression-like behavior of both male and female PS offspring rats, while the PDLIM5 promoter methylation is only observed in male PS offspring rats. Our study may provide new mechanism for the pathogenesis of depression and experimental evidence for sex-based precise treatment.
The hypothalamo‐pituitary‐adrenal (HPA) axis plays a key role in the neuroendocrine response to stress and in maintaining physiological homeostasis. However, stress that is chronic in nature can lead to HPA axis dysfunction and increase the risk for developing affective disorders, particularly if the stress is experienced during vulnerable periods in life. Sex differences in how the HPA axis responds to stress are well established, with females typically displaying heightened responses. The underlying cause of these sex differences are important to understand, as many neuropsychiatric disorders disproportionately affect females. Much research has provided evidence for gonadal sex steroids in underpinning sex differences in HPA axis responsivity, however we suggest that neuroactive metabolites of these steroids also play a key role in the brain in mediating sex differences in HPA axis responses to stress. The relationship between neuroactive steroids and stress is complex. Acute stress rapidly increases neuroactive steroid production, which can in turn modulate activity of the HPA axis. However under chronic stress conditions, stress can impact the brain’s capacity to generate steroids, and this in turn has corollary effects on HPA axis function that may increase the propensity for psychopathology, given both HPA axis dysfunction and deficits in neuroactive steroids are implicated in affective disorders. Hence here we review the evidence from animal and human studies for sex differences in the interactions between neuroactive steroids and the stress axis at various stages of life, under physiological and pathophysiological stress conditions and consider the implications for health and disease.
There is growing evidence that stressors occurring during pregnancy can impair biological and behavioral adaptation to stress in the adult offspring. Mechanisms by which stress in the pregnant rat can influence development of the offspring are still unknown. In the present study, we investigated the involvement of maternal corticosterone secretion during pregnancy on the hypothalamo-pituitary-adrenal axis activity of adult offspring. We investigated stress-induced corticosterone secretion and hippocampal type I and type II corticosteroid receptors in male adult rats submitted to prenatal stress born to either mothers with intact corticosterone secretion or mothers in which stress-induced corticosterone secretion was blocked by adrenalectomy with substitutive corticosterone therapy. Repeated restraint during the last week of pregnancy was used as prenatal stressor. Furthermore, the specific role of an injection of corticosterone before the restraint stress on adrenalectomized mothers with substitutive corticosterone treatment was also studied. We report here that blockade of the mother's stress-induced glucocorticoid secretion suppresses the prolonged stress-induced corticosteroid response and the decrease in type I hippocampal corticosteroid receptors usually observed in prenatally stressed adults. Conversely, corticosterone administered during stress, to mothers in which corticosterone secretion is blocked, reinstates the effects of prenatal stress. These results suggest for the first time that stress-induced increases in maternal glucocorticoids may be a mechanism by which prenatal stress impairs the development of the adult offspring's glucocorticoid response.
It is well known that the hypothalamo-pituitary-adrenal (HPA) axis is altered by early environmental experiences, particularly in the perinatal period. This may be one mechanism by which the environment changes the physiology of the animal such that individual differences in adult adaptative capabilities, such as behavioral reactivity and memory performance, are observable. To determine the origin of these behavioral individual differences, we have investigated whether the long-term influence of prenatal and postnatal experiences on emotional and cognitive behaviors in adult rats are correlated with changes in HPA activity. To this end, prenatal stress of rat dams during the last week of gestation and postnatal daily handling of rat pups during the first 3 weeks of life were used as two environmental manipulations. The behavioral reactivity of the adult offspring in response to novelty was evaluated using four different parameters: the number of visits to different arms in a Y-maze, the distance covered in an open field, the time spent in the corners of the open field, and the time spent in the open arms of an elevated plus-maze. Cognitive performance was assessed using a water maze and a two-trial memory test. Adult prenatally stressed rats showed high anxiety-like behavior, expressed as an escape behavior to novelty correlated with high secretion of corticosterone in response to stress, whereas adult handled rats exhibited low anxiety-like behavior, expressed as high exploratory behavior correlated with low secretion of corticosterone in response to stress. On the other hand, neither prenatal stress nor handling changed spatial learning or memory performance. Taken together, these results suggest that individual differences in adult emotional status may be governed by early environmental factors; however, perinatal experiences are not effective in influencing adult memory capacity.
In the forced swimming test, adrenal hormones regulate immobility time during a test swim given 24 hr after the initial training swim (e.g., the deficit in adrenalectomized animals is reduced when animals are given corticosterone [B] immediately after the training session). In this study, adrenalectomy decreased and B restored immobility during the test swims. The effects of adrenalectomy were completely reversed by 1 mg/kg doses of B, which results in plasma B levels that are comparable to values under basal resting conditions. Higher doses of B had no further effect. B given before or immediately after training partially reversed the effects of adrenalectomy. The complete reversal of the effects of adrenalectomy, however, required the presence of B during both training and testing, suggesting that B plays a role in the consolidation-retention and retrieval of the immobility response.
Glucocorticoids (GCs) act via intracellular mineralocorticoid (MR) and glucocorticoid receptors (GR). However, it has recently been recognized that GC access to receptors is determined by the presence of tissue-specific 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) that catalyze the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11beta-HSD type 1 (11beta-HSD1) is a bidirectional enzyme in vitro that acts predominantly as a reductase (regenerating corticosterone) in intact neurons. In contrast, 11beta-HSD type 2 (11beta-HSD2) is a higher affinity exclusive dehydrogenase that excludes GCs from MR in the kidney, producing aldosterone-selectivity in vivo. We have examined the ontogeny of 11beta-HSD mRNAs and enzyme activity during prenatal brain development and correlated this with GR and MR mRNA development. These data reveal that (1) 11beta-HSD2 mRNA is highly expressed in all CNS regions during midgestation, but expression is dramatically reduced during the third trimester except in the thalamus and cerebellum; (2) 11beta-HSD2-like activity parallels closely the pattern of mRNA expression; (3) 11beta-HSD1 mRNA is absent from the CNS until the the third trimester, and activity is low or undectectable; and (4) GR mRNA is highly expressed throughout the brain from midgestation, but MR gene expression is absent until the last few days of gestation. High 11beta-HSD2 at midgestation may protect the developing brain from activation of GR by GCs. Late in gestation, repression of 11beta-HSD2 gene expression may allow increasing GC activation of GR and MR, permitting key GC-dependent neuronal and glial maturational events.
We have characterized the gene for the mouse glucocorticoid receptor. The gene spans approximately 110 kilobases, and glucocorticoid receptor transcripts are assembled from nine exons. Expression of the gene is controlled by at least three promoters, resulting in glucocorticoid receptor transcripts with different 5' nontranslated exons. One promoter is cell-specific, found to be active only in T lymphocytes. The other two promoters are active to various degrees in all cell lines and tissues so far analyzed and are located in a CpG island. The promoter activities are accompanied by DNase I hypersensitivity sites in chromatin. In contrast to a conservation of exon-intron structure, differences in promoter organization suggest a divergence between the evolution of regulatory and coding regions among members of the steroid receptor super-family.
To discover whether reduced fetal and infant growth is associated with non-insulin dependent diabetes and impaired glucose tolerance in adult life.
Follow up study of men born during 1920-30 whose birth weights and weights at 1 year were known.
Hertfordshire, England.
468 men born in east Hertfordshire and still living there.
Fasting plasma glucose, insulin, proinsulin, and 32-33 split pro-insulin concentrations and plasma glucose and insulin concentrations 30 and 120 minutes after a 75 g glucose drink.
93 men had impaired glucose tolerance or hitherto undiagnosed diabetes. They had had a lower mean birth weight and a lower weight at 1 year. The proportion of men with impaired glucose tolerance fell progressively from 26% (6/23) among those who had weighted 18 lb (8.16 kg) or less at 1 year to 13% (3/24) among those who had weighed 27 lb (12.25 kg) or more. Corresponding figures for diabetes were 17% (4/23) and nil (0/24). Plasma glucose concentrations at 30 and 120 minutes fell with increasing birth weight and weight at 1 year. Plasma 32-33 split proinsulin concentration fell with increasing weight at 1 year. All these trends were significant and independent of current body mass. Blood pressure was inversely related to birth weight and strongly related to plasma glucose and 32-33 split proinsulin concentrations.
Reduced growth in early life is strongly linked with impaired glucose tolerance and non-insulin dependent diabetes. Reduced early growth is also related to a raised plasma concentration of 32-33 split proinsulin, which is interpreted as a sign of beta cell dysfunction. Reduced intrauterine growth is linked with high blood pressure, which may explain the association between hypertension and impaired glucose tolerance.
Adrenalectomized rats displayed a deficiency in retention of an immobility response acquired during an initial 15-min forced swimming procedure (Porsolt swimming test) and measured 24 h later in a 5-min retest session. The deficit could be restored dose dependently with the glucocorticoid dexamethasone (microgram range) administered 15 min after the initial test. The antiglucocorticoid RU 38486 administered subcutaneously (1 and 10 mg/kg) inhibited the dexamethasone effect and caused a parallel shift in the dose-response curve of dexamethasone. Intracerebroventricular administration of RU 38486 to intact rats immediately before the initial test attenuated retention of acquired immobility over a 100,000-fold lower dose range (ng) and increased the plasma corticosterone level. Local administration of 1 ng RU 38486 in the dentate gyrus of the hippocampus also diminished the percentage immobility, but did not influence the adrenocortical response. Injections of RU 38486 in parafascicular and paraventricular nucleus were ineffective on behaviour. In the latter nucleus the antiglucocorticoid disinhibited the activity of the hypothalamus-pituitary-adrenal axis. Intracerebroventricular pretreatment with promegestone did not interfere with RU 38486 action, ruling out involvement of its antiprogestin properties. Intracerebroventricular or subcutaneous treatment of intact rats with the antimineralocorticoid RU 28318 was not effective. Finally, adrenalectomized rats replaced with corticosterone delivered via subcutaneously implanted 100-mg corticosterone pellets showed normal behavioural performance, while a 25-mg implant did not. The present study with local infusions of RU 38486 indicates that glucocorticoid feedback via type 2 receptors exerts a long-term influence on behaviour in the hippocampus and controls the activity of the hypothalamus-pituitary-adrenal axis in the paraventricular nucleus.
One theory suggests that depression in adult life originates through parental indifference, abuse, and other adverse influences in childhood. The possible contribution of development in infancy has received little attention.1 We therefore examined the association between infant growth and later suicide in 15500 men and women. Depression underlies 70% of deaths by suicide.2
As previously described, all births in Hertfordshire from 1911 onwards were notified by the attending midwife.3 Health visitors saw the babies periodically throughout infancy, recorded the method of feeding, and wrote general comments on the baby's development and well being. At 1 year the babies were weighed. We traced 10141 (79%) of the boys born during 1911-30 and 5585 (60%) of the girls born during 1923-30. The average birthweight and weight at 1 year of those who were traced were the same as those of the babies who were not traced. We compared the numbers of deaths from suicide at ages 20-74 …
The fetal origins hypothesis states that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease. Animal studies have shown that undernutrition before birth programmes persisting changes in a range of metabolic, physiological, and structural parameters. Studies in humans have shown that men and women whose birth weights were at the lower end of the normal range, who were thin or short at birth, or who were small. in relation to placental size have increased rates of coronary heart disease. We are beginning to understand something of the mechanisms underlying these associations. The programming of blood pressure, insulin responses to glucose, cholesterol metabolism, blood coagulation, and hormonal settings are all areas of active research.
Background: Disturbances of the limbic–hypothalamic–pituitary–adrenal axis and the serotonin system are commonly found in depressive illness. Studying the effect of stress on these two neurobiological systems may give us important clues into the pathophysiology of affective illness and help us understand how stress and mood disorders are related.Methods: We studied the effect of chronic unpredictable stress and antidepressant treatment on serotonin 1A (5-HT1A), glucocorticoid (GR), and mineralocorticoid (MR) receptor levels in rat hippocampus, using in situ hybridization and receptor autoradiography. We also used in situ hybridization to quantify hippocampal 5-HT1A, GR, and MR messenger (mRNA) levels in a small group of suicide victims with a history of depression, compared to matched controls (n = 6).Results: We found that rats subjected to chronic unpredictable stress showed a significant elevation of basal plasma corticosterone compared to nonstressed rats. Chronic stress also caused a decrease in 5-HT1A mRNA and binding in the hippocampus. In addition, chronic stress produced alterations on the MR/GR mRNA ratio in this same region. The decreases in 5-HT1A mRNA and binding, as well as the MR/GR alterations, were prevented in animals that received imipramine or desipramine antidepressant treatment. Zimelidine was unable to reverse stress-induced increases in corticosterone, and was only partially successful in preventing the stress-induced receptor changes in the hippocampus. Suicide victims with a history of depression showed changes that were very similar to the changes found in chronic stress.Conclusions: Alterations in hippocampal 5-HT1A levels and in the MR/GR balance may be one of the mechanisms by which stress may trigger and/or maintain depressive episodes.
Regions of the amygdala are involved in anticipation of negative events. Chronic anticipation of negative events leads to what we call allostatic load, or arousal pathology. Two hormones appear to be involved in arousal pathology; corticotropin-releasing hormone in the brain and glucocorticoids. We suggest that increases in corticotropin-releasing hormone, by stress or glucocorticoids, in the amygdala may have functional consequences for allostatic load. Whereas, corticotropin-releasing hormone in the parvocellular region of the paraventricular nucleus of the hypothalamus is decreased by glucocorticoids thereby under negative feedback and homeostatic control, the central nucleus of the amygdala is to some extent under positive feedback and is increased by glucocorticoids, and perhaps under allostatic control. The human and animal literature suggest that a variety of psychopathologies (e.g., melancholia) may be tied to neurohormonal signals activating regions of the amygdala.
A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the + -maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the + -maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.
The effect of early prenatal dexamethasone (DEX) exposure on cognitive and behavioral development, behavior problems, and temperament were examined in 26 consecutively identified children aged 6 mo to 5 1/2 years, whose mothers had been DEX-treated during pregnancy because their offspring was at risk for congenital adrenal hyperplasia (CAH), and compared with 14 children from untreated CAH-risk pregnancies. Three children in each group were CAH-affected. Assessments were performed by way of mother-completed standard questionnaires. No significant differences in cognitive abilities or behavior problems were identified. On temperament questionnaires, DEX-exposed children showed more Shyness (p < .004), greater Emotionality (p < .03), less Sociability (p < .04), and a trend for greater Avoidance (p < .07) than unexposed children. DEX-exposed children also had significantly higher Internalizing (p < .002) and Total Problem scores (p < .05) on the behavior problem measure for 2–3 year olds. The results should be considered preliminary until they have been replicated by the study of a larger sample and direct examination of the children.
This study investigated the hypotheses that unpredictable prenatal stress (1) has effects on the offspring, similar to those induced by perinatal administration of glucocorticoids and (2) increases the vulnerability to stressful situations at adulthood. Rats were exposed to random noise and light stress throughout pregnancy. Offspring were tested for the development of spontaneous alternation behavior (SA) and at adulthood, their response to novel or aversive situations, open field, extinction and punishment following acquisition of an appetitive response and two-way active avoidance, were assessed. In prenatally stressed rats, the development of SA was significantly delayed. On repeated exposure to an open field they were less active; control rats had elevated plasma corticosterone (CCS) on days 2 and 4 of open field exposure, while prenatally stressed rats had significantly raised plasma CCS after each exposure (days 1–8). Furthermore, punishment-induced suppression of an appetitive response was enhanced. Acquisition of active avoidance was faciliated in female but reduced in male prenatally stressed offspring. It is suggested that random prenatal noise and light stress may cause impairment of development of hippocampal function which lasts into adulthood. This impairment is manifested as an increase in vulnerability and a decrease in habituation to stressful stimuli.
WEINSTOCK, M. Does prenatal stress impair coping and regulation of hypothalamic-pituitary-adrenal axis? NEUROSCI BIOBEHAV REV 21(1),1–10 1997.—Prenatally stressed (PS) human infants and experimental animals show attentional deficits, hyperanxiety and disturbed social behavior. Impaired coping in stressful situations in adult PS monkeys and rodents is associated with dysregulation of the HPA axis, characterized by decreased feedback inhibition of corticotropin-releasing hormone (CRH) and prolonged elevation of plasma glucocorticoids in response to stress. PS rats have higher levels of CRH in the amygdala, fewer hippocampal glucocorticoid receptors and less endogenous opioid and GABA/BDZ (benzodiazepine) inhibitory activity. The mechanisms by which maternal stress hormones induce these long-lasting changes in the developing fetal neuroaxis remain to be elucidated. It is suggested that impaired coping in stressful situations and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, result from the action of maternal hormones released during stress on the developing fetus. The similarities in coping behavior and dysregulation of the HPA axis in PS animals to those in humans with depression, suggest that gestational stress, at a critical time during fetal development, may increase the propensity to develop this condition. Copyright © 1996 Elsevier Science Ltd.
The association between hypertension and insulin resistance might be explained by increased activity of the principal glucocorticoid, cortisol. Recent data show that the intensity of dermal vasoconstriction after topical application of glucocorticoids is increased in patients with essential hypertension. In this report, we examine whether increased glucocorticoid sensitivity or secretion is associated with insulin resistance and is a cause or consequence of hypertension. We studied 32 men (aged 47 to 56 years) from a cross-sectional study and 105 men (aged 23 to 33 years) in whom predisposition to high blood pressure has been defined by their own blood pressure and the blood pressures of their parents. In both populations, increased dermal glucocorticoid sensitivity was associated with relative hypertension, insulin resistance, and hyperglycemia. In young men with higher blood pressure whose parents also had high blood pressure, enhanced glucocorticoid sensitivity was accompanied by enhanced secretion of cortisol, enhanced ligand-binding affinities for dexamethasone in leukocytes, and impaired conversion of cortisol to inactive metabolites (cortisone and 5beta-dihydrocortisol). Increased tissue sensitivity to cortisol, amplified by enhanced secretion of cortisol, is a feature of the familial predisposition to high blood pressure rather than a secondary effect of high blood pressure. It may be mediated by an abnormal glucocorticoid receptor, and it may contribute to the association between hypertension and insulin resistance.
Recent studies have shown that reduced fetal growth is associated with the development of the insulin resistance syndrome in adult life. The mechanisms are not known. However increased activity of the hypothalamic-pituitary-adrenal axis (HPAA) may underlie this association; the axis is known to be reset by fetal growth retardation in animals, and there is evidence in humans of an association between raised HPAA activity and the insulin resistance syndrome. We have, therefore, examined the relations among size at birth, plasma cortisol concentrations, and components of the insulin resistance syndrome in a sample of healthy men. We measured 0900 h fasting plasma cortisol and corticosteroid-binding globulin levels in 370 men who were born in Hertfordshire, UK, between 1920-1930 and whose birth weights were recorded. Fasting plasma cortisol concentrations varied from 112-702 nmol/L and were related to systolic blood pressure (P = 0.02), fasting and 2-h plasma glucose concentrations after an oral glucose tolerance test (P = 0.0002 and P = 0.04), plasma triglyceride levels (P = 0.009), and insulin resistance (P = 0.006). Plasma cortisol concentrations fell progressively (P = 0.007) from 408 nmol/L in men whose birth weights were 5.5 lb (2.50 kg) or less to 309 nmol/L among those who weighed 9.5 lb (4.31 kg) or more at birth, a trend independent of age and body mass index. These findings suggest that plasma concentrations of cortisol within the normal range could have an important effect on blood pressure and glucose tolerance. Moreover, this study provides the first evidence that intrauterine programming of the HPAA may be a mechanism underlying the association between low birth weight and the insulin resistance syndrome in adult life.
Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by various clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. Antidepressants could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquilisers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrichment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as iprindole and mianserin suggest that the method may be capable of discovering new antidepressants hitherto undetectable with classical pharmacological tests.
A meta-analysis was performed of 9 controlled trials of maternal beta-/dexamethasone treatment in which the incidence of RDS in infants born before 30 weeks gestation was reported. A significant decrease could be shown in 250 immature infants. The number of cases was to small for analysis of lower gestational ages or for the demonstration of a reduction in mortality. In a separate study of 135 infants born before 30 weeks gestation tracheal aspirate phospholipid analysis was performed using thin layer chromatography. 64 of them had been exposed prenatally to steroids. Significantly more of these infants had a mature L/S ratio > or = 2.7 (p < 0.02) and prenatal glucocorticoid treatment was associated with a markedly increased survival rate (odds ratio 2.4, p < 0.02). We conclude from the meta-analysis of the literature and from the findings of our study, that accelerated lung maturation follows prenatal steroid treatment with a reduction in RDS-incidence even in very immature fetuses. Consequently it would be appropriate to administer glucocorticoids combined with tocolysis since this has been shown to be beneficial for those women threatening to deliver prematurely at less than 30 weeks gestation.
Prenatal stress in rats usually results in behavioral and developmental changes in offspring. This experiment assessed body weight during the first three weeks postpartum and subsequent behavior of the offspring when tested as adults. Pregnant females allocated to the stress condition were exposed during the third week of pregnancy to either predictable (NOV1) or unpredictable (NOV2) psychological novelty stress. At this time, pregnant rats were also treated with various doses of oxytocin or vehicle solution. The exposure to unpredictable novelty stress during the third week of pregnancy resulted in pups which were significantly heavier at birth than either control animals or those which had received predictable exposure to the novelty stress. In contrast, oxytocin treatment appeared to lower body weight of offspring compared to control animals. This effect was observed right up until Day 21 postpartum for animals exposed to the larger dose (11.6 I.U.) of oxytocin. When tested as adults, NOV1 and NOV2 offspring were found to defecate more in the open field setting suggesting the they were more emotional than control animals. It was concluded that psychological stress during pregnancy has a subtle effect on development and subsequent effects on later emotionality of the offspring when tested as adults.
Altered gene expression and/or actions of the insulin-like growth factors (IGFs) have been implicated in the mediation of both pre- and postnatal growth retardation secondary to glucocorticoid excess. To investigate this possibility, we assessed the gene expression of the IGFs, the type I IGF receptor, and IGF-binding proteins (IGFBPs) in 20-day gestation liver and lung of growth-retarded fetuses whose mothers were treated with dexamethasone (DXM; 100 micrograms, ip, daily) on gestation days 15-19 (gestation = 21-22 days). DXM treatment in dams produced fetal growth retardation without decreasing litter size (32% decrease in fetal body weight). Both fetal liver and lung demonstrated decreased wet weight (48% and 47%, respectively) and DNA content (65% and 51%, respectively) compared to control animals. Our results suggest that increased expression of IGFBP-1, and possibly IGFBP-2, is involved in mediating the marked growth retardation. As assessed by solution hybridization assays and Northern blot analysis, there was an 8.5-fold increase in IGFBP-1 mRNA expression in the livers of DXM-treated fetal animals compared to that in sham-injected controls (P less than 0.002). IGFBP-2 mRNA expression was also increased (60%) in fetal liver, whereas IGFBP-3 was decreased (57%). In fetal lung, IGFBP-1 transcript abundance was also higher in DXM-treated fetal animals. Serum concentrations of IGFBP-1, but not those of IGFBP-2, were increased (approximately 4-fold) in the DXM-treated fetuses, as quantified by [125I]IGF-I ligand blotting and IGFBP-2 immunoblotting. Because hypoinsulinemia increases the expression of IGFBP-1 and -2, serum insulin concentrations were measured and found to be decreased in the DXM-treated fetuses (24 microU/ml) compared to control values (72 microU/ml). Analysis of mRNA expression for IGF-I, IGF-II, and the type 1 receptor transcripts did not support a role for decreased IGF or IGF receptor expression in the etiology of DXM-mediated growth retardation. IGF-I was unchanged in both liver and lung, and IGF-II transcripts were increased by 31% in liver and unchanged in lung of DXM-treated fetal animals. Northern analysis of hepatic and lung poly(A) RNA demonstrated no evidence for independent regulation of specific-sized IGF transcripts. Further, type 1 IGF receptor RNA abundance increased 42% in fetal liver and was unchanged in lung. Because IGFBPs may modulate IGF action, these results suggest that increased IGFBP-1, and possibly IGFBP-2, expression may be of importance in the etiology of DXM-induced fetal growth retardation.
A study was made of the effects of prenatal stress on the reactivity of the hypothalamic-pituitary adrenal (HPA) axis in male and female offspring. Rat dams were subjected to noise and light stress on an unpredictable basis throughout pregnancy. At 28 days of age mRNA for POMC, proenkephalin and prodynorphin were measured in the hypothalamus of the offspring. A marked reduction was found in POMC mRNA in PS females (PSF) but not in males (PSM), but the other mRNA's did not differ from controls (C). At 60 days of age, PSF has 3 times higher resting levels of serum corticosterone (COR) and significantly lower dexamethasone (DEX)3H hippocampal binding sites than CF. Overnight adrenalectomy abolished the difference in DEX binding. After 10 min exposure to open field PS males and females voided more fecal pellets and made fewer center entries than C offspring, testifying to increased emotionality. Open field stress caused a 3-5-fold rise in circulating COR in all groups within 15 min, which returned to baseline by 90 min in all rats except PSF. These data show that prenatal stress can cause permanent alterations in the behavior of both sexes in stressful situations but appears to cause a selective effect on the HPA axis in the female rat.
Previous studies have shown that maternal stress modifies 5-hydroxytryptamine (5-HT) receptor binding in several brain regions of the adult offspring and alters the intensity of the behavioral responses to 5-HT receptor agonists. We now report that the same stress, crowding combined with daily saline injections during the final week of pregnancy, elevates maternal plasma free tryptophan level without significantly affecting total tryptophan. The increased maternal plasma tryptophan was associated with significantly increased fetal brain levels of tryptophan, 5-HT and 5-hydroxyindoleacetic acid. These increases were maintained after birth until at least postnatal day 10. Since 5-HT is recognised as having a role in the control of neuron development during the perinatal period, we suggest that the stress-induced increase in fetal brain 5-HT synthesis may play a part in the mechanisms by which prenatal stress alters adult behavior.
There is considerable, although not entirely consistent, evidence that the hippocampus inhibits most aspects of HPA activity, including basal (circadian nadir) and circadian peak secretion as well as the onset and termination of responses to stress. Although much of the evidence for these effects rests only on the measurement of corticosteroids, recent lesion and implant studies indicate that the hippocampus regulates adrenocortical activity at the hypothalamic level, via the expression and secretion of ACTH secretagogues. Such inhibition results largely from the mediation of corticosteroid feedback, although more work is required to determine whether the hippocampus supplies a tonic inhibitory input in the absence of corticosteroids. It must be noted that the hippocampus is not the only feedback site in the adrenocortical system, since removal of its input only reduces, but does not abolish, the efficacy of corticosteroid inhibition, and since other elements of the axis appear eventually to compensate for deficits in feedback regulation. The importance of other feedback sites is further suggested not only by the presence of corticosteroid receptors in other parts of the brain and pituitary, but also by the improved prediction of CRF levels by combined hypothalamic and hippocampal receptor occupancy. The likelihood of feedback mediated by nonhippocampal sites underscores the need for future work to characterize hippocampal influence on HPA activity in the absence of changes in corticosteroid secretion. However, despite the fact that the hippocampus is not the only feedback site, it is distinguished from most potential feedback sites, including the hypothalamus and pituitary, by its high content of both type I and II corticosteroid receptors. The hippocampus is therefore capable of mediating inhibition over a wide range of steroid levels. The low end of this range is represented by corticosteroid inhibition of basal (circadian nadir) HPA activity. The apparent type I receptor specificity of this inhibition and the elevation of trough corticosteroid levels after hippocampal damage support a role for hippocampal type I receptors in regulating basal HPA activity. It is possible that basal activity is controlled in part through hippocampal inhibition of vasopressin, since the inhibition of portal blood vasopressin correlates with lower levels of hippocampal receptor occupancy, and the expression of vasopressin by some CRF neurons is sensitive to very low corticosteroid levels. At the high end of the physiological range, stress-induced or circadian peak corticosteroid secretion correlates strongly with occupancy of the lower affinity hippocampal type II receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
The aim of this study was to see whether neonatal handling can reverse the behavioral deficits induced in rats by unpredictable prenatal stress. Rats (24) were exposed to random noise and light stress (RS) on a random basis throughout pregnancy. Half the litters of RS and control (C) dams were subjected to neonatal handling (NH), 3' daily for 21 days. Behavioral measures, open field in both sexes and plus maze test in females only were conducted at 1.5-2 months, and spatial lateralization by amphetamine-induced rotation, in females at 3 months. RS caused significant increases in emotionality and timidity (higher incidence of defecation and less time in open arms of plus maze), and a change in directional bias towards the left. NH completely reversed all these behavioral abnormalities in RS rats but had little effect in C. It is concluded that NH can influence postnatal development of brain organisation in the opposite direction to that induced by prenatal stress.
1. Immobility in the forced swim test ("behavioral despair test") has often been regarded as an animal model of despair or depression. 2. Behavioral studies of forced swimming ("behavioral despair") are reviewed and compared with certain behavioral effects of exposure to inescapable shock (i.e., "learned helplessness"). 3. Exposure to inescapable shock clearly impairs subsequent coping responses. However, detailed behavioral studies of forced swimming indicate that immobility during forced swimming is not a failure of coping but instead reflects a relatively successful coping strategy that employs energy conserving behaviors. 4. Certain neurobiological studies of forced swimming are reinterpreted in light of the behavioral evidence that immobility during forced swimming reflects effects of learning and memory rather than effects of despair or depression. 5. Some implications for future neurobehavioral studies of forced swimming and uncontrollable shock are discussed.
Corticosteroids appear capable of exerting an impressive array of effects on the metabolism of neural tissues. The diversity of these effects is perhaps not surprising given the wide variety of biochemically and morphologically distinguishable cell types present in the combined central and peripheral nervous systems. In conclusion, it seems useful to summarize the state of knowledge in some of the most critical research areas discussed in this review and to predict what major advances are probably forthcoming in the next few years.
Two cohorts of boys were examined while attending a well-baby clinic and reexamined at the end of the first grade of elementary school. One cohort (n = 57) consisted of boys born in the year of the Six-Day War in 1967. The other cohort was born 2 years later (n = 63). Data on socio-demographic background, early development, behavior at school and at home were obtained from the mothers and the teachers. Statistical analysis showed that the "war children" had significant developmental delays and regressive, non-affiliative and dissocial behavior. The children, who were in their first half year of life at the time of the war, were much more disturbed than those of whom the mothers were pregnant at the time of the war. The findings suggest that a disturbed mother-child relationship existed in the former group.
Administrations of the glucocorticoid receptor antagonist (anti-glucocorticoid, RU38486) and the mineralocorticoid antagonist (anti-mineralocorticoid, RU28318) followed by frequent, sequential blood sampling were employed to investigate the possible role the brain mineralocorticoid receptor (MR, type I) and glucocorticoid receptor (GR, type II) have in the regulation of basal and stress-induced adrenocortical secretion in the rat. The anti-mineralocorticoid and anti-glucocorticoid were administered subcutaneously (s.c.) at doses of 2.5 mg and 1.0 mg/100 g body weight, respectively. Both antagonists were also given intracerebroventricularly (i.c.v.) at a dose of 100 ng/rat. Under basal non-stressed conditions (at the diurnal trough in the morning), injections of either saline, anti-glucocorticoid (s.c. or i.c.v.) or anti-mineralocorticoid (s.c.) did not have effect on the plasma corticosterone level. The anti-mineralocorticoid given intracerebroventricularly, however, caused an elevation of plasma corticosterone up to 60 min after the injection. Exposure of the rats to a novel environment resulted in a large increase in the plasma corticosterone level, which was slightly reduced in the rats treated with the anti-glucocorticoid. In vehicle-treated rats, the level returned to basal values at 90 min, while in the anti-glucocorticoid- and anti-mineralocorticoid-treated groups, it remained elevated for prolonged periods. The present study thus shows that (1) the anti-glucocorticoid RU38486 via the brain GR has no effect on the basal plasma corticosterone level in the morning but interferes with a glucocorticoid negative feedback following stress and (2) the anti-mineralocorticoid RU28318 via the brain MR elevates the basal plasma corticosterone level and enhances adrenocortical secretion following stress.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult rats handled (H) daily for the first 3 weeks of life show a dramatically altered adrenocortical response to stress. We found that H animals secreted less ACTH and corticosterone (B) during and following the termination of stress than did nonhandled (NH) controls. In contrast, H and NH animals did not differ in basal B secretion at any point in the diurnal cycle, nor in adrenocortical responses to exogenously administered oCRF or ACTH. Moreover, the clearance rate for B was similar in H and NH animals. H animals were more sensitive than NH animals to the inhibitory effects of either B or dexamethasone on stress-induced adrenocortical activity. In a dose-response study, both glucocorticoids administered 3 h prior to testing suppressed the adrenocortical response to a 20-min restraint stress to a greater extent in the H animals. Handling increased type II, glucocorticoid receptor binding capacity in the hippocampus of adult animals (approximately 50% increase in capacity, with no change in affinity). There were no handling-induced changes in type II receptor binding capacity in the hypothalamus or pituitary, nor in type I receptor binding capacity in the hippocampus. Following chronic (5 mg/kg/day) treatment with B, hippocampal type II receptor binding capacity was significantly reduced in the B-treated H animals, compared with saline-treated H animals, and indistinguishable from saline-treated NH animals. Down-regulated H animals, like NH animals, hypersecreted B following the termination of stress in comparison to the saline-treated H animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Health nurses interviewed 153 randomly selected mothers during the first month after delivery and obtained data on their pregnancies, and, by periodic visits up to four years of age, on the health, development and behaviour of their children. The object was to explore the relationships between child morbidity and a wide range of possibly noxious factors in pregnancy.
No relationship was found between the children's health and physical illness, accidents, work stresses or dental operations in the mothers. Situational stresses such as the death or severe illness of a family member, or shocks and frights, experienced by the expectant mother were also not significant. On the other hand, stresses involving severe, continuing personal tensions (in particular marital discord) were closely associated with child morbidity in the form of ill‐health, neurological dysfunction, developmental lag and behaviour disturbance. This association could not be attributed to prenatal maternal illness, to short gestation or to complications at delivery. Low socioeconomic status and adverse environment were not significantly related to child morbidity if there was no prenatal personal tension, but they were highly characteristic of the personal tension cases.
It is suggested that the effects of poverty on child development are mediated by prenatal personal tensions.
It is also suggested that continuous personal tension in pregnancy may be characteristic of population pressures, and that their morbid outcome in the children acts as a means of population control in the human race.
RÉSUMÉ
Etude longitudinale depuis la naissance sur les effets des tensions prénatales
Des infirmières de santé ont interrogé 153 mères sélectionnées au hasard sur leurs grossesses durant le premier mois après l'accouchement et au cours de visites périodiques par la suite. Elles purent obtenir des détails sur la santé, le développement et le comportement des enfants juqu'à l'âge de 4 ans. L'objet de l'étude a été d'explorer la relation entre la morbidité infantile et une grande étendue de facteurs nocifs possibles durant la grossesse. Aucune affection physique chez la mère, aucun accident, aucun accident du travail, ni intervention dentaire n'ont joué un tel rôle. Des tensions de situation telle que la mort ou une maladie grave chez un membre de la famille, un choc ou une grande frayeur, que la future mère avait dû surmonter, se montrèrent également sans influence sur la santé des enfants. Inversement, des tensions qui prennent une forme personnelle grave et continuelle—en particulier les discordes conjugales—étaient intimement associées avec la mauvaise santé des enfants, des dysfonctions neurologiques et des troubles du comportement. Cette association n'a pu être attribuée à une maladie maternelle prénatale concomitante, une pré‐maturité ou une complication de la délivrance. Le niveau socio‐économique bas et un environnement défavorable n'étaient pas reliés significativement à une morbidité infantile lorsqu'il n'y avait pas de tension personnelle prénatale chez la mère, mais étaient hautement caractéristiques des cas de tension personnelle. Il est suggéré que la pauvreté atteint le développement de l'enfant à travers ses influences néfastes sur les tensions personnelles de la mère durant la période prénatale.
Il est également suggéré (par analogie avec certaines agressions extéroceptives chez l'animal entrainant une viabilité faible et une mort foetale) que des tensions personnelles continues durant la grossesse sont caractéristiuqes de pressions de population, et que, chez les humains, leurs conséquences morbides agissent comme un moyen de contrôle de population.
ZUSAMMENFASSUNG
Auswirkungen praenataler Stressituationen: Eine Verlaufsstudie von Geburt an
153 willkürlich ausgewählte Mütter wurden während des ersten Monats nach ihrer Entbindung von Gesundheitsfürsorgerinnen über ihre Schwangerschaft befragt und durch wiederholte spätere Besuche wurden Informationen über den Gesundheitszustand, die Entwicklung und das Verhalten ihrer Kinder bis zum Alter von vier Jahren gesammelt.
Es war der Zweck dieser Studie, eine Beziehung zwischen kindlicher Morbidität und einem weiten Spektrum möglicher schädlicher Faktoren während der Schwangerschaft zu finden. Weder organische Krankheiten der Mütter, noch Unfälle, Arbeitsbelastungen, noch Zahnbehandlungen erwiesen sich als solche Faktoren. Psychische Stressituationen wie Tod oder Krankheit eines Familienmitglieds, Schock und Angst, mit denen die Schwangeren fertig wurden, hatten ebenfalls keinen Einfluß auf die kindliche Gesundheit. Jedoch waren Belastungen durch ernsthafte anhaltende persönliche Spannungen, insbesondere eheliche Konflikte eng mit dem Krankheits‐Gesundheitszustand, mit neurologischer Dysfunktion und Verhaltensstörungen der Kinder verbunden. Diese Beziehung konnte jedoch nicht auf begleitende mütterliche Krankheiten, Frühgeburtenraten oder Geburtskomplikationen bezogen werden. Niedriger sozio‐ökonomischer Status, und schlechte Umwelteinflüsse zeigten ohne gleichzeitige mütterliche Spannungen in der Schwangerschaft keine signifikante Beziehung zur kindlichen Morbidität, waren aber sehr charakteristisch für die Fälle mit persönlichen Spannungen. Es wird angenommen, daß Armut die kindliche Entwicklung beeinflußt und zwar durch ihren schlechten Einfluß auf die persönlichen Spannungen der Mutter während der Schwangerschaft.
Es wird weiterhin angenommen (analog zu bestimmten extero‐ceptiven Stressituationen bei Tieren, aus denen eine verminderte Lebensfähigkeit und Früchttod resultiert), daß fortgesetzte persönliche Spannungen während der Schwangerschaft charakteristisch hoher Bevölkerungsdichte sind und daß beim Menschen Häufigkeit und Schwere von Krankheiten als ein Mittel zur Kontrolle der Bevölkerungsdichte wirkt.
RESUMEN
Estudio continuado a partir del nacimiento de los efectos de sufrimientos pre‐natales
Enfermeras sanitarias entrevistaron a 153 madres seleccionadas al azar durante el primer mes después del parto, preguntándoles acerca de sus embarazos, y más adelante a base de visitas periódicas pudieron obtener datos sobre la salud, desarrollo y comportamiento de sus niños hasta la edad de 4 años.
El objeto del estudio fue explorar las relaciones entre la morbilidad infantil y un amplio margen de factores gestacionales posiblemente nocivos. No fueron calificados como tales las enfermedades fisicas de las madres, ni accidentes, stresses de trabajo y operaciones dentales. Stresses situacionales, tales como la muerte o enfermedad grave de un familiar, y shock y sustos que podría sufrir la gestante no tuvieron tampoco influencia en la salud de los niños. De otra parte stresses consecutivos a tensiones personales continuas (sobre todo desacuerdo marital) estaban asociades muy de cerca con la mala salud de los niños, disfunción neurológica y alteraciones en el comportamiento. Esta asociación no podría ser atribuida a enfermedad materna prenatal concomitante, prematuridad o complicaciones del parto. Un nivel socio‐económico bajo y un ambiente adverso no tenían relación significativa con la morbilidad del niño si no había al mismo tiempo tensiones personales prenatales en la madre; sin embargo eran altamente características de los casos con tensión personal. Se sugiere que la pobreza afecta al desarrollo del niño a través de su influencia adversa sobre las tensiones personales prenatales de la madre.
Se sugiere (por analogía con ciertos stresses esteroceptivos en animales que dan lugar a pobre viabilidad y muerte fetal) que las tensiones personales continuadas en la gestación son caracteristicas de presiones de la población y que en los humanos su acción mórbida actúa a la manera de un control de la población.
Female rats were subjected to stress treatments during pregnancy and the offspring were studied at several different ages. The ligands [3H]WB-4101, [3H]clonidine and [3H]dihydroalprenolol were used to measure alpha 1, alpha 2 and beta receptor binding in several brain regions. At 16 but not at 23, 40 or 60 days of age the offspring showed reduced alpha 1 and beta receptor binding in cerebral cortex whereas a previous study had shown a similarly transient elevation of norepinephrine (NE) level at 16 days of age. The 60 day-old offspring showed only a reduced alpha 2 binding which appeared to have no regional specificity. Consistent with our previous finding that in 60 day-old offspring NE levels were not significantly affected by maternal stress exposure in almost all brain regions studied, we find no effect on the ability of nerve endings to synthesise catecholamines. These data provide additional support for the proposal that prenatal stress results in permanent neurochemical changes and suggest that there may be a delayed or impaired development of the postsynaptic elements of noradrenergic neurons.
Transgenic mice that constitutively overexpressed rat insulin-like growth factor binding protein-1 (IGFBP-1) were generated to determine the effects of overexpression of IGFBP-1 on growth and development. In offspring of three of the founders that showed high levels of expression, birth weight was significantly reduced to approximately 83-92% of the weight of their nontransgenic littermates. The transgenic mice gained less weight and were approximately 3.5-8 g lighter than nontransgenic littermates at 40 days of age. The difference in body weight between transgenic and wild-type mice was most apparent around the time of weaning when transgenic mice showed a more marked growth deceleration than wild-type mice. No significant catch-up growth was apparent over the first 3 months of life. In addition, offspring of all three high-expressing founders demonstrated fasting hyperglycemia. The transgene was highly expressed in the brain, uterus, lung, kidney, and heart, but little expression was detected in the liver. The weight of the brain relative to body weight was significantly reduced in transgenic mice compared with wild-type mice, whereas the relative weight of most other organs was similar to wild-type mice. These data demonstrate that IGFBP-1 may function to inhibit IGF action in vivo and that this inhibition selectively impairs development of organs such as the brain.
Prenatal maternal stress in rats and mice can demasculinize and feminize the sexual behavior of adult male offspring. Causal mechanisms are unknown, but one attractive hypothesis is that stress activation of maternal adrenal glucocorticoid secretion is the responsible agent. To test this hypothesis, pregnant rats were exposed to a variety of substances which enhance glucocorticoid actions. These included ACTH (20 IU of a gel preparation, SC once daily), corticosterone (CORT; 7 mg/kg SC in oil, three times daily), or dexamethasone (DEX; 0.1 mg/kg, SC once daily). Controls included noninjected dams and a positive stress control group (restraint under bright lights three times daily). All treatments reduced maternal weight gain, DEX most potently. No treatment altered litter size, stillbirths, or sex ratio, but DEX reduced weight at birth, an effect still seen at postnatal day 85. DEX, CORT, and stress reduced male adrenal weight at birth, while DEX and CORT altered sexual differentiation as measured by anogenital distance. Stress impaired adult male sexual performance but not the lordosis quotient following exposure of animals to stud males. DEX affected both measures. No other treatment had any significant effect on sexual behavior. No treatment altered plasma LH levels, either basal or in response to an estrogen challenge in adult gonadectomized males. In adulthood there was no treatment effect on stress reactivity, measured behaviorally or by plasma glucocorticoids. Correlational analysis revealed that weight gain during pregnancy was the single best predictor of subsequent sexual performance. It is concluded that prenatal dexamethasone exposure demasculinizes and feminizes male offspring.(ABSTRACT TRUNCATED AT 250 WORDS)
Since 1986, prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) have been carried out in 239 pregnancies. In 145, diagnoses were made by amniocentesis, whereas 77 were diagnosed using chorionic villus sampling. A newly developed, rapid allele-specific polymerase chain reaction was used for DNA analysis in some cases. Of 239 pregnancies evaluated, 37 babies were affected with classical 21-OHD. Of these, 21 were females, 13 of whom were treated prenatally with dexamethasone. Dexamethasone administered at or before 10 weeks gestation (9 affected female fetuses) was effective in reducing virilization. Seven fetuses had affected female siblings (Prader stages 1-5); 3 of these were born with entirely normal female genitalia, whereas the other 4 were significantly less virilized (Prader stages 1-2) than their siblings. The remaining 2 newborns had male siblings; 1 was born with normal genitalia, and the other was Prader stage 1. No significant or enduring side-effects were noted in either the mothers or the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight, length, or head circumference from untreated unaffected newborns. Based on our experience, proper prenatal diagnosis and treatment of 21-OHD is effective in significantly reducing or eliminating virilization in the affected female. This spares the newborn female the consequences of genital ambiguity, i.e. genital surgery, sex misassignment, and gender confusion.
The influence of opioid receptor blockade on the developmental and behavioral effects of prenatal stress was studied. Time-mated dams were implanted with minipumps on day 17 of gestation containing vehicle (V) or naltrexone (NTX, 10 mg/kg/day). Noise and light stress was applied on an unpredictable basis, three times a week throughout gestation to half the dams. Maternal NTX completely prevented the reduction in anogenital distance in prenatally stressed (PS) males and restored the growth rate of both sexes. NTX also decreased the anxiety of PS rats in the plus-maze, increased the opioid component of exploration to control levels, but increased anxiety in control males. NTX did not restore the lower saccharin preference in PS females and decreased it in C females. This suggests that some morphological and behavioral changes induced by prenatal stress could result from excess opioid activity induced by maternal stress.
Previous research indicates that the offspring of dams exposed to stress during late gestation show altered hypothalamic-pituitary-adrenal (HPA) responses to stress. However, the results are inconsistent and a review of the literature suggests that the effects may differ depending upon the gender of the offspring. In the present study, we measured plasma adrenocorticotropin (ACTH) and corticosterone (B) levels prior to, and at 0, 20, 40 and 70 min following restraint stress in catheterized adult male and female offspring of dams stressed in the last week of gestation (i.e. days 15-19 of gestation). Prenatal stress significantly increased both plasma ACTH and B levels in response to restraint, but only in females; male offspring were largely unaffected. In addition, plasma corticosteroid-binding globulin (CBG) levels were significantly increased in prenatally-stressed females, but not in males. Despite these differences in plasma CBG, estimated free B levels following restraint were also significantly elevated in prenatally-stressed females. We then examined glucocorticoid receptor binding in a variety of forebrain structures. Prenatal stress had no effect on glucocorticoid receptor density in the hypothalamus or hippocampus in either males or females. Differences in glucocorticoid receptor density across groups were observed in the septum, frontal cortex, and amygdala. However, the pattern of observed differences across the groups was not consistent with the pattern of hormonal differences. In summary, the effect of prenatal stress on HPA function is substantially more marked in females than in males. Interestingly, a similar pattern of effects on HPA activity has been reported for prenatal alcohol exposure.
Corticotropin-releasing factor (CRF) is a neuropeptide found throughout the central nervous system that has a proposed role in modulating emotional and behavioral states, including stress and anxiety. The amygdala, which is important in the control of emotional and autonomic responses to stress, contains CRF nerve terminals, CRF cell bodies, and CRF receptors. In rats, exposure to prenatal stress results in offspring that display a hyperemotional state and increased anxiety. In this study the effects of prenatal stress on CRF release was measured in amygdala minces (1 mm3) obtained from adult (8-16 weeks of age) male offspring of dams subjected to daily saline injection (0.1 ml, s.c.) from gestational day 14 to 21. CRF release from amygdala was time- and calcium-dependent, and stimulated by KCl-induced depolarization. Depolarization-induced CRF release was significantly increased by 42% from the amygdala of prenatally stressed offspring versus controls. Prenatally stressed offspring also showed a 49% increase in CRF levels in the amygdala. The increased amounts of CRF released in response to depolarization were likely the consequence of increased tissue content of CRF, as fractional release under basal or KCl-stimulated conditions was not different in the prenatal stress group versus control. This suggests that a long-lasting up-regulation of the CRFergic neurotransmission may occur in the amygdala, which may be important in the generation of hyperemotional offspring after exposure to prenatal stress.
The glucocorticoid, corticosterone (CORT), is believed to have an important function in modulating nutrient ingestion and metabolism. Recent evidence described in this review suggests that the effects of this adrenal hormone are mediated through two steroid receptor subtypes, the type I mineralocorticoid receptor and the type II glucocorticoid receptor. These receptors, which have different affinities for CORT, respond to different levels of circulating hormone. They mediate distinct effects of the steroid, which can be distinguished by the specific nutrient ingested and by the particular period of the circadian cycle.
Under normal physiological conditions, the type I receptor is tonically activated, either by low basal levels of circulating CORT (0.5–2 μg%) normally available across the circadian cycle or possibly by the mineralocorticoid aldosterone. This type I activation is required for the maintenance of fat ingestion and fat deposition that occurs during most meals of the feeding cycle. In contrast, the type II receptor is phasically activated by moderate levels of CORT (2–10 μg%) normally reached during the circadian peak. Activation of this receptor is required for the natural surge in carbohydrate ingestion and metabolism that is essential at the onset of the active feeding cycle when the body's glycogen stores are at their nadir, and gluconeogenesis is needed to maintain blood glucose levels. This receptor is also activated during periods of increased energy requirements, such as, after exercise and food restriction, when CORT levels rise further (>10 μg%) and when its catabolic effects on fat and protein stores predominate to provide additional substrates for glucose homeostasis. These functions of CORT on fat and carbohydrate balance are mediated, in part, by type I and type II receptors located within the hypothalamic paraventricular nucleus, which is known to have key functions in controlling nutrient intake and metabolism, as well as circulating CORT levels. Moreover, the type II receptors within this nucleus, in addition to the arcuate nucleus, may interact positively with the peptide, neuropeptide Y, and the catecholamine, norepinephrine, both of which act to enhance natural carbohydrate feeding and CORT release at the onset of the natural feeding cycle.
Thus, under normal conditions, endogenous CORT has a primary function in controlling nutrient ingestion and metabolism over the natural circadian cycle, through the coordinated action of the type I and type II steroid receptor systems. Through this action, CORT has impact on total caloric intake and body weight gain over the long term. Moreover, under conditions of obesity, diabetes and food restriction, steroid receptor function is greatly disturbed in association with chronic high circulating levels of CORT and abnormal glucose homeostasis. These disturbances in steroid action, along with dysfunction in brain neurochemical processes, very possibly contribute to the maintenance of hyperphagia and body weight gain in obese and diabetic states.
Prenatal stress is considered as an early epigenetic factor able to induce long-lasting alterations in brain structures and functions. It is still unclear whether prenatal stress can induce long-lasting modifications in the hypothalamo-pituitary-adrenal axis. To test this possibility the effects of restraint stress in pregnant rats during the third week of gestation were investigated in the functional properties of the hypothalamo-pituitary-adrenal axis and hippocampal type I and type II corticosteroid receptors in the male offspring at 3, 21 and 90 days of age. Plasma corticosterone was significantly elevated in prenatally-stressed rats at 3 and 21 days after exposure to novelty. At 90 days of age, prenatally-stressed rats showed a longer duration of corticosterone secretion after exposure to novelty. No change was observed for type I and type II receptor densities 3 days after birth, but both receptor subtypes were decreased in the hippocampus of prenatally-stressed offspring at 21 and 90 days of life. These findings suggest that prenatal stress produces long term changes in the hypothalamo-pituitary-adrenal axis in the offspring.
Using in situ hybridization histochemistry, we report differential expression of corticotropin-releasing hormone (CRH) mRNA in the central nucleus of the amygdala (CEA) and the parvocellular region of the paraventricular nucleus of the hypothalamus (PVN) following systemic treatment with corticosterone (CORT) in adrenally-intact rats. Both injection of low (1 mg/kg/day) and high (5 mg/day) CORT reduced CRH mRNA expression in the PVN in a dose-dependent manner, although it returned to normal at the low dose by 14 days. By contrast, the high dose of CORT increased CRH mRNA transiently in the CEA at 4 days, although the low dose of CORT decreased it at 14 days. In a second experiment, we implanted a slowly-releasing CORT pellet for 2 weeks (200 mg, 60 day release) subcutaneously. This treatment produced an elevation of CRH mRNA in the CEA both at 1 and 2 weeks, whereas CRH mRNA in the PVN was decreased to a large extent as seen in the high CORT group of the first experiment. These results suggest that glucocorticoids can facilitate CRH mRNA expression in the CEA, a site implicated in anxiety and fear, while restraining the hypothalamic-pituitary-adrenal axis as indicated by the reduction in CRH mRNA in the PVN.
Low birthweight is associated with the subsequent development of common disorders of adult life, especially hypertension; maternal malnutrition has been suggested as the cause. We suggest an alternative aetiology—increased fetal exposure to maternal glucocorticoids. This hypothesis is supported by our findings that in rats decreased activity of the enzyme that acts as a placental barrier to maternal glucocorticoids (11 β-hydroxysteroid dehydrogenase) is associated with low birthweight. Furthermore, increased exposure of the fetus to exogenous glucocorticoids leads to low birthweight and subsequent hypertension in the offspring. Glucocorticoids acting during critical periods of prenatal development may, like other steroid hormones, exert organisational effects or imprint patterns of response that persist throughout life. Thus, the lifetime risk of common disorders may be partly determined by the intrauterine environment.
Hypertension is strongly predicted by the combination of low birthweight and a large placenta. This association could be due to increased fetal exposure to maternal glucocorticoids. Fetal protection is normally effected by placental 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which converts physiological glucocorticoids to inactive products. We found that rat placental 11 beta-OHSD activity correlated positively with term fetal weight and negatively with placental weight. Offspring of rats treated during pregnancy with dexamethasone (which is not metabolised by 11 beta-OHSD) had lower birthweights and higher blood pressure when adult than did offspring of control rats. Increased fetal glucocorticoid exposure secondary to attenuated placental 11 beta-OHSD activity may link low birthweight and high placental weight with hypertension.