Biomedical subjects

Stephen G Matthews

Publications and source records attributed to Stephen G Matthews.

At least 19 recordsLinked to original sources

PubMed2007

Foetal experience: lifelong consequences.

Modification of the foetal environment has lifelong consequences for endocrine function and behaviour. Maternal stress through activation of the hypothalamus-pituitary-adrenal axis can lead to increased anxiety levels and stress reactivity in offspring. Furthermore, these effects can pass across generations. The race is now on to understand the mechanisms involved and to find ways to prevent or reverse the effects of an "adverse" early environment in human populations.

Animals↗

PubMed2006

Repeated maternal glucocorticoid treatment affects activity and hippocampal NMDA receptor expression in juvenile guinea pigs.

The behavioural consequences of prenatal glucocorticoid exposure are not well understood, though emerging studies in humans indicate hyperactivity and altered cognitive development can occur. Further, recent reports indicate that N-methyl-d-aspartate receptors (NMDARs) may mediate the development of postnatal stress behaviours. We hypothesized that prenatal betamethasone (Beta) administration would alter behaviour and the expression of hippocampal NMDAR subunits NR1, NR2A and NR2B in juvenile guinea pig offspring. We found that repeated maternal Beta (1 mg kg(-1)) treatment on gestational days (gd) 40/41, 50/51 and 60/61 (term approximately 70 days) had no significant effect on birthweight or early growth. However, Beta produced sex-specific effects on open-field activity and hippocampal NMDAR subunit expression compared with controls. Female Beta offspring exhibited significantly increased locomotor activity while there was no effect in Beta males. Beta males exhibited a tendency for decreased anxiety-like behaviour. With respect to NMDAR subunit expression, Beta-exposed females exhibited significantly reduced NR1 mRNA in CA1/2 and CA3 subfields of the hippocampus; there were no effects in Beta males. In conclusion, repeated maternal treatment with Beta, in a similar regimen to that administered to pregnant women at risk of delivering preterm, has profound consequences on behaviour and development of crucial neurotransmitter systems in postnatal life.

Animals↗

PubMed2006

Psychological stressors as a model of maternal adversity: diurnal modulation of corticosterone responses and changes in maternal behavior.

Maternal adversity is associated with long-lasting consequences on cognitive development, behavior and physiological responses in rat offspring. Few studies have examined whether repeated maternal stress produces repeated activation of the hypothalamus-pituitary-adrenal (HPA) axis in mothers and whether it modifies maternal behavior. Here, we tested a novel model of perinatal stress using repeated exposure to "purely" psychological stressors throughout the gestation and lactation periods in rats. We first tested the diurnal influences of repeated 1-h strobe light exposure on maternal corticosterone secretion. Despite the hyporesponsiveness to stress documented in late pregnant and lactating mothers, we observed an enhanced response to strobe light in the afternoon compared to the morning in stressed mothers during lactation. Next, dams were exposed to 24-h forced foraging followed by 10-h wet bedding during the diurnal peak of corticosterone secretion. Although no corticosterone responses to forced foraging and wet bedding were observed, the combination of both stressors had a significant effect on maternal behavior. Mother-pup interactions were significantly altered during the first 8 days of lactation. Taken together, these findings suggest that lactating mothers maintain responsiveness to specific and repeated psychological stressors, in particular at the time of the diurnal peak in corticosterone secretion. Depending on the stressor applied, either neuroendocrine activation or changes in maternal behavior might be important determinants of the long-term consequences in the offspring. The combination of forced foraging, wet bedding and strobe light might represent a novel model of mild maternal adversity using "purely" psychological stressors.

Animals↗

PubMed2006

Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids.

Prenatal stress (PS) and maternal exposure to exogenous glucocorticoids can lead to permanent modification of hypothalamo-pituitary-adrenal (HPA) function and stress-related behaviour. Both of these manipulations lead to increased fetal exposure to glucocorticoids. Glucocorticoids are essential for many aspects of normal brain development, but exposure of the fetal brain to an excess of glucocorticoids can have life-long effects on neuroendocrine function. Both endogenous glucocorticoid and synthetic glucocorticoid exposure have a number of rapid effects in the fetal brain, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters HPA function in prepubertal, postpubertal and ageing offspring, in a sex-dependent manner. Prenatal stress and exogenous glucocorticoid manipulation also lead to the modification of behaviour, brain and organ morphology, as well as altered regulation of other endocrine systems. It is also becoming increasingly apparent that the timing of exposure to PS or synthetic glucocorticoids has tremendous effects on the nature of the phenotypic outcome. Permanent changes in endocrine function will ultimately impact on health in both human and animal populations.

Animals↗

PubMed2006

Effects of insulin treatment without and with recurrent hypoglycemia on hypoglycemic counterregulation and adrenal catecholamine-synthesizing enzymes in diabetic rats.

Untreated diabetic rats show impaired counterregulation against hypoglycemia. The blunted epinephrine responses are associated with reduced adrenomedullary tyrosine hydroxylase (TH) mRNA levels. Recurrent hypoglycemia further impairs epinephrine counterregulation and is also associated with reduced phenylethanolamine N-methyltransferase mRNA. This study investigated the adaptations underlying impaired counterregulation in insulin-treated diabetic rats, a more clinically relevant model. We studied the effects of insulin treatment on counterregulatory hormones and adrenal catecholamine-synthesizing enzymes and adaptations after recurrent hypoglycemia. Groups included: normal; diabetic, insulin-treated for 3 wk (DI); and insulin-treated diabetic exposed to seven episodes (over 4 d) of hyperinsulinemic-hypoglycemia (DI-hypo) or hyperinsulinemic-hyperglycemia (DI-hyper). DI-hyper rats differentiated the effects of hyperinsulinemia from those of hypoglycemia. On d 5, rats from all groups were assessed for adrenal catecholamine-synthesizing enzyme levels or underwent hypoglycemic clamps to examine counterregulatory responses. Despite insulin treatment, fasting corticosterone levels remained increased, and corticosterone responses to hypoglycemia were impaired in DI rats. However, glucagon, epinephrine, norepinephrine, and ACTH counterregulatory defects were prevented. Recurrent hypoglycemia in DI-hypo rats blunted corticosterone but, surprisingly, not epinephrine responses. Norepinephrine and ACTH responses also were not impaired, whereas glucagon counterregulation was reduced due to repeated hyperinsulinemia. Insulin treatment prevented decreases in basal TH protein and increased PNMT and dopamine beta-hydroxylase protein. DI-hypo rats showed increases in TH, PNMT, and dopamine beta-hydroxylase. We conclude that insulin treatment of diabetic rats protects against most counterregulatory defects but not elevated fasting corticosterone and decreased corticosterone counterregulation. Protection against epinephrine defects, both without and with antecedent hypoglycemia, is associated with enhancement of adrenal catecholamine-synthesizing enzyme levels.

Adrenal Glands↗

PubMed2005

Short periods of prenatal stress affect growth, behaviour and hypothalamo-pituitary-adrenal axis activity in male guinea pig offspring.

Prenatal stress can have profound long-term influences on physiological function throughout the course of life. We hypothesized that focused periods of moderate prenatal stress at discrete time points in late gestation have differential effects on hypothalamo-pituitary-adrenal (HPA) axis function in adult guinea pig offspring, and that changes in HPA axis function will be associated with modification of anxiety-related behaviour. Pregnant guinea pigs were exposed to a strobe light for 2 h on gestational days (GD) 50, 51, 52 (PS50) or 60, 61, 62 (PS60) (gestation length approximately 70 days). A control group was left undisturbed throughout pregnancy. Behaviour was assessed in male offspring on postnatal day (PND)25 and PND70 by measurement of ambulatory activity and thigmotaxis (wall-seeking behaviour) in a novel open field environment. Subsequent to behavioural testing, male offspring were cannulated (PND75) to evaluate basal and activated HPA axis function. Body weight was significantly decreased in adult PS50 and PS60 offspring and this effect was apparent soon after weaning. The brain-to-body-weight ratio was significantly increased in adult PS50 males. Basal plasma cortisol levels were elevated in PS50 male offspring throughout the 24 h sampling period compared with controls. In response to an ACTH challenge and to exposure to an acute stressor, PS60 male offspring exhibited elevated plasma cortisol responses. Plasma testosterone concentrations were strikingly decreased in PS50 offspring. Thigmotaxis in the novel environment was increased in PS50 male offspring at PND25 and PND70, suggesting increased anxiety in these animals. In conclusion, prenatal stress during critical windows of neuroendocrine development programs growth, HPA axis function, and stress-related behaviour in adult male guinea pig offspring. Further, the nature of the effect is dependant on the timing of the maternal stress during pregnancy.

Animals↗

PubMed2005

Multidrug resistance phosphoglycoprotein (ABCB1) in the mouse placenta: fetal protection.

The multidrug resistance phosphoglycoprotein ATP-binding cassette subfamily B (ABCB1) actively extrudes a range of structurally and functionally diverse xenobiotics as well as glucocorticoids. ABCB1 is present in many cancer cell types as well as in normal tissues. Although it has been localized within the mouse placenta, virtually nothing is known about its regulation. In the mouse, two genes, Abcb1a and Abcb1b, encode ABCB1. We hypothesized that there are changes in placental Abcb1a and Abcb1b gene expression and ABCB1 protein levels during pregnancy. Using in situ hybridization, we demonstrated that Abcb1b mRNA is the predominant placental isoform and that there are profound gestational changes in the expression of both Abcb1a and Abcb1b mRNA. Placentas from pregnant mice were analyzed between Embryonic Days (E) 9.5 and 19 (term approximately 19.5d). Abcb1b mRNA was detected in invading trophoblast cells by E9.5, peaked within the placental labyrinth at E12.5, and then progressively decreased toward term (P < 0.0001). Abcb1a mRNA, although lower than that of Abcb1b at midgestation, paralleled changes in Abcb1b mRNA. Changes in Abcb1 mRNA were reflected by a significant decrease in ABCB1 protein (P < 0.05). A strong correlation existed between placental Abcb1b mRNA and maternal progesterone concentrations, indicating a potential role of progesterone in regulation of placental Abcb1b mRNA. In conclusion, there are dramatic decreases in Abcb1a and Abcb1b mRNA and in ABCB1 at the maternal-fetal interface over the second half of gestation, suggesting that the fetus may become increasingly susceptible to the influences of xenobiotics and natural steroids in the maternal circulation.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2005

Maternal nutrient deprivation induces sex-specific changes in thyroid hormone receptor and deiodinase expression in the fetal guinea pig brain.

Thyroid hormone deprivation during fetal life has been implicated in neurodevelopmental morbidity. In humans, poor growth in utero is also associated with fetal hypothyroxinaemia. In guinea pigs, a short period (48 h) of maternal nutrient deprivation at gestational day (gd) 50 results in fetuses with hypothyroxinaemia and increased brain/body weight ratios. Thyroid hormone action is mediated by nuclear thyroid hormone receptors (TRs) and is dependent upon the prereceptor regulation of supply of triiodothyronine (T3) by deiodinase enzymes. Examination of fetal guinea pig brains using in situ hybridization demonstrated widespread expression of mRNAs encoding TRalpha1, alpha2 and beta1, with regional colocalization of deiodinase type 2 (D2) mRNA in the developing forebrain, limbic structures, brainstem and cerebellum at gd52. With maternal nutrient deprivation, TRalpha1 and beta1 mRNA expression was significantly increased in the male, but decreased in the female fetal hippocampus and cerebellum and other areas showing high TR expression under euthyroid conditions. Maternal nutrient deprivation resulted in elevated D2 mRNA expression in males and females. Deiodinase type 3 (D3) mRNA expression was confined to the shell of the nucleus accumbens, the posterior amygdalohippocampal area, brainstem and cerebellum, and did not change with maternal nutrient deprivation. In conclusion, maternal nutrient deprivation resulted in sex-specific changes in TR mRNA expression and a generalized increase in D2 mRNAs within the fetal brain. These changes may represent a protective mechanism to maintain appropriate thyroid hormone action in the face of fetal hypothyroxinaemia in order to optimize brain development.

Animals↗

PubMed2005

Hyperglycemia does not increase basal hypothalamo-pituitary-adrenal activity in diabetes but it does impair the HPA response to insulin-induced hypoglycemia.

Recently, we established that hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulin-induced hypoglycemia were impaired in uncontrolled streptozotocin (STZ)-diabetic (65 mg/kg) rats and insulin treatment restored most of these responses. In the current study, we used phloridzin to determine whether the restoration of blood glucose alone was sufficient to normalize HPA function in diabetes. Normal, diabetic, insulin-treated, and phloridzin-treated diabetic rats were either killed after 8 days or subjected to a hypoglycemic (40 mg/dl) glucose clamp. Basal: Elevated basal ACTH and corticosterone in STZ rats were normalized with insulin but not phloridzin. Increases in hypothalamic corticotrophin-releasing hormone (CRH) and inhibitory hippocampal mineralocorticoid receptor (MR) mRNA with STZ diabetes were not restored with either insulin or phloridzin treatments. Hypoglycemia: In response to hypoglycemia, rises in plasma ACTH and corticosterone were significantly lower in diabetic rats compared with controls. Insulin and phloridzin restored both ACTH and corticosterone responses in diabetic animals. Hypothalamic CRH mRNA and pituitary pro-opiomelanocortin mRNA expression increased following 2 h of hypoglycemia in normal, insulin-treated, and phloridzin-treated diabetic rats but not in untreated diabetic rats. Arginine vasopressin mRNA was unaltered by hypoglycemia in all groups. Interestingly, hypoglycemia decreased hippocampal MR mRNA in control, insulin-, and phloridzin-treated diabetic rats but not uncontrolled diabetic rats, whereas glucocorticoid receptor mRNA was not altered by hypoglycemia. In conclusion, despite elevated basal HPA activity, HPA responses to hypoglycemia were markedly reduced in uncontrolled diabetes. We speculate that defects in the CRH response may be related to a defective MR response. It is intriguing that phloridzin did not restore basal HPA activity but it restored the HPA response to hypoglycemia, suggesting that defects in basal HPA function in diabetes are due to insulin deficiency, but impaired responsiveness to hypoglycemia appears to stem from chronic hyperglycemia.

Animals↗

PubMed2005

Maternal adversity, glucocorticoids and programming of neuroendocrine function and behaviour.

The fetus may be exposed to increased endogenous glucocorticoid or synthetic glucocorticoid in late gestation. Approximately 7% of pregnant women in Europe and North America are treated with synthetic glucocorticoid to promote lung maturation in fetuses at risk of preterm delivery. Very little is known about the mechanisms by which synthetic glucocorticoid or prenatal stress influence neurodevelopment in the human, or whether specific time windows of increased sensitivity exist. Glucocorticoids are essential for many aspects of normal brain development, but exposure of the fetal brain to excess glucocorticoid can have life-long effects on neuroendocrine function and behaviour. Both endogenous glucocorticoid and synthetic glucocorticoid exposure have a number of rapid effects in the fetal brain, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters hypothalamo-pituitary-adrenal (HPA) function in prepubertal, postpubertal and aging offspring, in a sex-dependent manner. Prenatal glucocorticoid manipulation also leads to modification of behaviour, brain and organ morphology, as well as altered regulation of other endocrine systems. Permanent changes in endocrine function will impact on health, since elevated cumulative exposure to endogenous glucocorticoid is linked to the premature onset of pathologies associated with aging.

Animals↗

PubMed2005

Changes in basal hypothalamo-pituitary-adrenal activity during exercise training are centrally mediated.

The effects of exercise training on hypothalamo-pituitary-adrenal (HPA) function are unclear. We investigated whether pituitary-adrenal adaptation during exercise training is mediated by changes in neuropeptide and corticosteroid receptor gene expression in the brain and pituitary. Sprague-Dawley rats were subject to either daily swimming (DS) or sham exercise (SE) for 45 min/day, 5 days/week, for 2 (2W), 4 (4W), or 6 wk (6W) (n = 7-10/group). Corticosterone (Cort) and catecholamine responses during swimming were robust at 6W compared with 2W and 4W, indicating that HPA response to exercise during training is not attenuated when absolute intensity is progressively increased. In DS, basal (morning) plasma ACTH and Cort levels increased from 2W to 4W but plateaued at 6W, whereas in SE, they increased from 4W to 6W, with 6W values higher than in DS. In DS, there was a transient decrease in glucocorticoid receptor (GR) mRNA in the paraventricular nucleus (PVN) and pituitary and a transient increase in corticotrophin-releasing hormone (CRH) mRNA. In contrast, hippocampal mineralocorticoid receptor mRNA and PVN GR mRNA decreased from 4W to 6W in SE, with 6W values lower than in DS. These findings suggest that exercise training prevents an elevation in basal pituitary-adrenal activity potentially via transient alterations in the gene transcription of PVN and pituitary GR as well as CRH to suppress central drive to the HPA axis. In contrast, the increase in basal pituitary-adrenal activity with repeated sham exercise appears to be associated with decreases in hippocampal MR and PVN GR mRNA expression.

Adrenocorticotropic Hormone↗

PubMed2004

Insulin alone increases hypothalamo-pituitary-adrenal activity, and diabetes lowers peak stress responses.

Diabetes is associated with increased basal hypothalamo-pituitary-adrenal (HPA) activity and impaired stress responsiveness. Previously, we demonstrated that the HPA response to hypoglycemia is significantly impaired in diabetic rats. In this study our goals were to 1) differentiate between the effects of hyperinsulinemia and those of hypoglycemia per se, and 2) establish whether diabetes lowers peak stress responses. Normal and streptozotocin-diabetic rats were subjected to hyperinsulinemic-euglycemic glucose clamps to evaluate central and peripheral responses. These were compared with peak ACTH and corticosterone responses to restraint and hypoglycemia. Hyperinsulinemia increased CRH and vasopressin mRNA, and plasma ACTH and corticosterone in normal and diabetic rats. In normal animals, insulin-induced activation of ACTH and corticosterone was lower than the responses during either restraint or hypoglycemia. In contrast, ACTH and corticosterone activation in diabetic rats was similar with all three stressors. Pituitary-adrenal axis activation in diabetic animals was also much lower compared with that in normal controls. The response to hyperinsulinemia (euglycemia) was associated with increases in glucocorticoid receptor mRNA in the anterior pituitary and paraventricular nucleus. Hippocampal mineralocorticoid receptor mRNA expression was increased in normal, but not in diabetic, animals. We speculate that the ability to appropriately match the HPA response to the potency of a stressor is related to the ability to alter hippocampal mineralocorticoid receptor expression. In diabetes, this ability is impaired; hence, maximal HPA activation is greatly diminished. This is a novel observation that may have important implications in the treatment of impaired counterregulatory mechanisms in human diabetes.

Adrenal Cortex Hormones↗

PubMed2004

Effects of diabetes and recurrent hypoglycemia on the regulation of the sympathoadrenal system and hypothalamo-pituitary-adrenal axis.

Epinephrine, norepinephrine, and corticosterone responses to hypoglycemia are impaired in diabetic rats. Recurrent hypoglycemia further diminishes epinephrine responses. This study examined the sympathoadrenal system and hypothalamo-pituitary-adrenal axis for molecular adaptations underlying these defects. Groups were normal (N) and diabetic (D) rats and diabetic rats exposed to 4 days of 2 episodes/day of hyperinsulinemic hypoglycemia (D-hypo) or hyperinsulinemic hyperglycemia (D-hyper). D-hypo and D-hyper rats differentiated effects of hypoglycemia and hyperinsulinemia. Adrenal tyrosine hydroxylase (TH) mRNA was reduced (P < 0.05 vs. N) 25% in all diabetic groups. Remarkably, mRNA for phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine, was reduced (P < 0.05 vs. all) 40% only in D-hypo rats. Paradoxically, dopamine beta-hydroxylase mRNA was elevated (P < 0.05 vs. D, D-hyper) in D-hypo rats. Hippocampal mineralocorticoid receptor (MR) mRNA was increased (P < 0.05 vs. N) in all diabetic groups. Hippocampal glucocorticoid receptor (GR), hypothalamic paraventricular nucleus (PVN) GR and corticotropin-releasing hormone (CRH), and pituitary GR and proopiomelanocortin (POMC) mRNA levels did not differ. We conclude that blunted corticosterone responses to hypoglycemia in diabetic rats are not due to altered basal expression of GR, CRH, and POMC in the hippocampus, PVN, and pituitary. The corticosterone defect also does not appear to be due to increased hippocampal MR, since we have reported normalized corticosterone responses in D-hypo and D-hyper rats. Furthermore, impaired epinephrine counterregulation in diabetes is associated with reduced adrenal TH mRNA, whereas the additional epinephrine defect after recurrent hypoglycemia is associated with decreases in both TH and PNMT mRNA.

Adrenal Glands↗

PubMed2004

Prenatal glucocorticoid exposure alters hypothalamic-pituitary-adrenal function and blood pressure in mature male guinea pigs.

Pregnant guinea pigs were treated with dexamethasone (1 mg kg(-1)) or vehicle on days 40-41, 50-51 and 60-61 of gestation, after which animals delivered normally. Adult male offspring were catheterized at 145 days of age and subjected to tests of hypothalamic-pituitary-adrenal (HPA) axis function in basal and activated states. Animals exposed to dexamethasone in utero (mat-dex) exhibited increased hippocampus-to-brain weight ratio, increased adrenal-to-body weight ratio and increased mean arterial pressure. There were no effects on gestation length, birth weight and postnatal growth. There were no overall differences in diurnal plasma adrenocorticotropic hormone (ACTH) and cortisol profiles, though there were subtle differences during the subjective afternoon between control and mat-dex offspring. A significant decrease in initial ACTH suppression was observed following dexamethasone injection in mat-dex offspring compared to control offspring. Molecular analysis revealed significantly increased MR mRNA expression in the limbic system and particularly in the dentate gyrus in mat-dex offspring. In the anterior pituitary, both pro-opiomelanocortin (POMC) and glucocorticoid receptor (GR) mRNA levels were significantly elevated in mat-dex offspring. In conclusion, (1) repeated prenatal treatment with synthetic glucocorticoid (sGC) permanently programmes organ growth, blood pressure and HPA regulation in mature male offspring and these changes involve modification of corticosteroid receptor expression in the brain and pituitary; (2) the effects of prenatal sGC exposure on HPA function appear to change as a function of age, indicating the importance of investigating HPA and cardiovascular outcome at multiple time points throughout life.

Adrenal Cortex↗

PubMed2004

Glucocorticoids do not alter developmental expression of hippocampal or pituitary steroid receptor coactivator-1 and -2 in the late gestation fetal guinea pig.

Steroid receptor coactivator (SRC) proteins interact with glucocorticoid receptors in a ligand-dependent manner to enhance transcription. Although glucocorticoids are essential for normal brain maturation, little is known about the presence or regulation of SRC proteins in the developing central nervous system. In the current study we demonstrated that SRC-1 was highly expressed in the fetal limbic system (hippocampal CA3>CA1/2>CA4>dentate gyrus) at gestational d (gd) 40 (term, approximately 70 d), whereas SRC-2 was undetectable at all time points. Hippocampal SRC-1 mRNA and protein expression were reduced in male and female fetuses with advancing gestation. In contrast, SRC-1 mRNA levels increased significantly in the dentate gyrus near term. Repeated maternal injection (1 or 10 mg/kg on gd 40, 41, 50, 51, 60, and 61) with synthetic glucocorticoid had no effect on fetal limbic SRC-1 expression at gd 62 in either sex. SRC-1 and SRC-2 mRNA expression in the anterior pituitary did not change over the second half of gestation and was unaffected by prenatal exposure to synthetic glucocorticoid. In conclusion, SRC-1 expression undergoes spatial, temporal, and region-specific regulation during development, and limbic and pituitary SRC-1 and SRC-2 are not regulated by glucocorticoids in late gestation. Developmental changes in limbic SRC-1 expression probably have important consequences on steroid receptor signaling, which is known to be critical for brain maturation in late gestation.

Animals↗

PubMed2004

Regulation of N-methyl-D-aspartate receptor subunit expression in the fetal guinea pig brain.

N-methyl-d-aspartate receptors (NMDARs) are critical for neuronal maturation and synaptic formation as well as for the onset of long-term potentiation, a process critical to learning and memory in postnatal life. In the current study, we demonstrated that NMDAR subunits undergo spatial, temporal, and sex-specific regulation. During development, we observed increasing NR1 and NR2A expression at the same time as levels of NR2B subunits decreased in the hippocampus and cortex in the fetal guinea pig. We have also shown that glucocorticoids can modulate fetal NMDAR subunit expression in a sex-specific fashion. This is clinically important because synthetic glucocorticoids are administered to pregnant women at risk of preterm labor. Repeated exposure to exogenous glucocorticoids caused a dose-dependent decrease in NR1 mRNA levels and increased NR2A mRNA expression in the female hippocampus at Gestational Day 62. There are significant changes in NMDAR subunit expression in late gestation. It is possible that these alter NMDA-dependent signaling at this time. Prenatal exposure to exogenous glucocorticoids modifies the trajectory of NMDAR subunit expression in females but not in males.

Animals↗

PubMed2004

Developmental regulation of 5-HT1A receptor mRNA in the fetal limbic system: response to antenatal glucocorticoid.

The developmental changes in 5-HT1A receptor mRNA expression associated with advancing gestational age were examined in the fetal guinea pig hippocampus and dentate gyrus (DG) by in situ hybridization. We found that 5-HT1A receptor mRNA was present in the hippocampal CA1 subfield and dentate gyrus (DG), and was significantly (P < 0.05) elevated in the DG during the period of rapid brain growth [gestational day (gd) 50; term = 70 days]. Glucocorticoids have been shown to alter 5-HT1A receptor mRNA expression in the adult, but nothing is known about their impact on the developing fetal brain. Expression of 5-HT1A receptor mRNA in the fetal hippocampus was measured following repeated maternal administration (gd40, 41, 50, 51, 60 and 61) of synthetic glucocorticoid (dexamethasone; 1 and 10 mg/kg). Levels of 5-HT1A receptor mRNA were significantly (P < 0.005) elevated in CA1 and DG following repeated exposure to high-dose glucocorticoid (10 mg/kg) in male, but not in female fetuses. Because fetal exposure to glucocorticoids programs hypothalamo-pituitary-adrenal (HPA) function, and hippocampal serotonin is known to influence glucocorticoid receptor (GR) expression, the glucocorticoid-mediated changes in 5-HT1A receptor mRNA may play a role in the programming of HPA function.

Analysis of Variance↗

PubMed2004

Developmental regulation of the 5-HT7 serotonin receptor and transcription factor NGFI-A in the fetal guinea-pig limbic system: influence of GCs.

Fetal exposure to excess glucocorticoids (GCs) programs the developing hypothalamo-pituitary-adrenal (HPA) axis, and may predispose offspring to adult-onset disease. During development, serotonin (5-HT) influences transcription of hippocampal GR mRNA via the 5-HT7 receptor. The effect of 5-HT on GR involves the transcription factor NGFI-A. Given the developmental changes which we have previously reported in hippocampal GR mRNA expression, we hypothesized that (1) there are progressive developmental changes in 5-HT7 receptor and NGFI-A mRNA expression in the fetal guinea-pig limbic system, and (2) repeated exposure to synthetic GC treatment will significantly modify developmental expression of these genes. 5-HT7 receptor mRNA was highly expressed in the hippocampus and thalamus at gestational day (gd) 40 (term approximately 70 days), and significantly decreased (P < 0.05) with advancing gestation. Conversely, NGFI-A mRNA expression in the hippocampus and frontal cortex was almost undetectable at gd40, but was dramatically elevated (P < 0.05; 8-fold) near term. Changes in mRNA were refelected by NGFI-A protein levels. These changes were significantly correlated to hippocampal GR expression and fetal plasma cortisol concentrations. Synthetic GC treatment increased NGFI-A mRNA levels in CA1 and the cingulate cortex, but had no effect on 5-HT7 receptor expression. In conclusion our results suggest that (1) limbic 5-HT7 receptor expression is not directly linked to maturation of hippocampal GR in late gestation; (2) the up-regulation of NGFI-A expression near term is driven by glucocorticoid; and (3) premature exposure to synthetic glucocorticoid significantly increases NGFI-A-related transcriptional activity in the fetal limbic system.

Animals↗