Hippocampus Of Adult Offspring Research Articles

Long-term impact of maternal obesity on the gliovascular unit and ephrin signaling in the hippocampus of adult offspring.

Children born to obese mothers are at increased risk of developing mood disorders and cognitive impairment. Experimental studies have reported structural changes in the brain such as the gliovascular unit as well as activation of neuroinflammatory cells as a part of neuroinflammation processing in aged offspring of obese mothers. However, the molecular mechanisms linking maternal obesity to poor neurodevelopmental outcomes are not well established. The ephrin system plays a major role in a variety of cellular processes including cell-cell interaction, synaptic plasticity, and long-term potentiation. Therefore, in this study we determined the impact of maternal obesity in pregnancy on cortical, hippocampal development, vasculature and ephrin-A3/EphA4-signaling, in the adult offspring in mice. Maternal obesity was induced in mice by a high fat/high sugar Western type of diet (HF/HS). We collected brain tissue (prefrontal cortex and hippocampus) from 6-month-old offspring of obese and lean (control) dams. Hippocampal volume, cortical thickness, myelination of white matter, density of astrocytes and microglia in relation to their activity were analyzed using 3-D stereological quantification. mRNA expression of ephrin-A3, EphA4 andsynaptic markers were measured by qPCR in the brain tissue. Moreover, expression of gap junction protein connexin-43, lipocalin-2, and vascular CD31/Aquaporin 4 were determined in the hippocampus by immunohistochemistry. Volume of hippocampus and cortical thickness were significantly smaller, and myelination impaired, while mRNA levels of hippocampal EphA4 and post-synaptic density (PSD) 95 were significantly lower in the hippocampus in the offspring of obese dams as compared to offspring of controls. Further analysis of the hippocampal gliovascular unit indicated higher coverage of capillaries by astrocytic end-feet, expression of connexin-43 and lipocalin-2 in endothelial cells in the offspring of obese dams. In addition, offspring of obese dams demonstrated activation of microglia together with higher density of cells, while astrocyte cell density was lower. Maternal obesity affects brain size, impairs myelination, disrupts the hippocampal gliovascular unit and decreases the mRNA expression of EphA4 and PSD-95 in the hippocampus of adult offspring. These results indicate that the vasculature-glia cross-talk may be an important mediator of altered synaptic plasticity, which could be a link between maternal obesity and neurodevelopmental/neuropsychiatric disorders in the offspring.

Multi-Omics Data Integration Reveals Sex-Dependent Hippocampal Programming by Maternal High-Fat Diet during Lactation in Adult Mouse Offspring.

Early-life exposure to high-fat diets (HF) can program metabolic and cognitive alterations in adult offspring. Although the hippocampus plays a crucial role in memory and metabolic homeostasis, few studies have reported the impact of maternal HF on this structure. We assessed the effects of maternal HF during lactation on physiological, metabolic, and cognitive parameters in young adult offspring mice. To identify early-programming mechanisms in the hippocampus, we developed a multi-omics strategy in male and female offspring. Maternal HF induced a transient increased body weight at weaning, and a mild glucose intolerance only in 3-month-old male mice with no change in plasma metabolic parameters in adult male and female offspring. Behavioral alterations revealed by a Barnes maze test were observed both in 6-month-old male and female mice. The multi-omics strategy unveiled sex-specific transcriptomic and proteomic modifications in the hippocampus of adult offspring. These studies that were confirmed by regulon analysis show that, although genes whose expression was modified by maternal HF were different between sexes, the main pathways affected were similar with mitochondria and synapses as main hippocampal targets of maternal HF. The effects of maternal HF reported here may help to better characterize sex-dependent molecular pathways involved in cognitive disorders and neurodegenerative diseases.

Prenatal Zinc Supplementation Ameliorates Hippocampal Astrocytes Activation and Inflammatory Cytokines Expression Induced by Lipopolysaccharide in a Rat Model of Maternal Immune Activation.

Evidence suggests that gestational exposure to Lipopolysaccharide (LPS) results in fetal zinc deficiency and eventually neurodevelopmental abnormalities. In this study, we utilized a rat model of Maternal Immune Activation (MIA) to investigate the possible neuroprotective effects of zinc supplementation during pregnancy on hippocampal astrocytes activation as well as inflammatory cytokines expression in adult offspring. Pregnant rats received intraperitoneal injections of either LPS (0.5 mg/kg) or saline on Gestational Days (GD) 15 and 16, and orally gavaged with zinc sulfate (30 mg/kg) during pregnancy. Astrocyte density and histological assessment were evaluated in the hippocampus of adult offspring on Postnatal Days (PND) 60 to 62. Also, the mRNA levels of IL-6, TNF-α, IL-1β, NF-κB, and GFAP were measured using qPCR analysis. Prenatal exposure to LPS resulted in upregulated expression levels of IL-6, TNF-α, NF-κB, and GFAP in the hippocampus of adult pups. Moreover, the offspring from the LPS group showed an increased astrocyte density in the CA1 region with no histological alterations in CA1 and CA3 areas. However, maternal zinc supplementation ameliorated the LPS-induced inflammatory alterations. This study supports the premise that zinc supplementation during pregnancy might be an early treatment option to inhibit hippocampal inflammation induced by the maternal immune response to infectious agents. Maternal immune activation induced mild hippocampal inflammation in adult offspring.Zinc supplementation suppressed LPS-induced hippocampal inflammation in offspring.Zinc might be an early therapeutic option to inhibit neurodevelopmental impairments. Schizophrenia is a chronic and disabling psychiatric disorder, affecting an estimated one percent of the world's population. To date, the biological mechanisms underlying this mental disorder remain largely elusive, however, research has demonstrated the involvement of both genetic and environmental factors. Of environmental factors, gestational exposure to rubella, influenza, and genital-reproductive infections have gained particular interest among researchers. Based on this evidence, in the present study, we used an animal model of schizophrenia and showed the beneficial effect of zinc supplementation during pregnancy to protect against LPS-induced inflammation in the hippocampus of adult offspring. Collectively, our study provides support for the premise that early treatment might be a suitable option to prevent schizophrenia risk in progeny.

Role of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation and Subsequent Immune Challenge in the Behaviour and Microglial Cell Trajectory in Adult Offspring: A Study of the Neurodevelopmental Model of Schizophrenia.

Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1β, Tnf-α, Il-6, Arg1, Igf-1, Tgf-β and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the “two-hit” hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led to the appearance of schizophrenia-like disturbances in adult offspring. Our results revealed the deficits manifested as a diminished number of aggressive interactions, presence of depressive-like episodes, and increase of exploratory activity, as well as a dichotomy in the sensorimotor gating in the prepulse inhibition (PPI) test expressed as two behavioural phenotypes (MIAPPI-low and MIAPPI-high). Furthermore, in the offspring rats subjected to a prenatal challenge (i.e., MIA) we noticed the lack of modulation of behavioural changes after the additional acute immune stimulus (Poly I:C) in adulthood. The important finding reported in this article is that MIA affects the expression and levels of the neuron-microglia proteins in the frontal cortex and hippocampus of adult offspring. We found that the changes in the CX3CL1-CX3CR1 axis could affect microglial trajectory, including decreased hippocampal mRNA level of MhcII and elevated cortical expression of Igf-1 in the MIAPPI-high animals and/or could cause the up-regulation of an inflammatory response (Il-6, Tnf-α, iNos) after the “second hit” in both examined brain regions and, at least in part, might differentiate behavioural disturbances in adult offspring. Consequently, the future effort to identify the biological background of these interactions in the Poly I:C-induced MIA model in Sprague-Dawley rats is desirable to unequivocally clarify this issue.

Trans fat intake during pregnancy or lactation increases anxiety-like behavior and alters proinflammatory cytokines and glucocorticoid receptor levels in the hippocampus of adult offspring

Changes in dietary habits, including the increased consumption of processed foods, rich in trans fatty acids (TFA), have profound effects on offspring health in later life. Thus, this study aimed to assess the influence of maternal trans fat intake during pregnancy or lactation on anxiety behavior, as well as markers of inflammation, oxidative stress, and expression of glucocorticoid receptors (GR) of adult male offspring. Female Wistar rats were supplemented daily with soybean oil/fish oil (SO/FO) or hydrogenated vegetable fat (HVF) by oral gavage (3.0 g/kg body weight) during pregnancy or lactation. After weaning, male offspring received only standard diet. On the postnatal day 60, anxiety-like symptoms were assessed, the plasma was collected for the quantification of cytokines levels and the hippocampus removed for biochemical and molecular analysis. Our findings have evidenced that offspring from HVF-supplemented dams during pregnancy or lactation showed significantly greater levels of anxiety behavior. HVF supplementation increased plasma levels of proinflammatory cytokines and these levels were higher in the lactation period. In contrast, HVF supplementation decreased plasma levels of IL-10 in relation to SO/FO in both periods. Biochemical evaluations showed higher reactive species generation, protein carbonyl levels and catalase activity in offspring from HVF-supplemented dams during lactation. In addition, offspring from HVF-supplemented dams showed decreased GR expression in both supplemented periods. Together, these data indicate that consumption of TFA in different periods of development may increase anxiety-like behavior at least in part via alterations in proinflammatory and anti-inflammatory cytokine levels and GR expression in limbic brain regions.

Effect of Maternal Exercise on Diet-induced Redox Imbalance in Hippocampus of Adult Offspring

Physical exercise practice has been increasingly recommended in the prevention and treatment of chronic diseases, causing a positive effect from body weight/fat loss to improved cognitive function. Maternal exercise seems to induce the same positive lifelong adaptations to the offspring. We hypothesized that maternal exercise can prevent redox imbalance in adult offspring’s hippocampus exposed to a high-fat diet (HFD). Female Wistar rats were divided into three groups before and during pregnancy: (1) sedentary, (2) swimming exercise, and (3) swimming exercise with overload. On 60 days of age, the male pups were divided into standard diet or HFD for one month, yielding normal and HFD subgroups for each maternal condition. Maternal interventions did not alter gestational parameters, birth outcomes, and offspring weight gain from weaning to 90 days of age. The HFD consumption increased body fat, which was not prevented by maternal exercise. Serum glucose levels were increased by HFD, an effect that was prevented by unload maternal exercise. In the hippocampus, both maternal exercise intensities could increase antioxidant defense. Hippocampal redox homeostasis was impaired by HFD, causing increased superoxide levels, which was prevented by exercise without load, while overload caused only a reduction of the effect. In summary, the practice of swimming exercise without overload during pregnancy seems to be more beneficial when evaluated in animal model, preventing HFD induced redox imbalance and increasing antioxidant defense while overload swimming exercise during pregnancy demonstrated a negative effect on offspring submitted to HFD consumption.

Prenatal immune activation induces age-related alterations in rat offspring: Effects upon NMDA receptors and behaviors

Prenatal exposure to polyriboinosinic–polyribocytidylic acid (poly I:C) results in psychotic-like behavior in mature rat offspring as well as enduring modifications of glutamatergic excitatory synaptic transmission. However, little is known about the dynamic behavioral and glutamate N-methyl-D-aspartate (NMDA) receptor changes in rat offspring following poly I:C treatment of pregnant dams. In this study, poly I:C was administered to rats intravenously at a dose of 10 mg/kg on gestational day 9 in order to assess changes in behavior and NMDA receptors in offspring over time. Results demonstrate progressive worsening behaviors in adolescents and adults that manifest as increased anxiety, cognitive impairment, and pre-pulse inhibition deficits. Age-related alteration of NMDA receptors in the prefrontal cortex and hippocampus, either total number or distribution, were observed from weaning to adulthood. These results suggest that abnormalities of NMDA receptors occur prior to obvious schizophrenia-like behavioral manifestations. Hence, NMDA receptors may be potential therapeutic targets to prevent disease development during asymptomatic periods of schizophrenia, and may serve as targets for preventive and/or therapeutic strategies for schizophrenia. Further, PSD95, a scaffolding protein that is a component of the NMDA receptor signaling complex, is increased in the hippocampus of adult offspring, when serious behavioral abnormalities emerge. This result suggests that PSD95 may be involved in behavioral abnormalities of schizophrenia.

Activity-dependent Signaling and Epigenetic Abnormalities in Mice Exposed to Postnatal Ethanol

Postnatal ethanol exposure has been shown to cause persistent defects in hippocampal synaptic plasticity and disrupt learning and memory processes. However, the mechanisms responsible for these abnormalities are less well studied. We evaluated the influence of postnatal ethanol exposure on several signaling and epigenetic changes and on expression of the activity-regulated cytoskeletal (Arc) protein in the hippocampus of adult offspring under baseline conditions and after a Y-maze spatial memory (SP) behavior (activity). Postnatal ethanol treatment impaired pCaMKIV and pCREB in naïve mice without affecting H4K8ac, H3K14ac and H3K9me2 levels. The Y-maze increased pCaMKIV, pCREB, H4K8ac and H3K14ac levels in saline-treated mice but not in ethanol-treated mice; while H3K9me2 levels were enhanced in ethanol-exposed animals compared to saline groups. Like previous observations, ethanol not only reduced Arc expression in naïve mice but also behaviorally induced Arc expression. ChIP results suggested that reduced H3K14ac and H4K8ac in the Arc gene promoter is because of impaired CBP, and increased H3K9me2 is due to the enhanced recruitment of G9a. The CB1R antagonist and a G9a/GLP inhibitor, which were shown to rescue postnatal ethanol-triggered synaptic plasticity and learning and memory deficits, were able to prevent the negative effects of ethanol on activity-dependent signaling, epigenetics and Arc expression. Together, these findings provide a molecular mechanism involving signaling and epigenetic cascades that collectively are responsible for the neurobehavioral deficits associated with an animal model of fetal alcohol spectrum disorders (FASD).

Protective effect of astaxanthin against cognitive impairment in offspring prenatally exposed to maternal epilepsy

Objective To investigate the protective effect of prenatal astaxanthin treatment against cognitive impairment in adult offspring induced by exposure to maternal seizures in utero. Methods Female adult Sprague-Dawley rats were randomly divided into four groups: control group, astaxanthin group, kindling group and kindling+astaxanthin group. Each rat was implanted with electrodes. Those in the kindling and kindling+astaxanthin groups were kindled once a day by electrical stimulation of the amygdala. All rats were allowed to mate after one week's amygdala kindling. Rats in the kindling and kindling+astaxanthin groups continued to be treated with electrical stimulation every 48 hours from gestational day 1 to 20, and those in the astaxanthin and kindling+astaxanthin groups were injected intraperitoneally with 30 mg/(kg·d) of astaxanthin simultaneously. Naturally delivered offspring were raised till 12 weeks of age. Morris water maze test was performed to assess the cognitive function of adult offspring. Changes in the morphology of hippocampus were observed with Nissal's staining and transmission electron microscope. Expression of cyclic adenosine monophosphate response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in adult offsprings' hippocampus tissues at protein and mRNA levels were determined using Western-blotting and reverse transcription-polymerase chain reaction. Analysis of variance and LSD test were used as statistical methods. Results Morris water maze test showed that from the 3rd day to the 5th day, the kindling group had significantly longer escape latency [(36.33±7.85), (28.80±8.41), (29.50±11.72) s] than the control [(28.90±7.46), (17.59±9.12), (10.40±3.69) s] and kindling+astaxanthin groups [(28.30±5.75), (18.37±3.39), (15.23±6.63) s] (F=3.601, 9.811 and 14.226, all P<0.05). In probe trials, the kindling group had significantly fewer platform crossings as compared with the control and kindling+astaxanthin groups [(4.40±1.71) vs (7.20±1.62) and (6.50±1.84) times, F=6.586, P=0.001]. The kindling group spent dramatically less time in the target quadrant than the control and kindling+astaxanthin groups [(27.35±7.63) vs (58.29±10.48) and (40.41±7.06) s, F=25.825, P<0.001]. Nissl staining showed that hippocampal neurons of offspring in the control group were normal, but there was hippocampal damage in the kindling group and the damage was more severe than that in the kindling+astaxanthin group. Electron microscope observation showed that neurons and synapses in the hippocampal CA1 area of offspring in the control group were normal. However, obvious damage to neurons and synapses was induced in the kindling group and that was worse than the damage induced in the kindling+astaxanthin group. Expression of CREB and BDNF protein in the kindling group (0.19±0.06 and 0.32±0.04, respectively) were significantly lower than those in the control (0.81±0.11 and 0.93±0.04, respectively) and kindling+astaxanthin groups (0.60±0.07 and 0.80±0.06, respectively) (F were 34.015 and 71.074, both P<0.001). Moreover, the kindling group showed decreased expression of CREB and BDNF mRNA (0.48±0.11 and 0.43±0.08, respectively) as compared with the control (1.02±0.65 and 0.99±0.09, respectively) and kindling+astaxanthin groups (0.89±0.15 and 0.96±0.13, respectively) (F were 13.447 and 21.912, both P<0.01). Conclusion Treatment with astaxanthin could ameliorate the cognitive impairment and pathological damage in hippocampus of adult offspring induced by exposure to maternal seizures in utero through regulating the CREB-BDNF signal pathway. Key words: Pregnancy complications; Epilepsy; Xanthophylls; Oxidative stress; Rats

Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after maternal immune activation

Maternal immune activation (MIA) contributes to behavioral abnormalities relevant to schizophrenia in adult offspring, although the molecular mechanisms underlying MIA-induced behavioral changes remain unclear. Here we demonstrated that dietary intake of glucoraphanin (GF), the precursor of a natural antioxidant sulforaphane, during juvenile and adolescent stages prevented cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial prefrontal cortex (mPFC) of adult offspring after MIA. Gene set enrichment analysis by RNA sequencing showed that MIA caused abnormal expression of centrosome-related genes in the PFC and hippocampus of adult offspring, and that dietary intake of GF improved these abnormal gene expressions. Particularly, MIA increased the expression of suppressor of fermentation-induced loss of stress resistance protein 1 (Sfi1) mRNA in the PFC and hippocampus of adult offspring, and dietary intake of GF prevented the expression of Sfi1 mRNA in these regions. Interestingly, we found altered expression of SFI1 in the postmortem brains and SFI1 mRNA in hair follicle cells from patients with schizophrenia compared with controls. Overall, these data suggest that centrosome-related genes may play a role in the onset of psychosis in offspring after MIA. Therefore, dietary intake of GF-rich vegetables in high-risk psychosis subjects may prevent the transition to psychosis in young adulthood.

Glutamatergic synapse protein composition of wild-type mice is sensitive to in utero MTHFR genotype and the timing of neonatal vigabatrin exposure

The enzyme methylenetetrahydrofolate-reductase (MTHFR) is part of the homocysteine and folate metabolic pathways. In utero, Mthfr-deficient environment has been reported as a risk factor for neurodevelopmental disorders such as autism and neural tube defects. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between Mthfr deficiency and neonatal exposure to the GABA-potentiating drug vigabatrin (GVG) in mice alters anxiety, memory, and social behavior in a gender-dependent manner. In addition, a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the cerebral cortex was shown. Here we show that in utero MTHFR deficiency is sufficient to alter the levels of glutamate receptor subunits GluR1, GluR2, and NR2B in the cerebral cortex and hippocampus of adult offspring with a WT genotype. In addition, FMRP1, CAMKII α and γ, and NLG1 levels in WT offspring were vulnerable to the in utero genotype. These effects depend on brain region and the cellular compartment tested. The effect of in utero MTHFR deficiency varies with the age of neonatal GVG exposure to modify GluR1, NR2A, reelin, CAMKII α, and NLG1 levels. These changes in molecular composition of the glutamatergic synapse were associated with increased anxiety-like behavior.Complex, multifactorial disorders of the nervous system show significant association with several genetic and environmental factors. Our data exemplify the contribution of an in utero MTHFR-deficient environment and early exposure to an antiepileptic drug to the basal composition of the glutamatergic synapses. The robust effect is expected to alter synapse function and plasticity and the cortico-hippocampal circuitry.

Maternal dietary loads of alpha-tocopherol increase synapse density and glial synaptic coverage in the hippocampus of adult offspring.

An increased intake of the antioxidant α-Tocopherol (vitamin E) is recommended in complicated pregnancies, to prevent free radical damage to mother and fetus. However, the anti-PKC and antimitotic activity of α-Tocopherol raises concerns about its potential effects on brain development. Recently, we found that maternal dietary loads of α-Tocopherol through pregnancy and lactation cause developmental deficit in hippocampal synaptic plasticity in rat offspring. The defect persisted into adulthood, with behavioral alterations in hippocampus-dependent learning. Here, using the same rat model of maternal supplementation, ultrastructural morphometric studies were carried out to provide mechanistic interpretation to such a functional impairment in adult offspring by the occurrence of long-term changes in density and morphological features of hippocampal synapses. Higher density of axo-spinous synapses was found in CA1 stratum radiatum of α-Tocopherol-exposed rats compared to controls, pointing to a reduced synapse pruning. No morphometric changes were found in synaptic ultrastructural features, i.e., perimeter of axon terminals, length of synaptic specializations, extension of bouton-spine contact. Gliasynapse anatomical relationship was also affected. Heavier astrocytic coverage of synapses was observed in Tocopherol-treated offspring, notably surrounding axon terminals; moreover, the percentage of synapses contacted by astrocytic endfeet at bouton-spine interface (tripartite synapses) was increased.These findings indicate that gestational and neonatal exposure to supranutritional Tocopherol intake can result in anatomical changes of offspring hippocampus that last through adulthood. These include a surplus of axo-spinous synapses and an aberrant gliasynapse relationship, which may represent the morphological signature of previously described alterations in synaptic plasticity and hippocampus-dependent learning.

Age-Dependent Effects of Prenatal Stress on the Corticolimbic Dopaminergic System Development in the Rat Male Offspring

We have previously demonstrated that prenatal stress (PS) exerts an impairment of midbrain dopaminergic (DA) system metabolism especially after puberty, suggesting a particular sensitivity of DA development to variations in gonadal hormonal peaks. Furthermore we demonstrated that PS alters the long term androgens profile of the rat male offspring from prepubertal to adult stages. In this work we evaluated the sexual hormones activational effects on the DA system by analysing PS effects on the dopaminergic D2-like (D2R) and on the gonadal hormones receptor levels on cortical and hippocampal areas of prepubertal and adult male offspring. We further evaluated the dendritic arborization in the same areas by quantifying MAP2 immunoexpresion. Our results show that PS affected oestrogen receptor alpha (ERα) expression: mRNA er1s and ERα protein levels were decreased on prefrontal cortex and hippocampus of adult offspring. Moreover, PS reduced D2R protein levels in hippocampus of prepubertal rats. Morphological studies revealed that prepubertal PS rats presented decreased MAP2 immunoexpression in both areas suggesting that PS reduces the number of dendritic arborizations. Our findings suggest that PS exerts long-term effects on the DA system by altering the normal connectivity in the areas, and by modulating the expression of D2R and ERα in an age-related pattern. Since the developing forebrain DA system was shown to be influenced by androgen exposure, and PS was shown to disrupt perinatal testosterone surges, our results suggest that prenatal insults might be affecting the organizational role of androgens and differentially modulating their activational role on the DA development.

Chronic Prenatal Ethanol Exposure Alters Glucocorticoid Signalling in the Hippocampus of the Postnatal Guinea Pig

The present study tested the hypothesis that chronic prenatal ethanol exposure causes long-lasting changes in glucocorticoid signalling in postnatal offspring. Pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight/day), isocaloric-sucrose/pair-feeding or water throughout gestation, and maternal saliva cortisol concentration was determined 2 h after treatment at different stages of gestation. Electrically-stimulated release of glutamate and GABA, in the presence or absence of dexamethasone, as well as glucocorticoid and mineralocorticoid receptor mRNA expression, was determined in the hippocampus and prefrontal cortex of adult offspring of treated pregnant guinea pigs. Maternal saliva cortisol concentration increased throughout pregnancy, which was associated with increased foetal plasma and amniotic fluid cortisol concentration. Ethanol administration to pregnant guinea pigs increased maternal saliva cortisol concentration during early and mid-gestation. In late gestation, ethanol administration did not increase saliva cortisol concentration above that induced by pregnancy. Chronic prenatal ethanol exposure had no effect on stimulated glutamate or GABA release, but selectively prevented dexamethasone-mediated suppression of stimulated glutamate release, and decreased expression of mineralocorticoid, but not glucocorticoid, receptor mRNA in the hippocampus of adult offspring. These data indicate that maternal ethanol administration leads to excessively increased maternal cortisol concentration that can impact negatively the developing foetal brain, leading to persistent postnatal deficits in glucocorticoid regulation of glutamate signalling in the adult hippocampus.

Prenatal experience and postnatal stress modulate the adult neurosteroid and catecholaminergic stress responses

Allopregnanolone (3α-hydroxy-5α-regnan-20-one) is a neuroactive steroid recently shown to be involved in the neurochemical stress response via its positive modulation of the GABAA receptor complex. This experiment investigated the effects of postnatal stress (daily maternal separation during the first week of life) on the subsequent adult response to a stressor (10 min forced swim) in Long–Evans rats from one of three prenatal treatment groups (alcohol, pair-fed and control). Indices of stress response were allopregnanolone concentrations in plasma, cortex and hippocampus, and dopamine and norepinephrine concentrations in prefrontal cortex, nucleus accumbens and striatum. Females had higher levels of allopregnanolone than males in both plasma and brain. Prenatal alcohol exposure combined with early maternal separation stress resulted in an increase in the endogenous levels of allopregnanolone in the prefrontal cortex and hippocampus of adult offspring in response to a stressor compared to subjects without a prior history of postnatal stress ; this effect was greater in females. This increased allopregnanolone was also associated with decreased dopamine and norepinephrine levels in the prefrontal cortex. In the prenatal alcohol-exposed offspring, postnatal maternal separation blunted the increase in dopamine levels in the striatum seen in both control groups. Postnatal maternal separation increased norepinephrine levels in the nucleus accumbens regardless of prenatal experience, while in the prefrontal cortex only prenatal diet condition (pair-feeding and alcohol) resulted in lower norepinephrine levels. The results of this experiment suggest that experience, both pre- and postnatal, can have long-term consequences for the developing neurochemical responses to stressors.