Offspring Brain Research Articles

Intensity matters: brain, behaviour and the epigenome of prenatally stressed rats

There is a general consensus that prenatal stress alters offspring brain development, however, the details are often inconsistent. Hypothesising that variation to the level of stress would produce different maternal experiences; this study was designed to examine offspring outcomes following a single prenatal stress paradigm at two different intensities. Pregnant Long Evans rats received mild, high, or no-stress from gestational days 12–16. Offspring underwent early behavioural testing and global methylation patterns were analysed from brain tissue of the frontal cortex and hippocampus. The two different prenatal stress intensities produced significantly different and often, opposite effects in the developing brain. Mild prenatal stress decreased brain weight in both males and females, whereas extreme stress increased female brain weight. Mild prenatal stress slowed development of sensorimotor abilities and decreased locomotion, whereas high prenatal stress also slowed development of sensorimotor learning but increased locomotion. Finally, mild prenatal stress increased global DNA methylation levels in the frontal cortex and hippocampus whereas high prenatal stress was associated with a dramatic decrease. The data from this study provide evidence to support a dose-dependent effect of prenatal stress on multiple aspects of brain development, potentially contributing to long-term outcomes.

Gestational nicotine treatment modulates cell death/survival-related pathways in the brains of adolescent female rats

Gestational exposure to nicotine affects brain development, leading to numerous behavioural and physiological deficits in the offspring during adolescence. To analyse the molecular mechanisms underlying these effects, a pathway-focused oligonucleotide microarray was used to determine gene expression profiles in five brain regions (i.e. amygdala, prefrontal cortex, nucleus accumbens, periventricular nucleus of the hypothalamus, and caudate putamen CPu) of adolescent rats that received nicotine or saline during gestation. Following appropriate statistical and Gene Set Enrichment Analyses, 24 cell death/survival-related pathways were found to be significantly modulated by gestational nicotine. On the basis of their biological functions, these pathways can be classified into three categories: growth factor, death receptor, and kinase cascade. We employed a quantitative real-time PCR array to verify the findings by measuring the expression of 29 genes involved in cell death/survival-related pathways. Together, our findings indicate that gestational nicotine exposure has significant effects on gene expression in cell death/survival-related pathways in the brains of adolescent offspring. Such effects appear to be brain region-specific and are realized through regulation of the expression of growth factors and receptors, caspases, kinases, and transcription factors. On the basis of these findings, we offer a hypothetical model to explain how gestational nicotine exposure may affect cell death and survival in the brains of adolescent offspring by regulating the balance between growth-factor and death-receptor pathways.

Tissue‐Specific and Dose‐Related Accumulation of Arsenic in Mouse Offspring Following Maternal Consumption of Arsenic‐Contaminated Water

The developmental toxicity of arsenic is not as well characterized as other metals such as lead or mercury. Many previous animal studies have used an acute exposure paradigm, which does not model chronic, low-level human exposure. The following study administered 10, 20, 40, 80 or 100 ppm sodium arsenite in drinking water to pregnant C57BL6/J mice. Adipose, blood, brain, breastmilk in stomach, kidney and liver tissues were collected from male and female offspring on postnatal day (PND) 1 and 21 to allow for disposition comparisons between tissues, sexes and across time. The 100 ppm dose was foetotoxic. Significantly fewer female pups were born in litters exposed to 80 ppm, while significantly more male pups were born in litters exposed to 20 ppm. Total arsenic levels differed between tissues with the highest levels in the brain and kidney in PND1 offspring. Levels were higher on PND1 than PND21, and there were few sex differences. The dose-response relationships in PND1 tissues were curvilinear, but in PND21 liver and kidney tissues, arsenic levels in control animals were significantly higher than levels in exposed animals. The tissue and age-specific disposition suggests that common biomarkers such as blood and urinary arsenic are not accurate predictors of levels in sensitive organs such as the brain.

Effect of prenatal stress on expression of glutathione system in neonatal rat brain

Prenatal stress is known to adversely affect the fetal brain development and also neuronal loss. The mechanism(s) associated with prenatal stress induced developmental neurotoxicity remains obscure. Few studies point to the glutathione (GSH) antioxidant system which is an important molecular target for this toxicant. Hence the present study investigates the effect of prenatal stress on glutathione system in neonatal rat brain. Three to four months old pregnant Wistar rats were subjected to restraint stress during early or late gestational period. The offspring were sacrificed on 40th day and their brain homogenate was subjected to antioxidant studies. The serum corticosterone and adrenal ascorbic acid levels were also estimated from offspring. The prenatal stress has resulted in an increase in the serum corticosterone and reduced adrenal ascorbic acid levels in neonatal pups. Prenatal stress during early or late gestation life showed reduced glutathione, glutathione reductase (GSSG-Rd) and superoxide dismutase (SOD) activity in offspring brain homogenate. These data suggest that stress during early or late gestation period affect glutathione system in developing neonatal rat brain, which is associated with elevated serum corticosterone and reduced adrenal ascorbic acid levels.

Preconceptional alcoholic intoxication alters the distribution of metals in matured rat brain of offspring

It is known that alcohol possesses embryotoxic, teratogenic, neurotoxic and other effects. Alteration of the trace element and mineral metabolism can be one of the triggering mechanisms of metabolic changes during an alcoholic intoxication. The aim of the recent study was to compare the profiles of elements in brain structures of matured offspring which were born by female rats exposed and non-exposed to alcohol before conception. A decreasing tendency in the levels of all detected macro and trace elements in four brain structures was observed. The most prominent changes were found in the brain cortex. Experimental data show that short term consumption of alcohol by female rats before pregnancy alters the distribution of macro and trace elements in the offspring's brain structures.

Alterations of glial fibrillary acidic protein expression and neural apoptosis in brain of rat offspring born by cesarean section

To study changes of glial fibrillary acidic protein (GFAP) expression and neural apoptosis in rat hippocampus and cortex of cesarean delivered offspring. Thirty-eight pregnant SD rats were randomly allocated into 2 groups: 19 rats in vaginal delivery (VD) and 19 rats in cesarean section (CS). Forty-eight fetuses born by VD were kept intact, 40 fetuses were delivered by CS on day 21 of gestation. The fetal brain tissues were taken out on postnatal day 30 and 115, the expression profiles of GFAP in hippocampus and cortex were measured by immunohistochemical staining and western blot. Apoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. (1) The expression profiles of GFAP: on postnatal day 115, the mean number of GFAP-immunoreactive astrocytes of hippocampus 29.7 ± 10.9 in VD group was significantly lower than 36.2 ± 2.8 in CS group (P < 0.05). The average GFAP-positive cells in the cortex of frontal lobe of 23.2 ± 4.6 in VD group was significantly lower than 36.8 ± 5.9 in CS group (P < 0.01). Likewise, on postnatal day 30, the mean number of GFAP-immunoreactive astrocytes of frontal cortex of 27.8 ± 6.0 in VD group was remarkably lower than 39.4 ± 4.5 in CS group (P < 0.01). The average GFAP-positive cells in the hippocampus of 31.5 ± 3.5 in VD group were not significantly lower than 37.2 ± 7.0 in CS group (P > 0.05). The expression of GFAP was detected in hippocampus and frontal cortex by western blot, however, there was no significant different expression of GFAP between VD group and CS group. (2) Neuronal apoptosis: TUNEL staining results indicated that, on postnatal day 115, fewer apoptotic cells scattered in offspring hippocampus subregion were only shown in CS group, never in VD group. No TUNEL positive staining cells were labeled in hippocampal subregion in VD group, therefore significantly lower than that of CS group (P < 0.05). There were different influences of cesarean section on GFAP expression in hippocampus or cortex in different developmental stage of offspring. Cesarean section might increase GFAP expression in the hippocampus and frontal cortex, even trigger neuronal apoptosis of hippocampus region.

Abnormal Long-Range Neural Synchrony in a Maternal Immune Activation Animal Model of Schizophrenia

The synchrony of neural firing is believed to underlie the integration of information between and within neural networks in the brain. Abnormal synchronization of neural activity between distal brain regions has been proposed to underlie the core symptomatology in schizophrenia. This study investigated whether abnormal synchronization occurs between the medial prefrontal cortex (mPFC) and the hippocampus (HPC), two brain regions implicated in schizophrenia pathophysiology, using the maternal immune activation (MIA) animal model in rats. This neurodevelopmental model of schizophrenia is induced through a single injection of the synthetic immune system activator polyriboinosinic-polyribocytidylic acid, a synthetic analog of double-stranded RNA, a molecular pattern associated with viral infection, in pregnant rat dams. It is based on epidemiological evidence of increased risk of schizophrenia in adulthood after prenatal exposure to infection. In the present study, EEG coherence and neuronal phase-locking to underlying EEG were measured in freely moving MIA and control offspring. The MIA intervention produced significant reductions in mPFC-HPC EEG coherence that correlated with decreased prepulse inhibition of startle, a measure of sensory gating and a hallmark schizotypal behavioral measure. Furthermore, changes in the synchronization of neuronal firing to the underlying EEG were evident in the theta and low-gamma frequencies. Firing within a putative population of theta-modulated, gamma-entrained mPFC neurons was also reduced in MIA animals. Thus, MIA in rats produces a fundamental disruption in long-range neuronal synchrony in the brains of the adult offspring that models the disruption of synchrony observed in schizophrenia.

Maternal High-Fat Diet Alters Methylation and Gene Expression of Dopamine and Opioid-Related Genes

Maternal obesity during pregnancy increases the risk of obesity in the offspring. Obesity, arising from an imbalance of energy intake and expenditure, can be driven by the ingestion of palatable [high fat (HF), high sugar], energy-dense foods. Dopamine and opioid circuitry are neural substrates associated with reward that can affect animals' preference for palatable foods. Using a mouse model, the long-term effect of maternal consumption of a HF diet on dopamine and opioid gene expression within the mesocorticolimbic reward circuitry and hypothalamus of the offspring was investigated. Mice from dams fed a HF diet during pregnancy and lactation showed an increased preference for sucrose and fat. Gene expression, measured using quantitative real-time PCR, revealed a significant approximately 3- to 10-fold up-regulation of dopamine reuptake transporter (DAT) in the ventral tegmental area, nucleus accumbens, and prefrontal cortex and a down-regulation of DAT in the hypothalamus. Additionally, expression of both μ-opioid receptor (MOR) and preproenkephalin (PENK) was increased in nucleus accumbens, prefrontal cortex, and hypothalamus of mice from dams that consumed the HF diet. Epigenetic mechanisms have been associated with long-term programming of gene expression after various in utero insults. We observed global and gene-specific (DAT, MOR, and PENK) promoter DNA hypomethylation in the brains of offspring from dams that consumed the HF diet. These data demonstrate that maternal consumption of a HF diet can change the offsprings' epigenetic marks (DNA hypomethylation) in association with long-term alterations in gene expression (dopamine and opioids) and behavior (preference for palatable foods).

Maternal Overnutrition Impacts Offspring Adiposity and Brain Appetite Markers‐Modulation by Postweaning Diet

Maternal obesity has long-term consequences for the development of hypothalamic neurones involved in energy homeostasis and the metabolic profile in offspring. In the present study, we compared the effects of maternal obesity induced by longstanding high-fat diet (HFD) with milder postnatal overfeeding during suckling induced by litter size reduction. Female Sprague-Dawley rats consumed chow (C) or HFD. On postnatal day 1, litters from chow dams were adjusted to three per dam (small litter, CS) versus 12 control (normal litter, CN). Litters from HFD dams were adjusted to 12 per dam and fed HFD after weaning to induce obesity (HN). Thus, two degrees of maternal overnutrition were produced (CS and HN). To test whether postweaning diet can amplify the effects of maternal obesity, male offspring weaned onto chow or HFD were followed to 21 weeks. Maternal postnatal overnutrition (CS) and HFD-induced maternal obesity (HN) increased body weight and fat mass in offspring compared to those from control dams (CN). Significant glucose intolerance was induced by both degrees of maternal overnutrition, but only in offspring consuming HFD. HFD-induced maternal obesity (HN) was linked to increased offspring leptin, insulin, lipids, insulin resistance and hyperphagia, and was exaggerated by postweaning HFD. No effect of maternal postnatal overnutrition (CS) was seen on these parameters. Hypothalamic signal transducer and activator of transcription-3 and suppressor of cytokine signalling-3 mRNA were significantly elevated by maternal HFD (HN) in the HFD-fed offspring. The data obtained suggest that even mild maternal overnutrition (CS) led to increased adiposity, glucose intolerance and altered brain appetite regulators in offspring. A greater impact of HFD-induced maternal obesity was evident. Marked additive effects were observed when animals consumed a HFD postweaning.

Elevated corticosterone levels in stomach milk, serum, and brain of male and female offspring after maternal corticosterone treatment in the rat

Early influences such as maternal stress affect the developmental outcome of the offspring. We created an animal model of postpartum depression/stress based on giving high levels of corticosterone (CORT) to the rat dam, which resulted in behavioral and neural changes in the offspring. This study investigated whether highly elevated levels of maternal CORT during pregnancy or the postpartum result in higher levels of CORT in the stomach milk, serum, and brain of offspring. Dams received daily injections of CORT (40 mg/kg) or oil (control) either during pregnancy (gestational days 10-20) or the postpartum (Days 2-21). Pups that were exposed to high gestational maternal CORT had higher CORT levels in serum, but not in stomach milk or brain, on postnatal day (PND) 1. However, on PND7, pups that were exposed to high postpartum maternal CORT had higher CORT levels in stomach milk and brain, but not in serum. Conversely on PND18, pups that were exposed to high postpartum maternal CORT had higher CORT levels in serum, but not in brain (prefrontal cortex, hypothalamus, or hippocampus). Moreover, 24 h after weaning, there were no significant differences in serum CORT levels between the groups. Thus, CORT given to the dam during pregnancy or the postpartum results in elevated levels of CORT in the offspring, but in an age- and tissue-dependent manner. Developmental exposure to high CORT could reprogram the HPA axis and contribute to the behavioral and neural changes seen in adult offspring.

Placental BDNF/TrkB Signaling System is Modulated by Fetal Growth Disturbances in Rat and Human

The brain-derived neurotrophic factor (BDNF) has been shown to exert an important role during implantation, placental development, and fetal growth control in mice. Its expression is closely related to the nutritional status in several tissues such as in the nervous system. In a previous study, we demonstrated that maternal undernutrition (MU), during the perinatal life, modified both the BDNF and its functional receptor, the tyrosine kinase receptor B (TrkB) gene expression in the brain of growth-restricted rat offspring during sensitive developmental windows, suggesting that these early modifications may have long-lasting consequences. In the present study, we measured BDNF/TrkB mRNA and protein levels in rat placentas from mothers submitted to a 50% food restriction during gestation, and in human placentas from pregnancies with fetal growth restriction or fetal macrosomia. In the rat, two subtypes of placental TrkB receptors have been identified: the TrkB-FL and TrkB-T1 receptors. We found that MU induced intrauterine growth restriction (IUGR) of fetuses at term and decreased the placental BDNF mRNA and protein levels. Placentae from undernourished mothers exhibited an increased mRNA expression of TrkB-FL whereas both TrkB-FL and TrkB-T1 receptors proteins levels were not modified. In human IUGR placentas, both BDNF and TrkB receptor mRNA expressions were up-regulated. Finally, although neither BDNF nor TrkB mRNA levels were altered by fetal macrosomia alone, BDNF mRNA levels were decreased when macrosomia was associated with maternal type 1 diabetes. These results show that the placental BDNF/TrkB system is modulated in rats and humans during pregnancies with fetal growth perturbations and is affected by the maternal energetic status. These data suggest that this system may exert an important role for the feto-placental unit development and that it may also be implicated in the etiology of pathologies related to placental and fetal growth disturbances.

Prenatal Exposure to PFOS or PFOA Alters Motor Function in Mice in a Sex-Related Manner

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are organic surfactants widely used in various industrial and consumer applications. Due to their chemical properties, these perfluorinated compounds (PFCs) have also become persistent contaminants. The risk of possible intrauterine and lactational exposure to these chemicals poses a significant health concern for potential developmental effects. In the present study we have found that dietary exposure of mice to 0.3mg/kg of PFOS or PFOA throughout pregnancy results in different distribution pattern in the offspring brain and liver. In particular, exposure to PFOS led to four times higher accumulation of the chemical in the brains of newborn mice than PFOA. We have used a battery of behavioral tests to evaluate motor function, circadian activity, and emotion-related behavior in the exposed offspring. Exposure to PFOS resulted in decreased locomotion in a novel environment and reduced muscle strength only in male offspring. Prenatal exposure to PFOA was associated with changes in exploratory behavior in male and female offspring, as well as with increased global activity in males in their home cage. The neurobehavioral outcome of prenatal exposure to PFCs in mice is characterized by mild alterations in motor function and it appears to be sex-related.

Expression of Soluble Epoxide Hydrolase (SEH) in Brains of Female Offspring of Rats Fed High Salt During Pregnancy

SEH inactivates epoxyeicosatrienoic acids (EETs) which may function in the brain to regulate blood pressure. We have previously shown that adult female rats born to mothers fed a high‐salt (HS) diet during pregnancy exhibit a hyperresponsive pressor and tachycardic response to acute stress. Microarray analysis of mRNA from brains of these HS rats suggested that SEH expression was significantly decreased. In the present investigation we used Western blot to compare the expression of SEH protein in whole brains of HS and normal salt (NS) female rats. Relative expression of SEH protein was significantly increased in the HS rats (0.97 ± 0.06 NS vs 1.72 ± 0.32 HS, n=6). Immunohistochemistry using the ABC reaction showed that SEH staining was most prominent in the medial basal region of the hypothalamus in the area of the arcuate nucleus and in regions surrounding the subfornical organ and area postrema. Morphologically the stained cells appeared to be astrocytes. These brain areas are known to be involved in the stress response and/or control of the cardiovascular system. This raises the possibility that long‐term alteration in EETs metabolism in these areas could contribute to the altered stress responsiveness programmed by prenatal high salt. Supported by a BYU Mentored Environment Grant

Maternal iron deficiency: effects on fatty acid and eicosanoid metabolism and spatial memory in the adult guinea pig offspring

Iron deficiency is the most prevalent worldwide nutritional deficiency. Groups at risk in industrialized countries are infants and pregnant women. The goal of this study was to evaluate the long‐term consequences of maternal iron deficiency on the offspring's fatty acid and eicosanoid metabolism, behavior and spatial memory. Female guinea pigs consumed iron sufficient (IS) and iron deficient (ID) diets for 14 days before mating and throughout pregnancy and lactation. Iron restriction resulted in ID in pregnant females. On post‐natal day (PND) 9, all offspring (ID and IS) were weaned on the IS diet and at 42 days all offspring were iron replete. Locomotion was tested in pups on PND 24 and 40 and spatial memory from day 25 through 40. Pups from the ID group were significantly more active in the open‐field at both times of testing while spatial memory was comparable in both groups. On PND 42, dihomogammalinolenic 20:3(n‐6), docosapentaenoic 22:5(n‐3) and docosahexaenoic 22:6(n‐3) acid content was significantly higher in brain phospholipids of offspring born to ID dams. Prostaglandin E2 and F2α concentrations were also significantly higher in brains of offspring born to ID dams. This demonstrates that moderate iron deficiency during gestation and lactation results in alterations of brain fatty acid and eicosanoid metabolism and perturbation in behavior in adult offspring. Funded by CIHR and CRC.

Maternal thiamine restriction during lactation induces cognitive impairments and changes in glutamate and GABA concentrations in brain of rat offspring

Maternal thiamine deficiency causes changes in cellular energy metabolism that can interfere with offspring brain development. The purpose of the present study was to investigate the effects of thiamine restriction, during lactation, on offspring neurochemistry and cognitive parameters. Male young (31 days old) and adult (75 days old) rats, from control and restricted mothers, were submitted to spatial learning and memory assessment. GABAergic and glutamatergic parameters were measured in thalamus, prefrontal cortex and hippocampus by high performance liquid chromatography (HPLC). The young animals were assessed immediately after thiamine restricted period; the adults, however, underwent a recovery period of 45 days. In young rats, thiamine restriction significantly hindered body weight gain and learning speed; however, it did not affect the brain weight, GABA and glutamate parameters in any of the brain assessed areas. In adult rats the body weight gain was significantly hampered by thiamine restriction, while brain weight and spatial task were not affected. Also, in adult offspring, maternal thiamine restriction significantly decreased the glutamate and GABA contents in the three assessed brain areas and thalamus, respectively. One possible explanation for these findings is that an adjustment of the inhibitory (GABAergic) and stimulatory (glutamatergic) neuromodulation systems occurs, in order to reverse the behavioral deficits detected in young rats but not in adult ones. The present data show, for the first time, that maternal thiamine restriction during lactation induces cognitive impairments and neurochemical changes in offspring, corroborating the important role of thiamine in brain development.

Enduring consequences of maternal obesity for brain inflammation and behavior of offspring

Obesity is well characterized as a systemic inflammatory condition, and is also associated with cognitive disruption, suggesting a link between the two. We assessed whether peripheral inflammation in maternal obesity may be transferred to the offspring brain, in particular, the hippocampus, and thereby result in cognitive dysfunction. Rat dams were fed a high-saturated-fat diet (SFD), a high-trans-fat diet (TFD), or a low-fat diet (LFD) for 4 wk prior to mating, and remained on the diet throughout pregnancy and lactation. SFD/TFD exposure significantly increased body weight in both dams and pups compared to controls. Microglial activation markers were increased in the hippocampus of SFD/TFD pups at birth. At weaning and in adulthood, proinflammatory cytokine expression was strikingly increased in the periphery and hippocampus following a bacterial challenge [lipopolysaccharide (LPS)] in the SFD/TFD groups compared to controls. Microglial activation within the hippocampus was also increased basally in SFD rats, suggesting a chronic priming of the cells. Finally, there were marked changes in anxiety and spatial learning in SFD/TFD groups. These effects were all observed in adulthood, even after the pups were placed on standard chow at weaning, suggesting these outcomes were programmed early in life.

Effect of bisphenol A exposure during gestation and lactation on amino acid metabolism in the rat brain of offspring

Effect of bisphenol A exposure during gestation and lactation on amino acid metabolism in the rat brain of offspring

Mercury distribution in neonatal rat brain after intrauterine methylmercury exposure

Methylmercuric chloride (MMC) was orally administered to pregnant Wistar rats from gestational day 6 (G6) for 5 consecutive days. After delivery, the neonatal rats were decapitated and the cerebrum, cerebellum and hippocampus were excised on postnatal day (PND) 1, 7, 14, 21, 30 to determine total Hg contents and concentrations (six per stage). Both total Hg contents and concentrations in all the three regions increased as exposure dose increased and declined as postnatal time prolonged. Interestingly, differences of total Hg content between cerebrum and hippocampus at each time-point were significant ( P < 0.05). In the meantime, considering the Hg concentration, while no differences were observed before PND14 ( P < 0.05) among the three regions, Hg concentration in hippocampus was significantly higher than in cerebrum after that time period ( P < 0.05). We demonstrated that MeHg could pass through the placental and blood–brain barriers in a dose-dependent manner. Moreover, we found mercury redistribution occurred in offspring brain following the prolongation of postnatal time. The hippocampus was the major target of MeHg accumulation.

Maternal Iron Deficiency Alters Essential Fatty Acid and Eicosanoid Metabolism and Increases Locomotion in Adult Guinea Pig Offspring

Iron deficiency (ID) is the most prevalent worldwide nutritional deficiency. Groups at risk of developing ID anemia are infants and pregnant women, even in industrialized countries. Our goal in this study was to evaluate the long-term consequences of maternal ID on the offspring’s fatty acid and eicosanoid metabolism, behavior, and spatial memory. Female guinea pigs consumed iron-sufficient (IS) and –deficient (ID) diets for 14 d before mating and throughout pregnancy and lactation. Dietary iron restriction resulted in ID in pregnant females. On postnatal d 9, all offspring (ID and IS) were weaned to the IS diet and at 42 d, all offspring were iron replete. Locomotion was tested in pups on postnatal d 24 and 40 and spatial memory from d 25 to 40. Pups from the ID group were significantly more active in the open field at both times of testing, whereas spatial memory, tested in a Morris water maze, was comparable in both groups. On postnatal d 42, liver, RBC, and brain fatty acid composition were measured. Dihomogammalinolenic [20:3(n-6)], docosapentaenoic [22:5(n-3)], and docosahexaenoic [22:6(n-3)] acid contents were significantly higher in brain phospholipids of offspring born to ID dams. Prostaglandin E2 and F2α concentrations were also significantly higher in brains of offspring born to ID dams. This demonstrates that moderate ID during gestation and lactation results in alterations of brain fatty acid and eicosanoid metabolism and perturbation in behavior in adult offspring.

Prenatal Immune Challenge Is an Environmental Risk Factor for Brain and Behavior Change Relevant to Schizophrenia: Evidence from MRI in a Mouse Model

ObjectivesMaternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood.MethodWe used an established mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities.ResultsPolyI:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4th ventricle volume but did not disrupt sensorimotor gating.ConclusionsOur results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life.