Impairment In Offspring Research Articles

Environmental Enrichment Reverses Maternal Sleep Deprivation-Induced Anxiety-Like Behavior and Cognitive Impairment in CD-1 Mice.

Preclinical studies have clearly indicated that offspring of mothers who suffered sleep deprivation during pregnancy exhibit anxiety, depression-like behaviors, and cognitive deficits. The cognitive impairment induced by maternal sleep deprivation (MSD) is currently poorly treated. Growing evidence indicates that an enriched environment (EE) improves cognition function in models of Alzheimer’s disease, schizophrenia, and lipopolysaccharide. However, the effects of EE on hippocampal-dependent learning and memory, as well as synaptic plasticity markers changes induced by MSD, are unclear. In the present study, pregnant CD-1 mice were randomly divided into a control group, MSD group, and MSD+EE group. Two different living environments, including standard environment and EE, were prepared. When male and female offspring were 2 months, the open field test and elevated plus maze were used to assess anxiety-like behavior, and the Morris water maze was used to evaluate hippocampal learning and memory. Western blotting and real-time fluorescence quantitative polymerase chain reaction were used to detect the expression of brain-derived neurotrophic factor and Synaptotagmin-1 in the hippocampus of offspring. The results revealed that MSD-induced offspring showed anxiety-like behaviors and cognitive impairment, while EE alleviated anxiety-like behavior and cognitive impairment in offspring of the MSD+EE group. The cognitive impairment induced by MSD was associated with a decreased brain-derived neurotrophic factor and an increased Synaptotagmin-1, while EE increased and decreased brain-derived neurotrophic factor and Synaptotagmin-1 in the hippocampus of mice from the MSD+EE group, respectively. Taken together, we can conclude that EE has beneficial effects on MSD-induced synaptic plasticity markers changes and can alleviate anxiety-like behaviors and cognitive impairment.

Physical exercise ameliorates memory impairment in offspring of old mice.

For humans, maternal old age means the age of 35 or older at the time of childbirth. Maternal metabolism not only affects the cognitive function of the offspring, but also affects their physical and neurological development. This study aims to elucidate the effects of exercise training on spatial learning memory, neurogenesis, and apoptosis in the off-spring of old mice. Using mice, the offspring of old mothers showed impaired spatial learning memory, decreased brain-derived neurotrophic factor and postsynaptic density protein 95 levels, suppressed neurogenesis, and increased hippocampal apoptotic cell death. In contrast, the offspring of the old mothers had improved spatial learning memory, increased brain-derived neurotrophic factor and postsynaptic density protein 95 levels, increased neurogenesis, and decreased hippocampal apoptotic cell death when they received exercise training. The present results indicate that there is apparent spatial learning memory impairment among the offspring of old mothers, but by contrast, exercise can ameliorate spatial learning memory impairment. Exercise can be an effective countermeasure against memory decline in the offspring of old mothers.

In utero exposure to dietary emulsifier alters the behavioral activity in offspring

ObjectivePediatric mental health disorder is a combination of neuroinflammatory conditions with unknown etiology and currently, there are less awareness on the impacts of food additives on pediatric neuroinflammatory conditions and adolescent mental health disorders. Food additives such as dietary emulsifier (DE) (polysorbate 80, carrageenan and maltodextrin) are added to a variety of processed foods, and their consumption has increased dramatically worldwide which could be a risk factor for pediatric mental health disorders. Therefore, there is a critical need to understand the impact of maternal exposure to food additives associated pediatric mental health and the underlying mechanism.Materials and MethodsBehavioral testing such as tail flick assay, radial arm, rotarod and hot plate assay was done on the offspring from both control and DE exposed mice for the impaired motor activity, pain sensitivity and cognitive behavior. Colonic microbial composition was determined through 16sRNA pyrosequencing of fecal DNA samples from control and in utero DE‐exposed offspring. Level of pro inflammatory cytokines in the colon tissue as well as the serum sample was measured using Multianalyte cytokine assay kit from Qiagen.Summary of ResultsOur results show that in utero exposure to DE leads to decreased brain sizes and impaired motor learning in the offspring. Additionally, in utero exposure to DE leads to decreased pain sensitivity as a sign of stress in offspring. In utero exposure to DE shows on onset of cognitive impairment in offspring. In utero exposure to DE leads to an elevated M1 macrophage cytokine profile and CLGI symptoms in the gastrointestinal tract of offspring. In utero exposure to DE leads to gut dysbiosis in offspring. Among the DE‐exposed adolescents, the male offspring had significantly higher impact on these parameters compared to the DE‐exposed female offspring. In utero exposure to DE leads to imbalance in serum levels of dihydrotestosterone (DHT) and estradiol (E2) in the Offspring.ConclusionOur data suggest that maternal exposure to food additive is associated with the male biased cognitive impairment and neurobehavioral changes in the offspring. In future, we will determine the specific mechanism responsible for the sex specific alternation in offspring born to DE exposed mother to develop a preventative and therapeutic strategies.

Prenatal Isoflurane Exposure Induces Developmental Neurotoxicity in Rats: the Role of Gut Microbiota.

Fetal exposure to inhaled anesthetics, such as isoflurane, may lead to neurodevelopmental impairment in offspring. Yet, the mechanisms of prenatal isoflurane-induced developmental neurotoxicity have not been fully elucidated. Gut microbiota is a pivotal modulator of brain development and functions. While the antibiotic effect of isoflurane has been previously investigated, the relationship between prenatal isoflurane exposure and postnatal gut microbiota, brain biology, and behavior remains unknown. In the present study, we treated pregnant rats with 2% isoflurane for 4h on gestational day 14. Their offspring were tested with novel object recognition task on postnatal day 28 (P28) to assess cognition. Fecal microbiome was assessed using 16S RNA sequencing. We also analyzed hippocampal expression of brain-derived neurotrophic factor (BDNF) in P28 rat brains. To further explore the role of gut microbiota on prenatal isoflurane-induced developmental neurotoxicity, we treated rats with mixed probiotics on P14 for 14days and evaluated novel object recognition and hippocampal expression of BDNF on P28. Results indicate that prenatal exposure to isoflurane significantly decreased novel object recognition (novel object preference ratio: mean difference (MD) - 0.157; 95% confidence interval (CI) - 0.234 to - 0.080, P < 0.001) paralleled by diminished expression of hippocampal BDNF in juvenile rats. Prenatal exposure to isoflurane also significantly altered the diversity and composition of gut microbiota. Treatment with probiotics mitigated these changes in cognition (novel object preference ratio: isoflurane group vs. control group: MD - 0.177; 95% CI - 0.307 to - 0.047, P = 0.006; probiotic group vs. isoflurane group: MD 0.140; 95% CI 0.004 to 0.275, P = 0.042) and BDNF expression. Taken together, our findings suggest that gut dysbiosis may be involved in the pathogenesis of maternal isoflurane exposure-induced postnatal cognitive impairment. To determine the causal relationship between gut microbiota and cognition in prenatal anesthetic-induced developmental neurotoxicity, further studies are needed.

Maternal omega-3 fatty acid supplementation against prenatal lead exposure induced cognitive impairment in offspring mice.

Maternal lead exposure is associated with poor outcomes in fetal brain development such as cognitive dysfunction. Here, we aimed to reveal the effect and mechanism of omega-3 fatty acids in ameliorating maternal lead exposure-induced cognitive impairment in mouse offspring. The activity levels of locomotor and anxiety, memory and learning capacity, spatial working memory, and cognitive behavioral function were determined using the open field test, Morris water maze, Y-maze, and nest-building test, respectively. The protein levels of brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were measured using enzyme-linked immunosorbent assay or Western blot. The mRNA levels of BDNF, tyrosine kinase B (TrkB) and cyclic AMP response element binding protein (CREB) were measured by real-time qPCR. Malondialdehyde (MDA) and anti-oxidants, including SOD, GSH and CAT, were measured using bioassay kits. We found that supplementing omega-3 significantly improved cognitive behavioral function in offspring after prenatal lead exposure. The protein and mRNA levels of BDNF, TrkB and CREB in the prenatal lead exposure group were significantly upregulated by omega-3 supplementation. The MDA level in the prenatal lead exposure group was markedly elevated compared with the control group, which was significantly reduced by omega-3. Omega-3 restored anti-oxidants SOD, GSH and CAT to control levels after prenatal lead exposure. Omega-3 significantly upregulated Nrf2 nuclear expression and HO-1 expression after prenatal lead exposure. Overall, omega-3 supplementation significantly elevated the BDNF/TrkB/CREB pathway and restores anti-oxidants by upregulating the Nrf2/HO-1, thereby improving cognitive function in offspring after prenatal lead exposure.

Selective deficits in attentional set-shifting in mice induced by maternal immune activation with poly(I:C)

Maternal immune activation has been identified as a significant risk factor for schizophrenia. Using rodent models, past work has demonstrated various behavioral and brain impairments in offspring after immune-activating events. We applied 5 mg/kg of poly(I:C) on gestation day 9 to pregnant mouse dams, whose offspring were then stressed during puberty. We show impairments in attentional set-shifting in a T-maze, and a decreased number of parvalbumin-positive interneurons in the hippocampus as a result of peripubertal stress specifically in females.

Abstract 12467: Maternal Vaping Effects on Cerebrovascular Function in Offspring

Electronic cigarettes (E-cigs) are traditionally marketed as a safer alternative to smoking even during pregnancy. Previous studies have shown cerebrovascular dysfunction from direct chronic E-cig exposures, but little is known about the effect of indirect exposure to offspring while in utero. We hypothesize maternal vaping would induce cerebrovascular impairment in offspring, and that vaping at 30 watts would have greater effect compared to 5 watts. Female Sprague Dawley rats (N=8) were time mated, and once pregnant, the dams were randomly assigned to the following groups 1) 5 watts (N=3), 2) 30 watts (N=3), 3) and ambient air (control, N=2). Exposure (consisting of 20 puffs, 1hr/day, 5 days/week) began on gestational day 2-3 using whole-body chambers. E-liquid was 50% vegetable glycerin (VG), 50% propylene glycol (PG) and contained no nicotine or flavor. One male and female offspring per dam were studied 30-days after birth, where the middle cerebral artery (MCA) was isolated and reactivity assessed using dose response (10 -9 M to 10 -4 M) to acetylcholine (ACh), Serotonin (5-HT), L-arginine methyl ester (L-NAME), and sodium nitroprusside (SNP) via pressure myography. Maximal MCA dilation to ACh (10 -4 M) was impaired in both 5 and 30 watts compared to air (33±3% and 56±6%, respectively, p&lt;0.05), and 30-watt group was greater than 5 watt (p&lt;0.05). MCA vasoconstrictory response to 5-HT in both 5 and 30 watts were impaired compared to control (39±3% vs 52±8%, respectively, p&lt;0.05), but 5 and 30 watts were not different from each other (p=0.08). SNP was only different for 30 watts compared to control (19±7%, p&lt;0.05), and not for 5 watts (9±9%, p=0.07). Changes observed with 5 and 30 watts using L-NAME were not statistically different compared to control (7±11% vs 27±16%, respectively, p=0.15). These data show maternal vaping during pregnancy results in cerebrovascular impairment involving endothelial–dependent and –independent pathways in 1-month old offspring, and suggests that the magnitude of impairment is greater with increasing vaping wattage.

ITRAQ-based quantitative proteomic analysis of thoracic aortas from adult rats born to preeclamptic dams

BackgroundPreeclampsia and gestational hypertension can cause vascular function impairment in offspring. In our previous work, we described the protein expression profiles of umbilical artery tissues from patients with preeclampsia.MethodsTo gain insights into the mechanisms of vascular dysfunction in adult rats born to preeclamptic dams, we analyzed thoracic aorta tissues by using iTRAQ isobaric tags and 2D nano LC-MS/MS.ResultsBy using the iTRAQ method, we analyzed 1825 proteins, of which 106 showed significantly different expression in the thoracic aortic. Ingenuity pathway analysis (IPA) showed that the majority of differentially expressed proteins (DEPs) were associated with cardiovascular function. Further analysis indicated that glucose-6-phosphate dehydrogenase (G6PD), which is inhibited by miR-423-5p and activated by TP53, had the strongest effect on cardiovascular function. The expression of G6PD was upregulated in thoracic aorta tissues, as confirmed by Western blotting. The expression of two other vascular function-related proteins, cysteine- and glycine-rich protein 2 (CSRP2) and tubulin alpha-4 A (TUBA4A), was upregulated, as demonstrated by mass spectrometry (MS).ConclusionsAlthough the results require further functional validation, these data provide novel findings related to vascular function impairment in the adult offspring of preeclamptic mothers.

Gestational exposure to PM2.5 leads to cognitive dysfunction in mice offspring via promoting HMGB1-NLRP3 axis mediated hippocampal inflammation

PM2.5 is recently identified as a kind of material possessing severe biohazard. It can enter human body and exerts pathological effects on lung, eyes, and the central nervous system (CNS). Maternal exposure to PM2.5 can affect neural development and cause cognitive decline in offspring, with the underlying mechanisms unclear, however. The inflammasome monitors and responds to biological stressors, with HMGB1-NLRP3 inflammatory axis as an essential pathophysiological player outside the brain. The present work is to investigate its role in cognitive impairment induced by gestational exposure to PM2.5 in mice offspring. We found that HMGB1-NLRP3 pathway was activated in the hippocampus of mice offspring by gestational exposure to PM2.5 in a dose-dependent manner, with protein levels of HMGB1, NLRP3, and cleaved caspase-1 as approximately three times as high as those of control. And down-regulating HMGB1 during pregnancy could alleviate the resultant impairment on learning and working memory as well as hippocampal neurons, up-regulate the synapse related proteins of SYP and PSD-95 and correct the increased expression of 5-HT2A to comparable levels to control, as well as inhibiting the activation of microglia and decreasing the expression of HMGB1 and Iba1/HMGB1 double positive cells in the hippocampus of mice offspring. Meanwhile, protein levels of NLRP3, cleaved caspase-1, IL-1β and IL-18, as well as TLR4, phosphorylated NF-κB, and MAPKs, were almost down-regulated to those of control. Therefore, HMGB1 intervention inhibits the NLRP3 inflammasome mediated hippocampal inflammatory response through TLR4/MAPKs/NF-κB signaling pathway, alleviating PM2.5-induced cognitive dysfunction. Further in vitro results suggest that PM2.5 can activate microglia and HMGB1-NLRP3 inflammatory axis. Pretreatment with HMGB1 inhibitor significantly reduced the phosphorylation of MAPKs and NF-κB, and inhibited the inflammatory response mediated by NLRP3 inflammasome similarly to those in vivo. These results suggest that PM2.5 exposure promotes the inflammatory response in hippocampus mediated by HMGB1-NLRP3 inflammatory axis in microglia, resulting in cognitive dysfunction in offspring, which could be alleviated by simultaneous HMGB1 suppression. These findings provide a theoretical basis for preventing cognitive impairment in offspring caused by environmental pollution during pregnancy.

Pregnancy exposure of titanium dioxide nanoparticles causes intestinal dysbiosis and neurobehavioral impairments that are not significant postnatally but emerge in adulthood of offspring

BackgroundPregnancy exposure to titanium dioxide nanoparticles (TiO2NPs) is a vital consideration due to their inadvertent ingestion from environmental contamination. The potential health effects of TiO2NPs on the neurodevelopmental process should be seriously concerned in health risk assessment, especially for the pregnant women who are susceptible to the neurodevelopmental toxicity of nano-sized particles. However, the available evidence of neurodevelopmental toxicity of TiO2NPs remains very limited.MethodsIn the present study, the pregnant mice were intragastric administered with 150 mg/kg TiO2NPs from gestational day (GD) 8 to 21, the maternal behaviors and neurodevelopment-related indicators in offspring were all assessed at different time points after delivery. The gut microbial community in both dams and their offspring were detected by using 16S ribosomal RNA (rRNA) gene sequencing. The gut-brain axis related indicators were also determined in the offspring.ResultsThe results clearly demonstrated that exposure to TiO2NPs did not affect the maternal behaviors of pregnant mice, or cause the deficits on the developmental milestones and perturbations in the early postnatal development of offspring. Intriguingly, our data revealed that pregnancy exposure of TiO2NPs did not affect locomotor function, learning and memory ability and anxiety-like behavior in offspring at postnatal day (PD) 21, but resulted in obvious impairments on these neurobehaviors at PD49. Similar phenomena were obtained in the composition of gut microbial community, intestinal and brain pathological damage in offspring in adulthood. Moreover, the intestinal dysbiosis induced by TiO2NPs might be highly associated with the delayed appearance of neurobehavioral impairments in offspring, possibly occurring through disruption of gut-brain axis.ConclusionsThis is the first report elucidated that pregnancy exposure to TiO2NPs caused delayed appearance of neurobehavioral impairments in offspring when they reached adulthood, although these perturbations did not happen at early life after delivery. These findings will provide valuable insights about neurodevelopmental toxicity of TiO2NPs, and call for comprehensive health risk assessment of TiO2NPs on the susceptible population, such as pregnant women.Graphical abstract

Supplementation of milk polar lipids to obese dams improves neurodevelopment and cognitive function in male offspring.

Milk contains about 4% fat globules with its surface covered by polar lipids. Despite the abundant consumption of dairy products, the biological effects of dietary milk polar lipids on metabolic health have only been sparsely examined. Maternal obesity results in neurodevelopmental disorders and cognitive impairment in offspring. Considering the importance of maternal nutrition, the effects of polar lipids-enriched milk fat globule membrane (MFGM-PL) supplementation to dams during pregnancy and lactation on neurodevelopment and its long-term programming effects on offspring cognition were examined. Female Sprague-Dawley rats consumed 8-week control diet (CON) or high-fat diet (HFD) to induce obesity before mating. Then, female rats were fed CON or HFD with or without the supplementation of 400mg/kg body weight MFGM-PL during pregnancy and lactation. The offspring were fed 11-week HFD after weaning. MFGM-PL supplementation to obese dams suppressed body weight gain and hyperinsulinemia in both dams and offspring. Offspring born to obese dams displayed delayed neurological reflexes development, impaired neurogenesis before weaning, and cognitive impairment in adulthood, which were recovered by maternal MFGM-PL supplementation. Insulin resistance and aberrant brain-derived neurotrophic factor signaling were induced in the hippocampus of neonatal and adult offspring due to maternal and progeny HFD, but recovered by maternal MFGM-PL administration. This study demonstrates that maternal MFGM-PL supplementation can promote neurodevelopment and exert long-term effects against HFD-induced cognitive impairment in offspring via alleviating hippocampal insulin resistance. Hence, MFGM-PL is a promising ingredient for exerting beneficial programming effects on the brain health of offspring.

Metam sodium exposure during pregnancy and lactation in mice caused behavioral abnormalities and oxidative stress in offspring

Metam sodium (MS) is a widespread biocide with a broad-spectrum activity. Here, we addressed the behavioral impact of MS by exposing female mice to 50, 100 and 150 mg/kg of MS during both pregnancy and lactation, and evaluated the oxidative stress as a potential mechanism of MS-induced neurotoxicity. The results showed that MS affected fertility and reproduction parameters as well as some aspects of maternal behavior, especially at high doses. In offspring, MS caused a significant delay in the ontogeny of sensorimotor functions. In addition, treated mice exhibited during adulthood an increase of anxiety-like, depression-like behaviors as well as learning and memory impairment. These alterations were accompanied by an increase of the superoxide dismutase activity, and a significant decreased catalase and malondialdehyde activities in specific brain areas. The present work revealed that early exposure to MS induced sensorimotor and behavioral impairments in offspring likely associated with onset of oxidative stress.

Early Cortisol and Inflammatory Responses to Parental Cancer and Their Impact on Functional Impairment in Youth.

Purpose: Chronic stress is associated with increased risk for maladaptive psychological responses during childhood, adolescence, and young adulthood. Adults exposed to chronic stress during childhood exhibit dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity and inflammation. There are no studies examining the impact of stress on biological stress responses and functional impairment in adolescents and young adults early after the onset of a stressor. Methods: The sample consisted of 59 offspring, aged 11–25 years, 33 of parents diagnosed with cancer and 26 controls from families with no cancer or severe chronic illness in parents or siblings. Cancer patients and their families were recruited within an average of 62 days (SD = 35.9) and followed at 6 and 9 months later. Functional impairment was assessed and hair cortisol concentrations (HCC), salivary cortisol, and inflammatory markers were measured. Mixed regression analyses were conducted. Results: The stress group showed higher functional impairment (β = −5.5, 95% CI (−10.4, −0.06), p = 0.03, d= −0.40) and HCC (β = 10.5, 95% CI (−5.5, −0.50), p < 0.001, d = 1.43). However, HCC were reduced over time in the stress group (β= −0.3, 95% CI (−0.04, −0.01), p < 0.001, d = −1.08). Higher total cortisol output was associated with increased functional impairment over time (β = −3.0, 95% CI (−5.5, −0.5), p = 0.02, d = −0.60). Conclusions: Parental cancer is associated with early increase in cortisol, which was associated with increased functional impairment in offspring. Clinicians need to assess and monitor psychiatric symptoms and functioning in these offspring early on following parental cancer diagnosis.

Parental exposure to benzo(a)pyrene in the peripubertal period impacts reproductive aspects of the F1 generation in rats

Benzo(a)pyrene (BaP) is an ubiquitous environmental pollutant which can lead to adverse effects on male reproduction. However, the persistence of these changes on a multigenerational scale has not been sufficiently explored. This study evaluated if peripubertal exposure to BaP in male rats can induce reproductive impairment in offspring. Male rats received BaP at environmentally relevant doses (0, 0.1, 1, or 10 μg/kg/day) orally from post-natal (PND) 23–53. On PND 90, treated males were mated with non-treated females for obtaining the next generation (F1). The paternal exposure to BaP decreased the body weight of offspring on PND 1, 13 and 22, as well as it provoked a reduction in the relative anogenital distance of the males. This exposure also brought forward the onset of puberty, evidenced by an earlier vaginal opening and first estrous in females of the lowest dose group and by a delay in the testicular descent and preputial separation ages in males. The males presented a decrease in the daily sperm production and a disrupted sperm morphology. Furthermore, the testicular histology was altered, evidenced by a reduction in the Leydig cell numbers and in the seminiferous tubules diameter, as well as a disrupted seminiferous tubules staging. The estrous cyclicity and some fertility parameters were changed in the females, as well as alterations in the ovary and uterus histology were observed. BaP compromised several reproductive parameters of the F1 generation, suggesting that peripubertal exposure to this compound provokes permanent modifications in male germ line of F0 generation.

The mechanism of enriched environment repairing the learning and memory impairment in offspring of prenatal stress by regulating the expression of activity-regulated cytoskeletal-associated and insulin-like growth factor-2 in hippocampus

BackgroundPrenatal stress can cause neurobiological and behavioral defects in offspring; environmental factors play a crucial role in regulating the development of brain and behavioral; this study was designed to test and verify whether an enriched environment can repair learning and memory impairment in offspring rats induced by prenatal stress and to explore its mechanism involving the expression of insulin-like growth factor-2 (IGF-2) and activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus of the offspring.MethodsRats were selected to establish a chronic unpredictable mild stress (CUMS) model during pregnancy. Offspring were weaned on 21st day and housed under either standard or an enriched environment. The learning and memory ability were tested using Morris water maze and Y-maze. The expression of IGF-2 and Arc mRNA and protein were respectively measured by using RT-PCR and Western blotting.ResultsThere was an elevation in the plasma corticosterone level of rat model of maternal chronic stress during pregnancy. Maternal stress’s offspring exposed to an enriched environment could decrease their plasma corticosterone level and improve their weight. The offspring of maternal stress during pregnancy exhibited abnormalities in Morris water maze and Y-maze, which were improved in an enriched environment. The expression of IGF-2, Arc mRNA, and protein in offspring of maternal stress during pregnancy was boosted and some relationships existed between these parameters after being exposed enriched environment.ConclusionsThe learning and memory impairment in offspring of prenatal stress can be rectified by the enriched environment, the mechanism of which is related to the decreasing plasma corticosterone and increasing hippocampal IGF-2 and Arc of offspring rats following maternal chronic stress during pregnancy.

Prenatal Alcohol Exposure in Rats Diminishes Postnatal Cxcl16 Chemokine Ligand Brain Expression.

Maternal ethanol consumption during pregnancy is one of the main causes of Neurodevelopmental disorders (NDD). Prenatal alcohol exposure (PAE) produces several adverse manifestations. Even low or moderate intake has been associated with long-lasting behavioral and cognitive impairment in offspring. In this study we examined the gene expression profile in the rat nucleus accumbens using microarrays, comparing animals exposed prenatally to ethanol and controls. Microarray gene expression showed an overall downward regulatory effect of PAE. Gene cluster analysis reveals that the gene groups most affected are related to transcription regulation, transcription factors and homeobox genes. We focus on the expression of the C-X-C motif chemokine ligand 16 (Cxcl16) which was differentially expressed. There is a significant reduction in the expression of this chemokine throughout the brain under PAE conditions, evidenced here by quantitative polymerase chain reaction qPCR and immunohistochemistry. Chemokines are involved in neuroprotection and implicated in alcohol-induced brain damage and neuroinflammation in the developing central nervous system (CNS), therefore, the significance of the overall decrease in Cxcl16 expression in the brain as a consequence of PAE may reflect a reduced ability in neuroprotection against subsequent conditions, such as excitotoxic damage, inflammatory processes or even hypoxic-ischemic insult.

Prenatal stress impairs memory function in the early development of male-offspring associated with the gaba function

Prenatal stress (PS) induces cognitive deficits, abnormal behavior patterns and physical impairments in offspring, which disturbs the developmental process. GABA systems play a key role in the brain development. The developmental trajectories are less understood although PS increases the expression of GABAAR in young offspring. In the present study, we aimed to examine if the long-lasting effects on memory function and hippocampal synaptic plasticity induced by PS were associated with the GABA function throughout developmental process. Thus, a PS rat model was established by using restraint stress three 45-min periods per day from gestational day 15 until delivery. PS-exposed offspring exhibited the memory function deficits, LTP and depotentiation inhibitions in young and puberty offspring, but the disorder resolved at adult offspring. Meanwhile, the hippocampal spine density was decreased by PS in offspring. Additionally, we found that the balance of excitatory and inhibitory receptors was significantly disturbed after PS. The immunostaining of parvalbumin level was increased in the PS group. Overall, these all results suggest that the PS induces negative effects in memory and hippocampal synaptic plasticity in the early developmental stage, which could be an underlying mechanism of the disturbed GABA function.

Prenatal Pregabalin Exposure Alters Postnatal Pain Sensitivity and Some Behavioral Responses in Adult Offspring Rats.

Prenatal antiepileptic drug exposure could demonstrate both congenital malformations and behavioral impairments in offspring. This study was performed to assess the effects of prenatal exposure to pregabalin (PGB) on pain response, anxiety, motor activity and some behavior of adult offspring rats. Pregnant Wistar rats received PGB (7.5, 15 and 30 mg/kg/ip) during embryonic days 9.5- 15.5. The pain response, anxiety-like behaviors, locomotor activity, motor balance and coordination and anhedonia of adult offspring were examined by tail-flick and hot plate test, open field test, elevated plus maze (EPM), beam balance test and sucrose preference test in their 60th day of life, respectively. Prenatal exposure to PGB revealed significant dose-dependent reduction in pain sensitivity (increase in pain latency response) in the hot plate test, especially in females, while anxiety-like behavior assessed in EPM and open field significantly reduced in males. In the open field, locomotor activity reduced significantly after exposure to PGB 30 mg/kg and motor coordination decreased dose-dependently, especially in males. Anhedonia, as an indication of sucrose preference or pleasure response, was not changed. These findings suggest that prenatal PGB exposure could be associated with significant changes in pain response, anxiety, locomotor activity and coordination in adult offspring rats.

Propofol Attenuates Isoflurane-Induced Neurotoxicity and Cognitive Impairment in Fetal and Offspring Mice.

Anesthesia in pregnant rodents causes neurotoxicity in fetal and offspring rodents. However, the underlying mechanisms and targeted treatments remain largely to be determined. Isoflurane and propofol are among commonly used anesthetics. Thus, we set out to investigate whether propofol can mitigate the isoflurane-induced neurotoxicity in mice. Pregnant C57BL/6 mice at gestational day 15 (G15) were randomly assigned to 4 groups: control, isoflurane, propofol, and isoflurane plus propofol. Levels of interleukin (IL)-6 and poly-ADP ribose polymerase (PARP) fragment were measured in the brains of G15 embryos, and levels of postsynaptic density (PSD)-95 and synaptophysin were determined in the hippocampal tissues of postnatal day 31 (P31) offspring using Western blotting and immunohistochemical staining. Learning and memory functions in P31 offspring were determined using a Morris water maze test. Isoflurane anesthesia in pregnant mice at G15 significantly increased brain IL-6 (222.6% ± 36.45% vs 100.5% ± 3.43%, P < .0001) and PARP fragment (384.2% ± 50.87% vs 99.59% ± 3.25%, P < .0001) levels in fetal mice and reduced brain PSD-95 (30.76% ± 2.03% vs 100.8% ± 2.25%, P < .0001) and synaptophysin levels in cornu ammonis (CA) 1 region (57.08% ± 4.90% vs 100.6% ± 2.20%, P < .0001) and dentate gyrus (DG; 56.47% ± 3.76% vs 99.76% ± 1.09%, P < .0001) in P31 offspring. Isoflurane anesthesia also impaired cognitive function in offspring at P31. Propofol significantly mitigated isoflurane-induced increases in brain IL-6 (117.5% ± 10.37% vs 222.6% ± 36.45%, P < .0001) and PARP fragment (205.1% ± 35.99% vs 384.2% ± 50.87%, P < .0001) levels in fetal mice, as well as reductions in PSD-95 (49.79% ± 3.43% vs 30.76% ± 2.03%, P < .0001) and synaptophysin levels in CA1 region (85.57% ± 2.97% vs 57.08% ± 4.90%, P < .0001) and DG (85.05% ± 1.87% vs 56.47% ± 3.76%, P < .0001) in hippocampus of P31 offspring. Finally, propofol attenuated isoflurane-induced cognitive impairment in offspring. These findings suggest that gestational isoflurane exposure in mice induces neuroinflammation and apoptosis in embryos and causes cognitive impairment in offspring. Propofol can attenuate these isoflurane-induced detrimental effects.

1339-P: Peripheral RNA Biomarkers for Neurocognitive Impairment in the Mouse Models of Offspring from Mother with Diabetes

Diabetes during gestation negatively correlates with cognitive and behavioral functions of the child. To better understand the correlation, we aim at defining peripheral biomarkers of cognitive impairment in offspring from mother with diabetes (OMD). As the first step, we established mouse model of OMD. Six weeks old CD-1 female mice received intraperitoneal (i.p.) injection of streptozotocin (STZ) (150mg/kg). Following confirmation of diabetes 2 weeks post STZ injection, these animals were crossed with normal male to give OMD. The accelerated rotarod test was performed on OMD (n=26) and the control animals (n=30) at postnatal day 30-31. OMD shows impaired motor skill learning (p&amp;lt;0.05). From OMD and the control animals, three subtypes (T cell, B cell and monocytes) of white blood cells were sorted by using Flow cytometer for RNA sequencing. We performed both differential expression and splicing analyses. Interestingly, by comparing another mouse offspring model of fetal stress exposure, fetal alcohol spectrum disorders (FASD) model, offspring from dam received i.p. injections of 25% ethanol at 4.0 g/kg daily at embryonic day 16-17, that shows the same motor skill learning deficits, we found that common differential alternative splicing events between OMD and FASD. 13, 16, and 0 alternative splicing events are defined in T cell, B cell and monocytes respectively. In contrast, there are very few common differential gene expressions. Deep learning with those common alternative splicing biomarkers in T cell gave ∼0.8 accuracy in classification of good and poor learners. Collectively, these results demonstrate potential of the alternative splicing events as the biomarkers of cognitive impairment in OMD. Disclosure J. Sasaki: None. D. Dutta: None. K. Sugai: None. T. Sasaki: None. A. Bansal: None. S. Yamashita: None. M. Odawara: Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. M. Torii: None. K. Hashimoto-Torii: None. Funding National Institutes of Health (UH2AA026106)