Stress In Adult Offspring Research Articles

Microglia are necessary for probiotics supplementation to improve impaired fear extinction caused by pregnancy stress in adult offspring of rats

The prevention and treatment of fear-related disorders in offspring affected by pregnancy stress remains challenging at clinic. Here, we examined the effects of gut microbiota of stressed pregnant rats on the fear extinction of their offsprings, and the potential mechanisms. We found that gut microbiota transplantation from rats with pregnancy stress to normal pregnant rats impaired fear extinction, induced microglial activation and synaptic phagocytosis, increased synapse loss in offsprings. Probiotics supplement during pregnancy stress partly normalized pregnancy stress-induced gut microbiota dysbiosis of pregnant rats, and promoted fear memory extinction, inhibited fear memory reappearance, and limited microglial activation and synaptic phagocytosis in offsprings. These data revealed that gut microbiota of stressed pregnant mother improved the development of fear-related disorders of offspring, which may be associated with microglial synaptic pruning.

Maternal chewing alleviates prenatal stress-related neuroinflammation mediated by microglia in the hippocampus of the mouse offspring.

Prenatal stress affects the hippocampal structure and function in pups. Maternal chewing ameliorates hippocampus-dependent cognitive impairments induced by prenatal stress. In this study, we investigated hippocampal microglia-mediated neuroinflammation in pups of dams exposed to prenatal stress with or without chewing during gestation. Pregnant mice were randomly assigned to control, stress, and stress/chewing groups. Stress and stress/chewing animals were subjected to restraint stress for 45 min three times daily from gestation day 12 to parturition, and were given a wooden stick to chew during the stress period. Four-month-old male pups were intraperitoneally administered with lipopolysaccharide (LPS). Serum corticosterone levels were determined 24 h after administration. The expression levels of hippocampal inflammatory cytokines were measured, and the microglia were analyzed morphologically. Prenatal stress increased serum corticosterone levels, induced hippocampal microglia priming, and facilitated the release of interleukin-1β and tumor necrosis factor-α in the offspring. LPS treatment significantly increased the effects of prenatal stress on serum corticosterone levels, hippocampal microglial activation, and hippocampal neuroinflammation. Maternal chewing significantly inhibited the increase in serum corticosterone levels, suppressed microglial overactivation, and normalized inflammatory cytokine levels under basal prenatal stress conditions as well as after LPS administration. Our findings indicate that maternal chewing can alleviate the increase in corticosterone levels and inhibit hippocampal microglia-mediated neuroinflammation induced by LPS administration and prenatal stress in adult offspring.

Lasting Effects of Low to Non-Lethal Radiation Exposure during Late Gestation on Offspring's Cardiac Metabolism and Oxidative Stress.

Ionizing radiation (IR) is known to cause fetal programming, but the physiological effects of low-dose IR are not fully understood. This study examined the effect of low (50 mGy) to non-lethal (300 and 1000 mGy) radiation exposure during late gestation on cardiac metabolism and oxidative stress in adult offspring. Pregnant C57BL/6J mice were exposed to 50, 300, or 1000 mGy of gamma radiation or Sham irradiation on gestational day 15. Sixteen weeks after birth, 18F-Fluorodeoxyglucose (FDG) uptake was examined in the offspring using Positron Emission Tomography imaging. Western blot was used to determine changes in oxidative stress, antioxidants, and insulin signaling related proteins. Male and female offspring from irradiated dams had lower body weights when compared to the Sham. 1000 mGy female offspring demonstrated a significant increase in 18F-FDG uptake, glycogen content, and oxidative stress. 300 and 1000 mGy female mice exhibited increased superoxide dismutase activity, decreased glutathione peroxidase activity, and decreased reduced/oxidized glutathione ratio. We conclude that non-lethal radiation during late gestation can alter glucose uptake and increase oxidative stress in female offspring. These data provide evidence that low doses of IR during the third trimester are not harmful but higher, non-lethal doses can alter cardiac metabolism later in life and sex may have a role in fetal programming.

Parental obesity exacerbates cardiovascular responses to acute stress in male, but not female, offspring

The proportion of women and men of reproductive age who are overweight and obese has been increasing considerably, and maternal obesity and excessive gestational weight gain may predispose their offspring to health‐related consequences during childhood and adulthood. Obesity may also be associated with increased cardiovascular responses to mental stress. However, there is no available evidence on the effects of intergenerational obesity on cardiovascular responses to acute stress in adult offspring. In this study, we examined whether the pressor response to acute stress is exacerbated in obese offspring from obese parents. Offspring fed normal diet (ND) born from ND parents (N‐F1‐N, n=5 per sex) used as control, offspring fed high fat diet (HFD) born from ND parents (N‐F1‐H, n=5 per sex) and offspring fed HFD born from HFD parents (H‐F1‐H, n=5 per sex) were used. Parents were fed HFD or ND after they were weaned, while the offspring were placed on HFD from weaning until the end of experiments. Mice were implanted with telemetry probes for measurement of mean arterial pressure (MAP) and heart rate (HR). After a 10 day recovery period, baseline MAP and HR were continuously measured for 30 minutes before, during 5‐minute air‐jet stress consisting of pulses of compressed air directed at the animal’s forehead, and 30 minutes after the stress test. Male and female H‐F1‐H mice were heavier than N‐F1‐H and N‐F1‐N control mice (47.3±0.8 vs. 42.5±1.9 and 33.1±0.2 g and 41.1±0.1 vs. 37.2±0.1 and 24.1±0.1 g, respectively). Male H‐F1‐H mice had higher MAP (110±4 mmHg) compared to N‐F1‐H and control mice (100±6 and 99±3 mmHg). Acute air‐jet stress significantly increased MAP by 36±2 mmHg in male H‐F1‐H mice compared to only 26±3 and 28±3 mmHg in male N‐F1‐H and control mice, respectively. MAP remained significantly higher post stress in H‐F1‐H mice (133±2 vs. 114±6 and 110±3 mmHg). Baseline HR and HR responses to air‐jet were similar among the male groups. In females, however, baseline MAP and HR as well as MAP and HR responses to air‐jet stress test were similar among groups. These results indicate that male, but not female, offspring fed a HFD from obese parents have higher baseline blood pressure (BP) and greater BP responses during acute stress, and their BP remains elevated for a longer period post stress. These observations also suggest that parental obesity may have greater effect on male offspring cardiovascular system compared to female offspring.Support or Funding InformationNIDDK 1RO1121411, NHLBI‐PO1HL51971, NIGMS P20GM104357 and U54GM115428

Astaxanthin ameliorates prenatal LPS-exposed behavioral deficits and oxidative stress in adult offspring.

BackgroundPrenatal maternal lipopolysaccharide (LPS) exposure leads to behavioral deficits such as depression, anxiety, and schizophrenia in the adult lives. LPS-exposure resulted in the production of cytokines and oxidative damage. On the contrary, astaxanthin is a carotenoid compound, showed neuroprotective properties via its antioxidant capacity. This study examines the effect of astaxanthin on the prenatal maternal LPS-induced postnatal behavioral deficit in mice.ResultsWe found that prenatal LPS-exposed mice showed extensive immobile phase in the tail suspension test, higher frequent head dipping in the hole-board test and greater hypolocomotion in the open field test. All these values were statistically significant (p < 0.05). In addition, a marked elevation of the level of lipid peroxidation, advanced protein oxidation product, nitric oxide, while a pronounced depletion of antioxidant enzymes (superoxide dismutase, catalase and glutathione) were observed in the adult offspring mice that were prenatally exposed to LPS. To the contrary, 6-weeks long treatment with astaxanthin significantly improved all behavioral deficits (p < 0.05) and diminished prenatal LPS-induced oxidative stress markers in the brain and liver.ConclusionsTaken together, these results suggest that prenatal maternal LPS-exposure leads to behavioral deficits in the adults, while astaxanthin ameliorates the behavioral deficits presumably via its antioxidant property.

Maternal nicotine exposure and fetal programming of vascular oxidative stress in adult offspring

Despite the well-known harmful effects, many women continue to smoke throughout pregnancy. Consequently, nicotine replacement therapy (NRT) - which has been developed as a pharmacotherapy for smoking cessation - has been used as an alternative to smoking during pregnancy. However, like cigarette smoking, NRT results in biologically significant levels of nicotine crossing the placenta, leading to both fetal and neonatal exposure to nicotine, and yet, NRT safety during pregnancy has not been extensively evaluated. There is now evidence from studies in rats that maternal nicotine exposure throughout gestation results in fetal programming of vascular oxidative stress in the offspring during adulthood. This phenomenon involves vascular dysfunction mediated by reactive oxygen species in association with decreased superoxide dismutase activity and increased Nox2-NADPH oxidase expression in the vascular wall. If this phenomenon also occurs in humans, either smoking or NRT use during pregnancy may represent a novel risk factor for the unborn that results in accelerated cardiovascular disease in their adulthood.

Metabolic Disorders and Oxidative Stress Programming in Offspring of Rats Fed a High-fat Diet During Lactation: Effects of a Vinifera Grape Skin (ACH09) Extract

This study examined the effect of Vitis vinifera grape skin ACH09 extract (ACH09) on metabolic disorders and oxidative stress in adult offspring of rats fed a high-fat diet (HF) during lactation. Four groups of female rats were fed: control diet (7% fat); ACH09 (7% fat + 200 mg·kg·d ACH09 orally); HF (24% fat); HF+ ACH09 (24% fat + 200 mg·kg·d ACH09 orally) during lactation. From weaning onward, all female offspring were fed a control diet and killed when they were 90 or 180 days old. Systolic blood pressure was increased in adult offspring of HF-fed dams, and ACH09 prevented hypertension. Increased adiposity, plasma triglyceride, glucose levels, and insulin resistance were observed in offspring from both ages, and these changes were reversed by ACH09. The plasma oxidative damage assessed by malondialdehyde levels was increased, and nitrite levels decreased in the HF group of both ages, which were reversed by ACH09. In addition, ACH09 restored the decreased plasma and mesenteric artery antioxidant activities of superoxide dismutase, catalase, and glutathione peroxidase in the HF group. In conclusion, ACH09 protected normally fed offspring of HF-fed dams during lactation from phenotypic and metabolic characteristics of metabolic syndrome providing an alternative nutritional resource for the prevention of metabolic syndrome.

Maternal separation stress drastically decreases expression of transthyretin in the brains of adult rat offspring

Adversity in early life has been recognized as a risk factor for psychiatric disorders. In experimental animals, maternal separation (MS) during the neonatal period has been shown to be critical for susceptibility to stress in adult offspring. In this study, we used DNA microarray analysis of rat hippocampal samples to investigate differential gene expression caused by 8-hour MS (MS-8h) every other day during the neonatal period. We found 15 up-regulated and 9 down-regulated genes. We added samples from a daily 15-minute MS (MS-15m) group and performed quantitative real-time PCR to validate the results. Expression of transthyretin (TTR), which is specifically expressed in the choroid plexus (CP), was drastically reduced in the MS-8h group. Two other CP-enriched genes, angiotensin I converting enzyme I and insulin-like growth factor II (IGF-II), were also significantly down-regulated in the MS-8h rats, while significant reduction of IGF-II expression was also found in the MS-15m group. These MS-induced differential gene expressions could be involved in the molecular mechanisms of stress susceptibility. Our findings indicate that the CP, in addition to the neuronal and glial system, might play an important role in determining stress susceptibility.

Increased maternal corticosterone levels in rats: Effects on brain 5-HT1A receptors and behavioral coping with stress in adult offspring.

This study examined the consequences of elevated corticosterone levels in lactating rats on their offspring's serotonergic 5-hydroxytryptamine (5-HT)1A receptor system and behavioral coping with stress. The mothers received normal drinking water or water with corticosterone, which, via the milk, enters the circulation and brains of the pups. In adulthood, the corticosterone-nursed offspring showed a consistently more passive way of coping with environmental challenges. However, they did not seem to be more anxious. Autoradiographic analysis of the 5-HT1A receptor system revealed a decrease in the adult 5-HT1A receptor binding in the hippocampal CA1 region. The results support the hypothesis that differences in behavioral coping with stress by adult rats are associated with differences in the serotonergic system. At the same time, it suggests that adult coping and its neuronal substrates are not solely determined by genes but depend on subtle developmental factors as well.

Increased maternal corticosterone levels in rats: Effects on brain 5-HT-sub(1A ) receptors and behavioral coping with stress in adult offspring.

Increased maternal corticosterone levels in rats: Effects on brain 5-HT-sub(1A ) receptors and behavioral coping with stress in adult offspring.

Prenatal stress alters circadian activity of hypothalamo–pituitary–adrenal axis and hippocampal corticosteroid receptors in adult rats of both gender

Prenatal stress impairs activity of the hypothalamo–pituitary–adrenal (HPA) axis in response to stress in adult offspring. So far, very few data are available on the effects of prenatal stress on circadian functioning of the HPA axis. Here, we studied the effects of prenatal stress on the circadian rhythm of corticosterone secretion in male and female adult rats. To evaluate the effects of prenatal stress on various regulatory components of corticosterone secretion, we also assessed the diurnal fluctuation of adrenocorticotropin, total and free corticosterone levels, and hippocampal corticosteroid receptors. Finally, in the search of possible maternal factors, we studied the effects of repeated restraint stress on the pattern of corticosterone secretion in pregnant female rats. Results demonstrate that prenatal stress induced higher levels of total and free corticosterone secretion at the end of the light period in both males and females, and hypercorticism over the entire diurnal cycle in females. No diurnal fluctuation of adrenocorticotropin was observed in any group studied. The effects of prenatal stress on corticosterone secretion could be mediated, at least in part, by a reduction in corticosteroid receptors at specific times of day. Results also show that prepartal stress alters the pattern of corticosterone secretion in pregnant females. Those data indicate that prenatally stressed rats exhibit an altered temporal functioning of the HPA axis, which, taken together with their abnormal response to stress, reinforces the idea of a general homeostatic dysfunction in those animals. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 302–315, 1999

Prenatal stress alters circadian activity of hypothalamo-pituitary-adrenal axis and hippocampal corticosteroid receptors in adult rats of both gender

Prenatal stress impairs activity of the hypothalamo-pituitary-adrenal (HPA) axis in response to stress in adult offspring. So far, very few data are available on the effects of prenatal stress on circadian functioning of the HPA axis. Here, we studied the effects of prenatal stress on the circadian rhythm of corticosterone secretion in male and female adult rats. To evaluate the effects of prenatal stress on various regulatory components of corticosterone secretion, we also assessed the diurnal fluctuation of adrenocorticotropin, total and free corticosterone levels, and hippocampal corticosteroid receptors. Finally, in the search of possible maternal factors, we studied the effects of repeated restraint stress on the pattern of corticosterone secretion in pregnant female rats. Results demonstrate that prenatal stress induced higher levels of total and free corticosterone secretion at the end of the light period in both males and females, and hypercorticism over the entire diurnal cycle in females. No diurnal fluctuation of adrenocorticotropin was observed in any group studied. The effects of prenatal stress on corticosterone secretion could be mediated, at least in part, by a reduction in corticosteroid receptors at specific times of day. Results also show that prepartal stress alters the pattern of corticosterone secretion in pregnant females. Those data indicate that prenatally stressed rats exhibit an altered temporal functioning of the HPA axis, which, taken together with their abnormal response to stress, reinforces the idea of a general homeostatic dysfunction in those animals.

Prenatal Stress Altered Adrenocortical Response to Conditioned Fear Stress in Adult Offspring.

To more precisely understand the predisposition factors for depressive illness and post-traumatic stress disorder, it is necessary to make an animal model revealing the dysregulation of Hypothalamo-Pituitary-Adrenal (HPA) axis, which is frequently seen in depressive illness and stress-related disorder. In the present study, we have investigated the effects of prenatal stress on the adrenocortical response and behavioral alterations to stressful stimuli in adult offspring, since the decreased or the enhanced suppression of HPA response are frequently observed in depressive illness and post-traumatic stress disorder, respectively. Our results are summarized as follows :1. Prenatal saline injection stress produced the disinhibition of HPA response to conditioned fear stress in adult male offspring. In addition, the prolonged immobility duration in the forced swimming stress was observed in the prenatally stressed groups compared with controls. Taken together, the prenatal saline injection stress model may have a face validity as an animal model of depression.2. In contrast, prenatal saline injection stress produced the enhanced suppression of HPA response to conditioned fear stress in adult female offspring, suggesting that the prenatal saline injection stress model modified by some sex steroids may provide a good tool to investigate the pathophysiology of post-traumatic stress disorder.

Differential effects of prenatal stressful stimuli on hypothalamo-pituitary-adrenal response to stress in adult offspring

Differential effects of prenatal stressful stimuli on hypothalamo-pituitary-adrenal response to stress in adult offspring