Glial fibrillary acidic protein in the brain of prenatally stressed rats

The content of glial fibrillary acidic protein (GFAP) was studied in the brain structures of rats borne by intact females and females that underwent stress. In the offspring of stressed rats, the GFAP content in the brain gray and white matter on the 15th postnatal day noticeably dropped. On the 30th postnatal day, the GFAP content in the cortex and pons increased, while it somewhat decreased in the striatum and cerebellum. The results suggest that formation of the intermediate astrocyte filaments in the animals subjected to prenatal stress is markedly disturbed.     

The effect of prenatal stress on activity of the neurosteroids synthesis enzyme in the "critical period" of brain sexual differentiation in male rats

The effect of daily immobillisation stress in female rats on the 15th to 18th days of pregnancy upon synthesis enzyme for neurosteroids of alpha-reductase in their male offspring brain, was studied. A decrease in the enzyme activity in the cortex and hypothalamus of male foetuses occurred within 24 hr following the latest stress, whereas it was increased in the cortex of newborn offspring. An enhancement of the 5 alpha-reductase activity in the cortex, hippocampus and hypothalamus was also found in prenatally stressed males on the 5th day of life. A decrease in the testosterone and progesterone contents in the blood plasma of the animals under study was revealed on the 19th day of their embryonic life as well as in newborn rats, the blood level of progesterone, at that, remained decreased even at the age of 5 days. A possible part ofneurosteroids in action of prenatal stress upon sexual differentiation of the brain is discussed.     

Effect of prenatal stress on the hormonal response to acute and chronic stress and on immune parameters in the offspring

The effect of prenatal stress on the time course of the corticosterone response to acute and chronic stress and on hematological and immunological parameters in the offspring were analized in the present study. Pregnant Sprague-Dawley rats were stressed daily for 2 hours during the last week of gestation, and female and male off-spring were studied during adulthood. Corticosterone response to acute immobilization stress was not significantly different in either control or prenatally stressed rats. However, after 10 days of immobilization stress the corticosterone response completely disappeared in the control animals but not in the prenatally stressed group: high levels of corticosterone were found during the first hour of stress, although they were lower than those found in acutely stressed rats. Adrenal hypertrophy in response to prenatal stress was observed in females but not in male offspring, and chronic stress only increased adrenal weights in the male control group. Prenatal stress decreased the total peripheral leukocyte count, altered its diferential count decreasing lymphocytes and increasing neutrophil and eosinhophil counts, and significantly reduced the percentage of peripheral lymphocyte T CD8+ subset in male offspring. Chronic stress also reduced the percentage of the peripheral T CD8+ lymphocyte subset in the control group but not in the prenatally stressed group. These results suggest that the exposure to stress during pregnancy alters the adaptative response of the hypothalamus-pituitary-adrenocortical axis to chronic stress and presumably the immune competence in the offspring.     

Chronic mild prenatal stress exacerbates the allergen-induced airway inflammation in rats

The effects of chronic mild prenatal stress on leukocyte infiltration into the airways was investigated in rat offspring. The chronic prenatal stress consisted of transitory and variable changes in the rat's living conditions. Offspring at adult age were actively sensitized (day 0) and intratracheally challenged (day 14) with ovalbumin. Bronchoalveolar lavage was performed in the offspring at 48 h after intratracheal challenge with ovalbumin. A significant increase in total leukocyte infiltration was observed in the non-stressed offspring group and this was associated with a marked recruitment of eosinophils without a significant effect on the influx of neutrophils and mononuclear cells. In the prenatal stressed offspring, the counts of both total leukocyte and eosinophils, as well as mononuclear cells, was increased by 50% compared to the non-stressed offspring. We provide here the first experimental evidence that chronic mild unpredictable prenatal stress produces a marked increase in the allergen-induced airway inflammation in the rat offspring.     

产前束缚应激子代大鼠海马神经颗粒素表达降低

神经颗粒素（neurogranin,NG）是脑特异性突触后蛋白,参与在学习记忆功能中起核心作用的信号转导通路及突触可塑性。本研究旨在探讨产前束缚应激对子代大鼠海马NG表达的影响。连续7d对孕晚期大鼠进行束缚应激,建立产前束缚应激模型,分为对照雌、雄组,应激雌、雄组。采用免疫组化方法观察NG在产前束缚应激子代大鼠海马不同亚区的分布特点;采用蛋白免疫印迹方法检测产前束缚应激子代大鼠海马NG蛋白的表达。结果显示：各组子代大鼠海马各区均有NG蛋白表达,CA1和CA3区表达高于齿状回（dentate gyrus,DG）;应激组雌、雄子代大鼠海马NG的表达明显低于对照组（P〈0．01）,应激组雌性子代比雄性子代减少更显著,对照组雌、雄子代之间无差异。免疫组化与蛋白免疫印迹方法所得结果一致。上述结果表明,NG在产前束缚应激子代大鼠海马表达降低,并且雌性比雄性降低明显,NG对产前束缚应激子代大鼠有差异性调制,NG表达减少可能与产前束缚应激子代大鼠学习记忆能力下降有关。     

The effect of prenatal stress on the carboxypeptidase H activity in the hypothalamo-pituitary-adrenal-gonadal system of the rat

Effects of dams stress on the carboxypeptidase H: the neuropeptide exchange enzyme in the hypothalamo-pituitary-adrenall-gonadal system, was studied in the litter of different age (0, 14, 28, 45, and 120 day after birth) was studied. The sex differences in dynamic of enzyme activity in intact animals are substantiated. The effect of prenatal stress on carboxypeptidase H activity dependes on age and sex of animals. Prenatal stress is altering during the age dynamics of enzyme activity. This in the pituitary gland and hypothalamus of prenatal stressed female rats was a control for the male rats. In the adrenal and gonadal gland of prenatal stressed males, this was a control for the female rats female. The role of carboxypeptidase H in pubescence and mechanisms of effect of prenatal stress on sex system functional are discussed.     

The effects of prenatal stress on expression of CaMK-II and L-Ca2+ channel in offspring hippocampus

The purpose of the present study was to characterize the expressions of phosphorylated Ca(2+)/calmodulin-dependent protein kinase II (p-CaMK-II), total CaMK-II, and L-type Ca(2+) channel in offspring hippocampus that was induced by prenatal restraint stress. Pregnant rats were divided into two groups: the control group and the prenatal stress (PNS) group. Pregnant rats in the PNS group were exposed to restraint stress on day 14-20 of pregnancy three times daily for 45 min. Adult offspring rats were used in this study. The results demonstrated that prenatal restraint stress induced a significant increase in the expression of p-CaMK-II, total CaMK-II, and L-Ca(2+) channel by western blot analysis in offspring hippocampus. The immunohistochemistry results revealed that PNS increased the expressions of CaMK-II and L-Ca(2+) channel in the hippocampal CA3 of offspring rats. These data suggest that PNS can have long-term neuronal effects within hippocampal structure involved in the feedback mechanisms of the hypothalamo-pituitary-adrenal axis.     

Prenatal Stress Produces Social Behavior Deficits and Alters the Number of Oxytocin and Vasopressin Neurons in Adult Rats

The present study investigated the long-lasting effects of prenatal repeated restraint stress on social behavior and anxiety, as well as its repercussions on oxytocin (OT) and vasopressin (VP)-positive neurons of the paraventricular (PVN) and supraoptic (SON) nuclei from stressed pups in adulthood. Female Wistar rats were exposed to restraint stress in the last 7 days of pregnancy. At birth, pups were cross-fostered and assigned to the following groups: prenatally non-stressed offspring raised by prenatally non-stressed mothers (NS:NS), prenatally non-stressed offspring raised by prenatally stressed mothers (S:NS), prenatally stressed offspring raised by prenatally non-stressed mothers (NS:S), prenatally stressed offspring raised by prenatally stressed mothers (S:S). As adults, male prenatally stressed offspring raised both by stressed mothers (S:S group) and non-stressed ones (NS:S group) showed impaired social memory and interaction. In addition, when both adverse conditions coexisted (S:S group), increased anxiety-like behavior and aggressiveness was observed in association with a decrease in the number of OT-positive magnocellular neurons, VP-positive magnocellular and parvocellular neurons of the PVN. The NS:S group exhibited a reduction in the amount of VP-positive magnocellular neurons compared to the S:NS. Thus, the social behavior deficits observed in the S:S and NS:S groups may be only partially associated with these alterations to the peptidergic systems. No changes were shown in the OT and VP cellular composition of the SON nucleus. Nevertheless, it is clear that a special attention should be given to the gestational period, since stressful events during this time may be related to the emergence of behavioral impairments in adulthood.     

“Green odor” inhalation by stressed rat dams reduces behavioral and neuroendocrine signs of prenatal stress in the offspring

Chronic maternal stress during pregnancy results in the “prenatally stressed” offspring displaying behavioral and neuroendocrine alterations that persist into adulthood. We investigated how inhalation of green odor (a mixture of equal amounts of trans-2-hexenal and cis-3-hexenol) by stressed dams might alter certain indices of prenatal stress in their offspring. These indices were depression-like behavior (increased immobility time in the forced-swim test) and acute restraint stress-induced changes in hypothalamo-pituitary-adrenocortical (HPA) axis activity [plasma corticosterone (CORT) and ACTH levels and the number of Fos-immunoreactive cells in the hypothalamic paraventricular nucleus (an index of neuronal activity)]. Pregnant rats were exposed to restraint stress for 60 min/day for 10 days (gestational days 10-19). The prenatally stressed offspring exhibited significant increases in depression-like behavior and in restraint stress-induced ACTH, CORT, and Fos responses, unless their dam had been exposed to green odor. The behavioral effect of the odor was also seen in offspring that were fostered by unstressed dams. The results obtained in the dams themselves were as follows. In vehicle-exposed stressed dams, but not in green odor-exposed ones, total body and adrenal weights were significantly decreased or increased, respectively. Depression-like behavior was not observed in the vehicle-exposed stressed dams themselves. Green odor inhalation prevented the impairment of maternal behavior induced by restraint stress. Thus, exposure of dams to stress may affect both the fetal brain and fetal HPA axis, and also maternal behavior, leading to altered behavioral and neuroendocrine responses in the offspring. Such effects may be prevented by the stressed dams inhaling green odor.     

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.     

Content of NCAM, the neural cell adhesion molecule, in the brain of rats subjected to prenatal stress

The content of NCAM, the neural cell adhesion molecule, was studied in the cerebral cortex, hippocampus, striatum, cerebellum, and pons of 15- and 30-day-old rats, the offspring of intact females and females subjected to stress during pregnancy. At the 30th day of the postmatal development, opposite NCAM concentration changes were observed in the cortex and other brain parts of the offspring of stressed rats. These differences can be related to a deficiency of mature synapses in the forebrain of prenatally stressed rats and adaptation rearrangements in the neuronal systems of the brainstem and cerebellum.     

Prenatal stress differentially affects habituation of corticosterone responses to repeated stress in adult male and female rats

Environmental factors operating early in life have long-lasting and important consequences for the mental and physical health of the adult organism. In particular, prenatal exposure to stress represents one category of adverse early environmental events that are associated with development of depression and schizophrenia in adulthood. In the present studies, we examined whether prenatal stress alters the habituation of hypothalamic-pituitary-adrenal (HPA) activity that occurs with repeated stress exposure in adulthood. We compared corticosterone responses to the first vs. the eighth restraint, with lower responses to the eighth vs. the first considered evidence of habituation. In males, prenatal stress prevented the habituation of corticosterone responses to repeated restraint that was observed in non-prenatally stressed rats. Limited evidence of habituation was seen in either group of females and prenatally stressed females did not exhibit the enhanced corticosterone response during recovery from the eighth restraint that was seen in non-prenatally stressed females. Together, these results suggest a sex-specific interaction between prenatal stress and adult chronic stress on HPA activity.     

Role of glucocorticoids in coat depigmentation in animals selected for behavior

The involvement of glucocorticoid hormones in the appearance of white spots during embryogenesis in domesticated gray rats was studied. It was shown that in fully pigmented gray rats, prenatal stress and exposure to dexamethasone on days 12–14 of gestation elicited a delay in the migration and development of melanoblasts in embryos. This led to a fourfold increase in the number of offspring with depigmentation on the ventral side of the body. It was also demonstrated that in adult offspring of mothers treated with dexamethasone, the response of the hypothalamo-pituitary-adrenal axis to the emotional stress was lower compared to the controls. The role of glucocorticoids in the appearance of coat depigmentation under animal domestication is discussed.     

The role of glucocorticoids in the appearance of coat depigmentation in animals selected for behavior

The involvement of glucocorticoid hormones in the appearance of white spottings during embryogenesis in domesticated gray rats was studied. It was shown that prenatal stress and exposure to dexamethasone on the 12-14 days of pregnancy of fully pigmented gray rats elicited the slowing of melanoblast migration and its development in embryos. It was associated with a 4-fold increase of the offspring percentage with the depigmentation on the ventral side of body in adults. It was also demonstrated that response of H PA axis to emotional stress was lower in adult offsprings from prenatal-stressed and dexamethason-treated mothers than in adult offspring from control mothers. The role of glucocorticoids in the appearance of coat depigmentation under animal domestication is discussed.     

Prenatal stress induces long-term effects in cell turnover in the hippocampus-hypothalamus-pituitary axis in adult male rats

Subchronic gestational stress leads to permanent modifications in the hippocampus-hypothalamus-pituitary-adrenal axis of offspring probably due to the increase in circulating glucocorticoids known to affect prenatal programming. The aim of this study was to investigate whether cell turnover is affected in the hippocampus-hypothalamus-pituitary axis by subchronic prenatal stress and the intracellular mechanisms involved. Restraint stress was performed in pregnant rats during the last week of gestation (45 minutes; 3 times/day). Only male offspring were used for this study and were sacrificed at 6 months of age. In prenatally stressed adults a decrease in markers of cell death and proliferation was observed in the hippocampus, hypothalamus and pituitary. This was associated with an increase in insulin-like growth factor-I mRNA levels, phosphorylation of CREB and calpastatin levels and inhibition of calpain -2 and caspase -8 activation. Levels of the anti-apoptotic protein Bcl-2 were increased and levels of the pro-apoptotic factor p53 were reduced. In conclusion, prenatal restraint stress induces a long-term decrease in cell turnover in the hippocampus-hypothalamus-pituitary axis that might be at least partly mediated by an autocrine-paracrine IGF-I effect. These changes could condition the response of this axis to future physiological and pathophysiological situations.     

Prenatal stress in rat causes long-term spatial memory deficit and hippocampus MRI abnormality: differential effects of postweaning enriched environment

Prenatal stress (PS) can cause long-term hippocampus alternations in structure and plasticity in adult offspring. Enriched environment (EE) has an effect in rescuing a variety of neurological disorders. Pregnant dams were left undisturbed (prenatal control, PC) or restrained 6h per day from days 14 to 21 (prenatal stress, PS). Control and prenatal stressed offspring rats were subjected to a standard rearing environment (SE) or an EE on postnatal days 22-120 (PC/SE PC/EE, PS/SE, and PS/EE; n=5, each group). At ～4 months of age, all rats underwent Morris water maze test and brain MRI examination. Hippocampi were then dissected for biochemical analyses, including, Western blot for NMDA receptor (NR) subunits and synaptophysin and RT-PCR forβ1 integrin and tissue-plasminogen activator (t-PA). MRI showed all 5 rats in the PS/SE group and 5 in the PS/EE group exhibited increased signals in bilateral hippocampus and increased T2 time in the PS/SE group. Exposure to EE treatment on postnatal days 22-120 counteracted the deficit in spatial memory and increased NR1 protein expression, but it did not affect the rate of high signals and increased T2 time, decreased NR2, synaptophysin, β1 integrin and t-PA mRNA expressions in PS adult offspring. The results of this study indicate PS in rats causes long-term spatial memory deficits and gross hippocampus pathology. Postnatal EE treatment has differential benefits in terms of spatial learning, signaling molecules, and gross hippocampus pathology.     

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     

Effect of alcoholic intoxication of female mice prior to pregnancy on the ultrastructure of neurons in the sensorimotor cortex of the progeny

Sensorimotor cortex in the offspring of female rats alcoholized in the prepregnancy period revealed signs of delayed neuronal development and dystrophic changes in the neurons especially on the 14th day after birth. In 21-day-old animals the reparative changes increased, but normalization of neuronal ultrastructure was not observed. The dystrophic changes suggest that prenatal brain hypoxia plays an important role in the pathogenesis of alcohol-induced neuronal lesions in the offspring.     

Responses of the hypothalamic-pituitary-adrenal axis to noradrenergic and hormonal stimulation in prenatally stressed rats

We studied the effects of maternal stress (the so-called prenatal stress, PS, provided by immobilization of pregnant female Wistar rats for 1 h daily during the 15–21st gestational days) on the corticosterone response in the blood plasma evoked by infusion of 10 μg noradrenaline bitartrate into the III cerebral ventricle or by injection of β-1-24-corticotropin in 3-month-old male and female offspring. The animals were bearing an intracerebroventricular stainless steel guide cannula implanted eight to nine days before the experiment, and a Silastic catheter inserted into the external jugular vein 24 h prior to the experiment. Blood samples were periodically taken from conscious unrestrained rats (before and then 30, 60 and 90 or 120 min after noradrenaline or corticotropin challenge). In the male offspring PS augmented and prolonged an increase in the plasma corticosterone level resulting from adrenergic stimulation of the hypothalamus, as compared with that in non-stressed animals. In prenatally stressed female offspring tested in diestrus, there was no response of the hypothalamic-pituitary-adrenal (HPA) axis to intracerebroventricular noradrenaline stimulation, in contrast to what was observed in the control. Prenatal stress did not modify the adrenal cortex responsiveness to corticotropin either in male or in female offspring. The results demonstrate differential effects of PS on the adrenergic activation of the HPA axis in males and females. A decrease in the acute HPA stress-responsiveness in prenatally stressed male rats, which was demonstrated in an earlier study, and the maintenance or even enhancement of this effect in prenatally stressed females are not likely to be connected with the state of hypothalamic adrenergic reactivity.     

Anxiety induced by prenatal stress is associated with suppression of hippocampal genes involved in synaptic function

Exposure of pregnant women or animals to stress during a critical period of foetal brain development increases the likelihood of anxiety, depression and learning deficits that are associated with structural alterations in the offspring hippocampus. In this study, we report the effect of gestational stress in rats on anxiogenic behaviour and hippocampal gene expression of their 23-day-old female offspring. As the rat brain continues to develop after birth, we also used the procedure of handling (H) during the first 10 days of life to reverse the anxiogenic behaviour of prenatally stressed (PS) rats. By means of micro-array analysis on hippocampal extracts, we found that the expression of about 6.1% of 9505 valid genes was significantly altered by prenatal stress (p<0.05). Of these, 48% were over-expressed and 52% under-expressed. The latter included approximately 300 genes that participate in axonal growth, regulation of ion channels and transporters, trafficking of synaptic vesicles and neurotransmitter release. About 30% of the genes that were down-regulated in PS rats were restored to control levels by H. These include genes that play a role in pre-synaptic organization and function. Our results provide a possible relationship between hippocampal gene expression and changes in behaviour resulting from prenatal stress.