Chronic exposure to a novel odor increases pups' vocalizations, maternal care, and alters dopaminergic functioning in developing mice

This study was designed to assess the stress effect of manipulation of the olfactory environment in developing mice. In a first experiment it was found that mouse pups could be stressed (as measured by an increase in ultrasonic calls) by removing the litter from the dam for 15 min/day for the first 14 days of life and exposing them to a novel odor (clean bedding). This stress procedure also produced a long-term modification in maternal behavior. The stress response (ultrasounds) and the modification of maternal behavior were prevented by providing the litter with home cage bedding during maternal separation. In a second experiment it was demonstrated that early stress influenced apomorphine-induced wall climbing behavior in 15-day-old mice, suggesting stress-induced alterations in the dopaminergic system. Pups exposed to clean bedding during infancy exhibited more wall climbing behavior than pups never separated from the mother. Moreover, preventing the early stress response during mother-offspring separation, by providing pups with home cage bedding, eliminated the increase in apomorphine-induced wall climbing. Taken together these results suggest that olfactory cues are decisive in characterizing stressful situations inducing both immediate and long-lasting effects in mouse pups.     

A quantitative assessment of the effects of malnutrition on behavioral development in laboratory mice

The aim of this study was to compare the effects of malnutrition on behavioral development in mice with those due to heredity obtained in a previous study. To this end behavioral development was assessed using a developmental time scale which allowed comparison of the two studies. Pregnant B6D2F1/J mice were maintained on either a protein restricted or normal protein diet from Day 7 to Day 24 postconception, at which time the low protein group was returned to the normal diet until behavioral testing at Day 32. Behavioral development in the control group replicated the values obtained in previous studies, whereas the malnourished pups were retarded by 1.4 days. This was of the same order of magnitude as that reported previously for maternal inbreeding. Measures of maternal and pup body weight at birth, Day 24 and Day 32 indicated that although the malnourished animals were initially significantly lighter in weight they had recovered by Day 32. Litter size however, declined between birth and time of behavioral testing in the malnourished group.     

Prenatal maternal stress: Differential effects upon male and female offspring responses to restraint stress as adults

Pregnant primiparous rats were subjected to four days of light restraint stress on postconception days 7 through 10, inclusive, coincident with the development of the fetal gastrointestinal system. Twenty male and twenty female offspring from prenatally stressed and nonstressed rats were then subjected to two hours of supine cold-restraint as adults. Eighty percent of nonprenatally stressed offspring developed gastric lesions, while 47.5% of offspring of prenatally stressed mothers displayed lesions. A significant sex-stress interaction was detected, indicating that male offspring from prenatally stressed mothers display less severe gastric lesions in response to restraint stress as adults than do male offspring from nonprenatally stressed mothers. Female offspring from both prenatal stress conditions showed similar levels of stress-induced lesions.     

Maternal Prenatal Stress and Other Developmental Risk Factors for Adolescent Depression: Spotlight on Sex Differences

Maternal stress during pregnancy has been linked to premorbid abnormalities associated with depression (e.g., difficult temperament, cognitive deficits) in offspring. However, few studies have looked across developmental periods to examine maternal stress during pregnancy and offspring depression during adolescence and whether these associations differ by sex. The current study used data from 1711 mother-offspring dyads (offspring sex: 49.8% male) in a longitudinal birth cohort study. Maternal narratives collected during pregnancy were qualitatively coded for stress-related themes by independent raters. Latent class analysis (LCA) identified distinct subgroups of offspring based on exposure to maternal prenatal stress and other developmental factors from the prenatal, childhood, and adolescent periods that have been associated with depression and/or maternal prenatal stress. LCA identified subgroups that were compared to determine whether and to what extent they differed on adolescent depressive symptoms. LCA revealed a subgroup of “high-risk” individuals, characterized by maternal factors during pregnancy (higher ambivalence/negativity and lower positivity towards the pregnancy, higher levels of hassles, lower maternal education and higher maternal age at birth, higher pre-pregnancy BMI) and offspring developmental factors (decreased cognitive functioning during childhood and adolescence, lower perceived parental support during adolescence, and higher levels of maternal depression during adolescence). High-risk females exhibited elevated conduct symptoms and higher birth order, while high-risk males exhibited decreased internalizing symptoms and lower birth order. Both high-risk males and females reported elevated depressive symptoms during adolescence relative to their “low-risk” counterparts.     

Hypothalamo-pituitary-adrenocortical axis function and hedonic behavior in adult male and female rats prenatally stressed by maternal food restriction

Neuroendocrine activation during stress is affected by many factors contributing to the variability of the stress response. The present study was aimed at evaluating long-term changes in hypothalamo-pituitary-adrenocortical (HPA) axis function and in hedonic behavior in adult offspring prenatally stressed by maternal food restriction, with attention on possible gender differences. Adult offspring were blood sampled via a tail artery cannula. Prenatally stressed females had significantly higher adrenal weights compared to males. Plasma ACTH levels, which rose in response to acute stress induced by handling, were significantly higher in females compared to those in males. A similar pattern was found in plasma corticosterone. The rise in ACTH levels was more pronounced in prenatally stressed rats though the rise in corticosterone failed to be modified. Corticotropin releasing hormone (CRH) and proopiomelanocortin mRNA levels in the hypothalamic paraventricular nucleus and anterior pituitary, respectively, were found to be unchanged. The present experiments failed to reveal a decrease in hedonic behavior in prenatally stressed rats. In contrast, in male offspring a tendency to a higher sucrose preference was observed. These data together with observed changes in hormone and CRH mRNA levels indicate that the gestational stress used did not result in a depression-like state in adult offspring.     

Maternal separation in early life impairs tumor immunity in adulthood in the F344 rat

Neonatal stress alters the hypothalamic-pituitary-adrenal (HPA) axis in rodents, such that, when these animals are exposed to stress as adults they hypersecrete corticosterone. Given that glucocorticoids are immunosuppressive, we examined the impact of maternal separation on HPA axis reactivity, natural killer (NK) cytotoxicity, and tumor growth in Fischer 344 rats following chronic restraint stress in adulthood. Pups underwent a chronic stress protocol whereby they were separated from their dams for 3 h on postnatal days 1-21. In adulthood, corticosterone responses were assessed following exposure to chronic (6 days for 10 h) restraint stress. Rats allocated to the chronic stress condition were inoculated with MADB106 tumor cells on day 4 of the restraint protocol. Blood was assessed for NK cytotoxicity on the final day of the chronic restraint protocol, and tumor colonization was assessed 3 weeks thereafter. Maternal separation impaired developmental weight gain (P < 0.05), depressed NK cytotoxicity (P < 0.05), and increased tumor colonization in the presence of chronic restraint stress in adulthood (P < 0.00 l). These findings occurred independently of circulating plasma corticosterone as only adult stress exposure potentiated corticosterone responses (P < 0.05). Our findings indicate that maternal separation and chronic stress can impair NK cytotoxicity and hence tumor immunity, but these effects are not directly mediated by perturbations in HPA axis function.     

Rat gestation during space flight: Outcomes for dams and their offspring born after return to earth

Sprague-Dawley rats were studied to learn whether gestation in the near-zero gravity, high radiation environment of space impacts selected mammalian postnatal events. Ten rats spent days nine to twenty of pregnancy aboard the space shuttle orbiterAtlantis (STS-66). Their movement, was studied shortly after return to Earth; subsequently, several of their offspring were cross-fostered and examined through postnatal day 81 (P81) for whole body growth and somatic motor development. Values for the flight animals were compared to ground-based control groups. Relative to controls, the pregnant flight rats showed a marked paucity of locomotion during the first few hours after returning to Earth. There was greater likelihood of perinatal morbidity for the offspring of flight dams when compared to the control groups. Whole body weight of surviving offspring, averaged for each group separately, showed typical sigmoidal growth curves when plotted against postnatal age. The flight group for our study had a larger ratio of female to male pups, and that was sufficient to account for the lower average daily weight gained by the flight animals when compared to the control groups. Walking was universally achieved by P13 and preceded eye opening which was complete in all pups by P17. Thus, both of these developmental horizons were attained on schedule in the flight as well as the control rats. Characteristic changes were observed in hind limb step length and gait width as the pups grew. These patterns occurred at the same time in each group of rats. Therefore, prenatal space flight from days nine to twenty of gestation did not interfere with the establishment of normal patterns for hind paw placement during walking.     

Ingestive behavior in rat pups is modified by maternal sodium depletion

Developmental programming by maternal stress during pregnancy is found to influence behavioral development in the offspring. The main objective of this study was to investigate the effect of maternal sodium depletion in rats during pregnancy on the development of thirst mechanisms in the offspring. Pregnant rats underwent 3 episodes of saline depletion, induced by injecting sc 10 mg of Furosemide in saline (0.5 ml). The treatment, given on the 14th, 17th and 20th days post-conception, is thought to induce acute sodium depletion on dams. The offspring were tested for their drinking responses to Isoproterenol (500 μg/kg sc). In accordance to the known sequence of ontogenic development of drinking mechanisms, all groups of pups drunk after being stimulated with Isoproterenol at 6 days of age. The offspring from Furosemide-treated dams drank significantly less than the control group after Isoproterenol (p<0.001). Nevertheless, basal intake (water drunk after vehicle-saline only) was also significantly lower in these pups (p<0.001). In conclusion, offspring exposed to saline depletion in utero, modify their thirst responses at 6 day of age. This confirms that in utero conditions determine thirst responses in the offspring and they could provide adaptive advantages.     

Maternal Psychopathology and Early Child Temperament Predict Young Children’s Salivary Cortisol 3 Years Later

Neuroendocrine dysfunction is hypothesized to be an early emerging vulnerability marker for depression. We tested whether the main and interactive effects of maternal psychopathology and early child temperamental vulnerability for depression assessed at age three predicted offspring’s basal cortisol function at age 6 years. 228 (122 males) children participated in the baseline and follow-up assessments. At age three, maternal lifetime psychopathology was assessed with a diagnostic clinical interview, and child temperamental positive affectivity (PA) and negative affectivity (NA) were assessed using laboratory observations. At age six, children’s waking and evening cortisol were assessed on 2 days. Maternal lifetime anxiety predicted offspring’s higher morning cortisol at age six. Child temperamental NA at age three predicted higher evening cortisol at age six. There was a significant interaction between maternal lifetime depression and child temperamental PA at age three in predicting offspring’s morning cortisol at age six. For the offspring of mothers with lifetime depression, higher PA at age 3 predicted lower morning cortisol at age 6. These findings highlight the importance of examining the main and interactive effects of maternal psychopathology and early child temperamental vulnerability in predicting the development of offspring’s stress physiology. Findings hold significance in identifying etiological mechanisms of risk and delineating the complex developmental pathways to psychopathology.     

Prenatal diagnosis and management of intrauterine growth restriction: A long‐term prospective study on outcome and maternal stress

This study examines long‐term effects of antenatal management of intrauterine growth restriction (IUGR) on developmental outcome and on maternal coping using a prospective cross‐sectional design. Sixty‐nine families were evaluated using psychological testing and risk questionnaires. The effects of timing of diagnosis (prenatal/perinatal) and of pregnancy management [induction of labor (IL)/conservative management (CM)/none, i.e., diagnosed‐at‐birth (DaB)] on maternal stress were tested at 6 years' postbirth. In general, prenatal management protocols of IUGR were efficient in preventing major disabilities; however, 49% of the variance in maternal stress at 6 years' postbirth could be attributed to the child's presenting behavior and to pregnancy management of IUGR condition. Mothers who received CM treatment reported being more stressed by their child's poor emotional adjustment (ps < .01–.002) and distractibility (p < .029), and to have more difficulty in accepting them (p < .01). Prenatal psychological consultation to better handle stress for parents whose fetus is diagnosed with IUGR is recommended, particularly when pregnancy is managed conservatively and familial–educational resources are low.     

围生期双酚A暴露对不同性别子代小鼠行为的影响

探讨围生期母体双酚A(bisphenol A, BPA)暴露对幼年期(生后21~30天, postnatal day 21~30, PND 21~30)和青年期(生后56~63天, PND 56~63)不同性别子代小鼠行为的影响。母鼠从妊娠第7天至断乳前(产后21天)进行BPA(0.05、0.5、5、50 mg/kg/day)灌胃染毒, 同时设对照组。每个剂量组分别在PND 21和PND 56开始测试雌雄子代小鼠各项行为。以旷场行为检测小鼠的自发活动及探究行为, 以高架十字迷宫检测小鼠的焦虑行为, 以水迷宫检测小鼠的空间学习记忆能力, 以跳台检测小鼠的被动回避记忆行为。结果表明, BPA使PND 21雌雄子鼠和PND 56雄性子鼠自发活动减少(p<0.05或p<0.01), 理毛和站立行为发生性别分化(p<0.05或p<0.01); PND 21子鼠的3分钟跑动格数有明显的剂量效应关系, 其中5~50 mg/kg/day组特别显著。BPA显著增加PND 21雌雄子鼠和PND56雌性子鼠在高架十字迷宫中进入开放臂次数和停留时间(p<0.05或p<0.01)并减少封闭臂的进入时间, 但没有明显的剂量效应关系; BPA减少PND 56雄性子鼠开放臂的进入并增加其封闭臂的进入, 干扰了幼年期和青年期小鼠焦虑行为的性别分化。BPA剂量依赖性地延长PND 21和PND 56雄性子鼠在水迷宫搜索平台的平均距离, 其中5~50 mg/kg/day剂量组具有差异显著性(p<0.05或p<0.01), 但对雌性子鼠空间学习记忆行为没有影响。此外, 5~50 mg/kg/day BPA增加PND 21雄性子鼠在跳台实验中的错误次数并缩短其跳下平台潜伏期, PND 56雌雄子鼠的被动回避记忆仅被50 mg/kg/day BPA减弱。以上结果提示, 围生期BPA暴露可影响子代小鼠幼年期和青年期的多种行为及行为的性别差异, 不同行为对BPA的敏感程度不同, 其中以自发活动和探究行为最敏感。     

Simple disturbance of the dam in the neonatal period can alter haloperidol-induced catalepsy in the adult offspring

Three experiments were performed to determine whether apparently minimal disturbances of dams and litters would influence haloperidol-induced akinesia. In Experiment I, Long-Evans hooded rats (a) were left unmanipulated, (b) received nestcage relocation and observation, (c) received nestcage relocation/observation and maternal separation, or (d) received nestcage relocation/observation and pup handling. The male adult offspring received open-field testing and later received forepaw-on-dowel catalepsy testing following saline, morphine (20 mg/kg), or haloperidol (2 mg/kg). In Experiment II, hooded rats received (a) no manipulation, (b) nestcage relocation, (c) maternal separation, or (d) pup handling. At weaning, dams were tested in the open-field. Activity wheel locomotion of the offspring was assessed following saline or haloperidol for 3 days/week for 3 weeks; then, 5 and 7 days later, rats received haloperidol (0.5 mg/kg) and catalepsy testing. In both experiments, manipulations involving the dam reduced the offsprings' haloperidol-induced catalepsy, but, in Experiment II, a history of haloperidol administration distinguished between the effects of nestcage relocation and maternal separation. In Experiment III, Swiss albino mice received (a) no treatment, (b) nestcage relocation and maternal separation, (c) relocation/separation and mild cold stress of pups, (d) relocation/separation and pup handling, or (e) relocation/separation and severe cold stress of pups. Adult male mice received saline or haloperidol (2.5 mg/kg) and inclined grid catalepsy testing. Mice receiving relocation/separation and mice receiving relocation/separation and severe cold stress showed enhanced catalepsy versus control mice. Thus, it was concluded that seemingly innocuous events in infancy can influence the intensity of extrapyramidal side effects of neuroleptics in adulthood.     

生命早期双酚A暴露对子代成年小鼠焦虑和抑郁行为的影响及其神经机制

双酚A (bisphenol A, BPA)对脑和行为发育的影响已引起关注, 本研究探讨围生期不同发育阶段母体BPA暴露对仔鼠成年后焦虑和抑郁行为的影响。分别在妊娠期(妊娠第7天~出生)和哺乳期(出生第1~14天) 将母鼠暴露于BPA (0.4、4 mg/kg/day), 以旷场、明暗箱、镜子迷宫、高架十字迷宫等多种模型检测生后56天(postnatal day 56)仔鼠的焦虑行为, 以强迫游泳模型检测其抑郁行为。结果显示, 妊娠期BPA暴露的成年雌性仔鼠在所有4种模型中均检测到促焦虑作用, 而哺乳期BPA暴露的雌鼠、妊娠期或哺乳期BPA暴露的雄鼠仅在2种模型中检测到促焦虑作用。妊娠期BPA暴露显著加重雌雄仔鼠的抑郁行为, 而哺乳期仅高剂量BPA加重仔鼠的抑郁行为。进一步的Western blot分析显示, 妊娠期或哺乳期BPA暴露显著下调成年后雌雄仔鼠海马和杏仁核AMPA受体GluR1亚基的表达, 但对NMDA受体NR1亚基的影响不一致。以上结果提示, 妊娠期或哺乳期BPA暴露对成年雌雄仔鼠均有不同程度的促焦虑和抑郁作用, 其中妊娠期暴露对雌鼠的作用最显著, 海马和杏仁核AMPA受体活动的减弱可能与围生期BPA暴露加重仔鼠成年后的焦虑和抑郁行为有关。     

Maternal supplementation of nucleotides improves the behavioral development of prenatal ethanol-exposed mice

Maternal ethanol consumption during pregnancy can induce learning deficits in the offspring. The objective of this study was to assess whether supplementation of exogenous nucleotides during pregnancy and lactation would ameliorate prenatal ethanol-induced learning and memory deficits in the offspring of mice, and to explore the possible mechanisms. In the present study, pregnant C57BL/6J mice were exposed to ethanol (5 g/kg body weight) intragastrically from gestational day (GD) 6 to GD15. The dams in exogenous nucleotide intervention groups were fed with feed containing 0.01 %, 0.04 %, or 0.16 % nucleotide powder, with control and ethanol groups receiving normal feed. The dams were allowed to deliver naturally and to breast feed their offspring. After weaning, behavioral tests were carried out in the offspring of each group. Serum oxidation indexes were analyzed, and the hippocampus of each offspring was collected and detected for acetyl cholinesterase (AChE) activity and the expression of p-CREB, CREB, and BDNF. The results showed that maternal supplementation with exogenous nucleotides during pregnancy could ameliorate prenatal ethanol-induced learning and memory deficits in the offspring of mice, through improving their antioxidant capacity, reversing hippocampus AChE levels, and allowing the expression of some proteins related to learning and memory. However, different sensitivities were found between the two sexes.     

Maternal behavior of rats is affected by hormonal condition of pups

Previous research has found that maternal rats discriminate male from female offspring and provide more anogenital licking to males. Two experiments were performed to determine whether this discrimination is based on hormonal condition of young. It was found that 500 micrograms of testosterone, estradiol, or dihydrotestosterone injected on the day of birth into female pups led to their receiving an equivalent amount of maternal anogenital licking as males and significantly more than either oil or untreated females. The different steroids had similar effects. Maternal nonanogenital licking was not affected by sex or hormonal condition of pups, but it was significantly increased by injection per se. Effects on maternal behavior of hormonal condition or neonatal injection of young were apparent 1 and 9 days after injection.     

Can the behaviour abnormalities induced by gestational stress in rats be prevented or reversed?

Gestational stress increases circulating maternal hormones that produce changes in behaviour and impair the feedback regulation of the hypothalamic pituitary adrenal axis of the offspring. Prenatally-stressed (PS) rats also release more corticotropin-releasing hormone (CRH) in the limbic system in response to stimulation than controls. This contributes to their exaggerated fear of intimidating situations and depressive-like behaviour. By using different treatments given to the pregnant mother, to neonatal or adult offspring, it has been possible to learn more about the mechanisms underlying the behavioural abnormalities induced by gestational stress. Many of these treatments were also able to prevent or reverse the abnormalities. They included maternal adrenalectomy and replacement of her basal hormone levels to avoid the prolonged elevation of plasma corticosterone, administration of anti-anxiety agents to reduce her reactions to the stress and continuous blockade of opioid receptors to prevent down-regulation of the foetal opioid system and subsequent alterations in behaviour. Hyperanxiety in the adult PS offspring could also be avoided if, as neonates, they were handled daily for 10 days, or given an antidepressant, amitriptyline for 4-5 weeks in the prepubertal period. Increased fear of novelty in adult PS rats could also be abolished by the intracerebro-ventricular administration of a CRH antagonist. This suggests that the new non-peptide CRH1 receptor antagonists that enter the brain might provide an effective treatment for the behaviour abnormalities in the offspring arising as a result of gestational stress.     

Effects of stress on nonassociative learning processes in male and female rats

In this study we assessed habituation and sensitization of the acoustic startle response (ASR) to discern whether intense, inescapable stress affects nonassociative learning differently in male and female rats. Rats were inescapably stressed 2 hours per day over 3 consecutive days. ASR magnitudes were measured at several times post-stress (1, 4, 8, and 15 days after cessation). Females generally showed greater ASR magnitudes (compared to males), but both sexes exhibited short and long-term habituation across the testing days. ASR magnitudes were only affected by stress in male subjects. The effect in males was an increase in short-term sensitization of the ASR on post-stress day-4. The results suggest that stressed males and females react differently to ASR testing, in that stress males appear to develop an exaggerated ASR response over repeated test sessions due to short-term sensitization. The source of the short-term sensitization is discussed with regards to possible stress-induced enhanced contextual learning during ASR testing on post-stress day-1.     

Effects of Stress on Nonassociative Learning Processes in Male and Female Rats

In this study we assessed habituation and sensitization of the acoustic startle response (ASR) to discern whether intense, inescapable stress affects nonassociative learning differently in male and female rats. Rats were inescapably stressed 2 hours per day over 3 consecutive days. ASR magnitudes were measured at several times post-stress (1, 4, 8, and 15 days after cessation). Females generally showed greater ASR magnitudes (compared to males), but both sexes exhibited short and long-term habituation across the testing days. ASR magnitudes were only affected by stress in male subjects. The effect in males was an increase in short-term sensitization of the ASR on post-stress day-4. The results suggest that stressed males and females react differently to ASR testing, in that stress males appear to develop an exaggerated ASR response over repeated test sessions due to short-term sensitization. The source of the short-term sensitization is discussed with regards to possible stress-induced enhanced contextual learning during ASR testing on post-stress day-1.     

Aggravation of DSS-induced colitis after chronic subordinate colony (CSC) housing is partially mediated by adrenal mechanisms

Chronic subordinate colony housing (CSC) is a relevant chronic psycho-social stressor for male mice. Here, we investigated effects of CSC on the severity of dextran sulphate sodium (DSS)-induced colitis and the involvement of adrenal mechanisms. After 19 days of CSC, male C57BL/6 mice were treated with 1% DSS (8 days). After 8 days, inflammatory shortening of the colon and the histological inflammation score were increased in CSC mice. Additionally, the increased secretion of pro-inflammatory cytokines by mesenteric lymph node cells found on day 2 and 4 of DSS treatment was down-regulated in CSC mice on day 8 of DSS treatment, paralleled by an increase in plasma corticosterone. In contrast, in unstressed controls, elevation of cytokine secretion was delayed and only found on day 8 of DSS treatment, associated with a prompt rise in plasma corticosterone. To reveal adrenal mechanisms in CSC-induced effects on colitis, mice were adrenalectomized, exposed to CSC and treated with DSS (8 days). In adrenalectomized CSC mice, the severity of DSS-induced colitis was reduced, as body weight loss, shortening of colon, histological damage score, and cytokine secretion from mesenteric lymph node cells were diminished compared with sham-operated CSC mice. In conclusion, exposure to chronic psycho-social stress increases the severity of acute DSS colitis, an effect which is, at least partly, mediated by adrenal mechanisms.