Genotype modulates prenatal stress effects on aggression in male and female mice

Prenatal stress (heat and restraint) significantly increased postpartum aggression (proportion of animals fighting and/or the intensity of the behavior) in C57BL/6J female mice and reduced the behavior in DBA/2J females. For intermale aggression, prenatal stress increased the behavior (intensity of aggression) in C57BL/6J males but did not affect aggressive behavior in DBA/2J animals. Infanticidal behavior (the killing of young) exhibited by male mice was not influenced by prenatal stress in either strain. Relative anogenital distance measurements in neonates at birth did not serve as a reliable predictor of strain variation in prenatal stress effects. Prenatal stress did not influence this measure of prenatal androgen exposure in DBA/2J or C57BL/6J females. For males, prenatal stress elevated relative anogenital distance in C57BL/6J mice and decreased this measure in DBA/2J animals. Prenatal stress effects on aggressive behavior in male and female mice therefore depend upon genotype. Strain-dependent differences may be modulated by differences in endocrine reactivity to prenatal stress/and or differential central neural tissue sensitivity to hormones.     

The effects of prenatal maternal stress on children's cognitive development: Project Ice Storm

There exists considerable research on the effects of prenatal maternal stress on offspring. Animal studies, using random assignment to experimental and control groups, demonstrate the noxious effects of prenatal maternal stress on physical, behavioural and cognitive development. The generalizability of these results to humans is problematic given that cognitive attributions moderate reactions to stressors. In humans, researchers have relied upon maternal anxiety or exposure to life events as proxies for the stressors used with animals. Yet, the associations between maternal anxiety or potentially non-independent life events and problems in infants are confounded by genetic transmission of temperament from mother to child. We summarize the literature on prenatal maternal stress and infant cognitive development, leading to the conclusion that the human literature lacks the ability to separate the effects of the objective exposure to a stressor and the mother's subjective reaction. We then describe our prospective Project Ice Storm in which we are following 150 children who were exposed in utero to a natural disaster. We demonstrate significant effects of the objective severity of exposure on cognitive and language development at age two years with important moderating effects of the timing during pregnancy. The implications of our findings are discussed.     

The mediating role of maternal responsiveness in some longer term effects of postnatal depression on infant development

We hypothesized a mediating role for low maternal responsiveness in certain child developmental deficits found previously to be associated with postnatal depression. Forty depressed inpatients and 48 control (non-depressed) mothers and their infants were followed until 42 months postpartum. Mother–infant interactions were impaired at 6 months postpartum in the depressed group. Subsequent cognitive deficits were found in children's Full Scale IQ on the Wechsler Preschool Primary Scale of Intelligence (Revised) at 42 months of age. Statistical modeling of the mediation hypothesis confirmed that these effects were overwhelmingly explained by lowered maternal responsiveness at 6 months. Similarly, increased temperamental difficulties were apparent in children of depressed mothers but were not correlated with maternal responsiveness. Male infants of depressed mothers were disproportionately vulnerable (compared to females) to impaired cognitive abilities associated with maternal depression. The data concur with previous work and provide empirical support for the theoretical prediction that early disturbances of the mother–infant interaction will mediate some developmental deficits in the children of depressed mothers.     

No postnatal maternal effect on male aggressiveness in wild-derived strains of house mice

Male aggressiveness is a complex behavior influenced by a number of genetic and non-genetic factors. Traditionally, the contribution of each of these factors has been established from experiments using artificially selected strains for high/low aggressive phenotypes. However, little is known about the factors underlying aggressive behavior in natural populations. In this study, we assess the influence of genetic background vs. postnatal maternal environment using a set of cross-fostering experiments between two wild-derived inbred strains, displaying high (STRA, derived from Mus musculus domesticus) and low (BUSNA, derived from Mus musculus musculus) levels of aggressiveness. The role of maternal environment was tested in males with the same genetic background (i.e. strain origin) reared under three different conditions: unfostered (weaned by mother), infostered (weaned by an unfamiliar dam from the same strain), and cross-fostered (weaned by a dam from a different strain). All males were tested against non-aggressive opponents from the A/J inbred strain. Resource-holding potential was assessed through body weight gains and territory ownership. The STRA males were shown to be aggressive in both neutral cage and resident-intruder tests. On the contrary, the BUSNA males were less aggressive in all tests. We did not find a significant effect of postnatal maternal environment; however, we detected significant maternal effect on body weight with differences between the strains, fostering type and interactions between these factors. We conclude that the aggressiveness preserved in the two strains has significant genetic component whose genetic basis can be dissected by quantitative trait loci analysis.     

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.     

The effects of neonatal gonadectomy and prenatal stress on cortical thickness and asymmetry in rats

In Study I measures of cortical thickness were taken in 90-day-old male and female Sprague-Dawley, Wistar, and Long-Evans rats that were born to pregnant females shipped to the laboratory in late pregnancy and that were either gonadectomized at birth or left intact. No evidence for hemispheric differences in cortical thickness was found in any of the groups. Gonadectomy resulted in increased cortical thickness in male Sprague-Dawley and Wistar rats and in small increases in thickness of the left hemisphere in Long-Evans rats, especially males. No effects of gonadectomy were found in females of any strain. The lack of the expected right-over-left difference in cortical thickness in intact males may have been due to prenatal stress caused by housing, handling, and shipping. In Study 2 measures of cortical thickness were taken in 90-day-old male and female Sprague-Dawley rats that were bred in our laboratory, but otherwise similarly treated at birth. In this second study, the expected right-over-left hemispheric difference in cortical thickness was found in intact male rats; none was found in gonadectomized males or in either of the female groups. The lack of asymmetry in gonadectomized males appeared to be due to an increase in thickness in the left hemisphere. Taken together these studies provide support for the idea that hormones of testicular origin suppress cortical enlargement in the perinatal period, particularly in the left hemisphere.     

The effects of prenatal stress on motivation in the rat pup

Exposure to prenatal stress (PNS) has been shown to induce a set of psychological and behavioral changes in developing offspring. We used the rodent model to investigate whether PNS produces changes in the ability of the pup to express social motivation. We used a set of behavioral tasks including monitoring ultrasonic vocalizations after isolation, a conditioned place preference, and a novel and familiar odor approach test. Pregnant Long-Evans rats were exposed to an unpredictable, variable stressor twice daily during the third week of gestation. Isolation vocalizations were assessed on postnatal day (PND) 10. Pup affinity for the dam was evaluated on PND 15. Typically, pups display a selective preference for an odor-paired environment only after the odor has been associated with the dam. This previous association produces a positive conditioned stimulus (CS). Normally, pups exposed to a neutral CS (odor paired with cotton balls) do not form this place preference. Results indicate that PNS exposed pups had significantly increased distress vocalizations and an equal preference for the positive and neutral conditioned stimuli. This type of alteration in forming early preferences could be detrimental because of decreases in the specificity of social learning and an impaired responsiveness in social relationships.     

Early maternal separation has mild effects on cardiac autonomic balance and heart structure in adult male rats

Early life adverse experiences have long-term physiologic and behavioral effects and enhance stress sensitivity. This study examined the effects of maternal separation (MS) on cardiac stress responsivity and structure in adulthood. Male Wistar rats were separated from the dams for 3?h per day from postnatal days 2 through 15. When exposed to 5-day intermittent restraint stress (IRS) as adults, MS, and control rats showed similar acute modifications of cardiac sympathovagal balance, quantified via heart rate variability analysis. In addition, MS had no effect on cardiac pacemaker intrinsic activity (as revealed by autonomic blockade with scopolamine and atenolol) and did not affect the circadian rhythmicity of heart rate, neither before nor after IRS. However, MS differed from control rats in cardiac parasympathetic drive following IRS, which was heightened in the latter but remained unchanged in the former, both during the light and dark phases of the daily rhythm. The evaluation of adult cardiac structure indicated that stress experienced during a crucial developmental period induced only modest changes, involving cardiomyocyte hypertrophy, increased density of vascular structures, and myocardial fibrosis. The mildness of these functional-structural effects questions the validity of MS as a model for early stress-induced cardiac disease in humans.     

Histamine reverses a memory deficit induced in rats by early postnatal maternal deprivation

Early partial maternal deprivation causes long-lasting neurochemical, behavioral and brain structural effects. In rats, it causes a deficit in memory consolidation visible in adult life. Some of these deficits can be reversed by donepezil and galantamine, which suggests that they may result from an impairment of brain cholinergic transmission. One such deficit, representative of all others, is an impairment of memory consolidation, clearly observable in a one-trial inhibitory avoidance task. Recent data suggest a role of brain histaminergic systems in the regulation of behavior, particularly inhibitory avoidance learning. Here we investigate whether histamine itself, its analog SKF-91844, or various receptor-selective histamine agonists and antagonists given into the CA1 region of the hippocampus immediately post-training can affect retention of one-trial inhibitory avoidance in rats submitted to early postnatal maternal deprivation. We found that histamine, SKF-91844 and the H2 receptor agonist, dimaprit enhance consolidation on their own and reverse the consolidation deficit induced by maternal deprivation. The enhancing effect of histamine was blocked by the H2 receptor antagonist, ranitidine, but not by the H1 receptor antagonist pyrilamine or by the H3 antagonist thioperamide given into CA1 at doses known to have other behavioral actions, without altering locomotor and exploratory activity or the anxiety state of the animals. The present results suggest that the memory deficit induced by early postnatal maternal deprivation in rats may in part be due to an impairment of histamine mediated mechanisms in the CA1 region of the rat hippocampus.     

The effects of the child with Down syndrome on maternal stress

This article examines the nature and correlates of stress in mothers of children with Down syndrome. In the first part of our study, we compared 27 mothers of children with Down syndrome with 15 mothers of children with heterogeneous causes of learning difficulty. Using Abidin's (1995) Parenting Stress Index (PSI), mothers in the Down syndrome group reported lower total child‐related stress levels, particularly concerning the degree to which the mother considers the child acceptable and reinforcing. In the second part, we identified predictors of stress in mothers of children and adolescents with Down syndrome (N = 37). Children's behaviour problems related to higher levels of overall and specific domains of child‐related stress, and children who were reported as being more cheerful and outgoing had parents who judged their offspring as more acceptable and reinforcing. Mothers also rated their children as less reinforcing when offspring were older.     

Evaluation of prenatal androgen and ovarian secretions on receptivity in female and male rats

Offspring of rats infected daily from Day 16 through Day 20 of gestation with either 2 mg of testosterone propionate (TP) in .1 ml of sesame oil or oil alone were tested for sexual receptivity following injections of 3.3 microgram of estradiol benzoate (EB) and .5 mg of progesterone (P) beginning at 40, 80, or 120 days of age. At each age, neonatally gonadectomized males and females from TP-injected litters exhibited less receptivity than corresponding oil-injected controls. Prenatally androgenized females were similar to neonatally castrated oil-injected males at all ages. Ovarian implants from birth to 35 days of age significantly increased receptivity in neonatally castrated males and androgenized females. Increasing the age at which testing was initiated systematically reduced receptivity in all groups.     

Anxiolytic effects of repeated victory in male Wistar rats

Recurring evidence suggests that social stress has anxiogenic‐like effects in laboratory rodents. However, despite the fact that competitive situations are stressful, success in competitive situations reduces anxiety in humans. The aim of the present study was to investigate whether repeated experience of winning in aggressive encounters affects anxiety measures in laboratory rodents. Male rats were housed together with a female for 2 weeks. Cohabitation with females was necessary to induce high levels of aggressiveness in these animals. During the second week, half of the male rats were exposed daily for 30 min to an intruder of smaller size, and the other half remained undisturbed in their home cage. Group‐housed male rats were also used as controls. Residents attacked and defeated intruders, who did not retaliate. After the fifth encounter, all animals were tested for anxiety on the elevated plus‐maze. Repeated victory lowered anxiety measures considerably, despite the fact that aggressive encounters are stressful even for the victor. It is concluded that repeated victory has an anxiolytic action in male rats. The similarities with human data suggest that repeated winning in rats can be used as a laboratory model for success‐induced changes in human anxiety. Aggr. Behav. 26:257–261, 2000. © 2000 Wiley‐Liss, Inc.     

Social determinants of health,prenatal maternal stress,and earlier birth during the COVID-19 pandemic

During the COVID-19 pandemic, pregnant women, especially those from socioeconomically disadvantaged and marginalized groups, experienced unprecedented stress. Prenatal stress and social determinants of health (SDoH) such as lower education and lack of a relationship partner are known to contribute to earlier birth. However, whether SDoH and stress independently contribute or whether the harmful impact of SDoH is mediated by stress is unknown. Moreover, the contributions of these factors has not been investigated in the context of a communal health crisis such as the COVID-19 pandemic. To examine these processes, we used a longitudinal cohort of 2473 women pregnant during the COVID-19 pandemic who reported a live birth. We compared structural equation models predicting gestational age at birth from SDoH (race/ethnicity, education, financial security, health insurance, relationship status, and lifetime abuse) and from prenatal maternal stress related and unrelated to the COVID-19 pandemic. Results indicate that the association of SDoH with earlier birth was partially mediated by prenatal stress. These findings help uncover mechanisms explaining health disparities in the U.S. and highlight the need to address both SDoH and the stress that these factors produce in under-resourced and marginalized communities.     

The impact of prenatal maternal stress and optimistic disposition on birth outcomes in medically high-risk women.

A sizable body of evidence indicates that prenatal maternal stress (PNMS) has an adverse impact on birth outcomes, including birth weight and gestational age at delivery. The authors hypothesized that effects of PNMS are attributable in part to dispositions such as pessimism that lead women to view their lives as stressful and that effects of PNMS and disposition on birth outcome are mediated by prenatal health behaviors. Using structural equations modeling procedures, the authors examined prospective impact of PNMS and dispositional optimism on birth weight and gestational age in a medically high-risk sample (N = 129), controlling for effects of risk and ethnicity. After its strong inverse association with optimism was accounted for, PNMS had no impact on birth outcomes. Women who were least optimistic delivered infants who weighed significantly less, controlling for gestational age. Optimists were more likely to exercise, and exercise was associated with lower risk of preterm delivery. Results suggest that chronic stress in pregnancy may be a reflection of underlying dispositions that contribute to adverse birth outcomes.     

The relationship between romantic and prenatal maternal attachment: The moderating role of social support

The aim of this study was to examine the relationships between three types of maternal attachment bonds: anxious romantic, avoidant romantic and prenatal. The moderating role of perceived social support is also analysed. Ninety-one pregnant women in or near their thirtieth week of gestation (M = 29.59; SD = 4.57) were recruited, all of whom completed a series of questionnaires to assess the quality of their romantic and prenatal attachment bonds and their levels of perceived social support. The results reveal that both anxious and avoidant romantic attachments were significantly associated with low levels of maternal prenatal attachment. Moreover, the level of social support perceived during pregnancy moderated the relationship between anxious and prenatal attachments but had no effect on avoidant romantic and prenatal attachments. Our discussion of these findings considers the emotional and behavioural characteristics of various forms of insecure romantic attachments. Overall, the data highlight the relevance of the quality of intimate close relationships on maternity experiences and women's caregiving abilities.     

Differential vascular adaptive response to stress exposure in male and female rats: role of gonadal hormones and endothelial cells

Although there are reports concerning a vascular adaptive response to stress in males, this is not yet defined in females. The aim of this study was to delineate functional gender differences in the rat vascular adaptive response to stress and to determine the ability of sex hormones to modulate the stress-induced vascular adaptive response. Responses to noradrenaline were evaluated in aortas, with and without endothelium, from intact, gonadectomized and gonadectomized-hormone-replaced males and females submitted or not to stress (2-h immobilization). Reactivity of the aorta of stressed and non-stressed intact males and females (n = 6-14 per group) was also examined in the presence of L-NAME or indomethacin. Stress decreased and gonadectomy increased maximal responses to noradrenaline in aortas with intact endothelium from both genders. Stress also reduced noradrenaline potency in males. In females, but not males, stress decreased the gonadectomy-induced noradrenaline hyper-reactivity to near that of intact non-stressed rats. Hormone replacement restored the gonadectomy-induced impaired vascular adaptive response to stress. L-NAME, but not indomethacin, abolished the stress-induced decrease in aorta reactivity of males and females. None of the procedures altered reactivity of aortas denuded of endothelium. CONCLUSION: Stress-induced vascular adaptive responses show gender differences. The magnitude of the adaptive response is dependent on testicular hormones and involves endothelial nitric oxide-system hyperactivity.     

Early-life stress affects extinction during critical periods of development: An analysis of the effects of maternal separation on extinction in adolescent rats

Adolescence is a period of heightened susceptibility to anxiety disorders, yet we have little experimental evidence on what factors may lead to psychopathology in adolescence. Preclinical models of extinction are commonly used to study the treatment of anxiety symptoms. Interestingly, recent research has shown that there are fundamental changes in the process of extinction across development, which may have implications for our understanding of psychopathology across the lifespan. Specifically, this research shows that the process of extinction parallels the nonlinear function of prefrontal cortex development, such that extinction behaviour is similar in juvenile and adult rats, but involves different processes in infancy and adolescence (periods of rapid growth and pruning, respectively). Our previous studies have shown that early-life stress accelerates the transition between infant and juvenile extinction systems. In the current series of experiments, we examined whether the same early-life stress, maternal separation (MS), would lead to an earlier transition between the juvenile and adolescent extinction systems, and between the adolescent and adult extinction systems. We show that MS adolescent rats exhibit more adult-like extinction behaviour, and that adolescent-like extinction emerges earlier in development (i.e. in pre-adolescent rats). These results may have important implications for the understanding and treatment of anxiety symptoms in adolescent populations.     

Adaptation of anterior pituitary hormones to chronic noise stress in male rats

We have studied the effects of acute and chronic noise on serum levels of pituitary hormones in male Wistar rats. Acute noise increased serum levels of corticosterone, prolactin, and luteinizing hormone and decreased serum GH. FSH was unaffected by this stressor. Chronic noise did not modify basal levels of any hormone studied, however responsiveness of some hormones to the same stimuli was altered. Reduced corticosterone, prolactin, and GH responses to noise was observed after previous chronic exposure to this stimuli. LH response followed the same pattern although it did not reach statistical significance. It might be concluded that adaptation to a repeated stress stimulus is not confined to the pituitary-adrenal axis, however, the degree of adaptation could vary between different hormones.