Prenatal stress alters early neurobehavior, stress reactivity and learning in non-human primates: a brief review

In this paper we review three prospective longitudinal studies from our laboratory examining the effects of prenatal stress on early neuro behavior, stress reactivity and learning performance in rhesus monkeys. Either a noise stressor or ACTH treatment was administered to pregnant monkeys during specific periods of pregnancy and offspring were examined repeatedly across development. In all three studies, the prenatally stressed monkeys showed reduced attention and impaired neuromotor functioning during the first month of life compared to controls from undisturbed pregnancies. When the monkeys were separated from their mothers or peers at 6-8 months of age, prenatally stressed monkeys exhibited more disturbance behavior and showed hypothalamic-pituitary-adrenal axis dysregulation. During adolescence, they exhibited impairments in learning, compared to controls.     

Hormonal and behavioural abnormalities induced by stress in utero: an animal model for depression

Prenatal stress in rats can exert profound influence on the off spring's development, inducing abnormalities such as increased "anxiety", "emotionality" or "depression-like" behaviours.Prenatal stress has long-term effects on the development of the hypothalamo-pituitary-adrenal(HPA) axis and forebrain cholinergic systems. These long-term neuroendocrinological effects are mediated, at least in part, by stress-induced maternal corticosterone increase during pregnancy and stress-induced maternal anxiety during the postnatal period. We have shown a significant phase advance in the circadian rhythms of corticosterone secretion and locomotor activity in prenatally-stressed (PNS) rats. When subjected to an abrupt shift in the light-dark(LD) cycle, PNS rats resynchronized their activity rhythm more slowly than control rats. In view of the data suggesting abnormalities in the circadian timing system in these animals, we have investigated the effects of prenatal stress on the sleep-wake cycle in adult male rats. PNS rats exhibited various changes in sleep-wake parameters, including a dramatic increase in the amount of paradoxical sleep. Taken together, our results indicate that prenatal stress can induce increased responses to stress and abnormal circadian rhythms and sleep in adult rats.Various clinical observations in humans suggest a possible pathophysiological link between depression and disturbances in circadian rhythmicity. Circadian abnormalities in depression can be related to those found in PNS rats. Interestingly, we have recently shown that the increased immobility in the forced swimming test observed in PNS rats can be corrected by chronic treatment with the antidepressant tianeptine, or with melatonin or S23478, a melatonin agonist. Those results reinforce the idea of the usefulness of PNS rats as an appropriate animal model to study human depression and support a new antidepressant-like effect of melatonin and the melatonin agonist S23478.     

Effects of prenatal ethanol exposure on juvenile play-fighting and postpubertal aggression in rats

The effects of prenatal ethanol exposure on juvenile play-fighting and postpubertal aggressive behavior in rats were longitudinally assessed in the context of more conventionally applied physical and behavioral measures. Pregnant animals were treated with either 2 gm/kg/day ethanol or isocaloric sucrose over gestation Days 6-19. Reproduction and somatic variables included maternal weight over gestation, offspring weight over Days 1-90, and age at eye opening and incisor eruption. Behavioral variables consisted of negative geotaxis, olfactory discrimination, activity, juvenile play-fighting, and postpubertal aggression. Ethanol offspring had lower birth weights, but there was no significant prenatal treatment effect on subsequent offspring weights or on any other reproductive or somatic variable. Both male and female ethanol-exposed offspring exhibited more play-fighting responses when paired with same-sex controls. Postpubertal aggression levels were assessed in males only. Ethanol-exposed offspring were more aggressive than controls and there was a significant positive correlation between play-fighting and postpubertal aggression ranks. No other behavioral measures discriminated between prenatal treatment groups and none were significantly correlated with either play-fighting or postpubertal aggression rank. The results are consistent with the position that juvenile play-fighting and postpubertal aggression are subserved by common substrates. They also are consistent with predictions derived from the hypothesis concerning a response-inhibition deficit as an effect of prenatal ethanol exposure on behavior.     

Token transfer between mother and offspring chimpanzees (Pan troglodytes): mother–offspring interaction in a competitive situation

Chimpanzees can flexibly use tokens in cognitive tasks, but it is still unknown if they can share and/or compete over tokens as they do for food. This study aimed to evaluate the interactions spontaneously occurring between mother and offspring chimpanzees when tokens exchangeable for food were provided. Forty tokens were scattered on the floor in an experimental playroom. Three mother and offspring chimpanzee pairs were tested. Each token was exchangeable for a piece of food in a vending machine installed on the wall of the playroom. In the beginning of the study, both mother and offspring took tokens and exchanged them for pieces of food independently. Later, two offspring started to take more tokens than their mothers. At that time, the offspring whimpered or cried more often than during earlier sessions. This behavior compelled the mothers to abstain from taking tokens. The mothers sometimes shared their tokens with their offspring, or were tolerant of their offspring taking their tokens from their hand. For one pair, the offspring sometimes shared tokens with her mother when her mother begged for the tokens. These results suggest that chimpanzees’ cognitive abilities enable them not only to use tokens, but also to compete for tokens, as they do for food. The results also suggest that token sharing between mother and offspring may be bidirectional and that transfer of tokens mainly occurs as a result of begging, although on some occasion offspring were able to obtain a token directly from his/her mother through tolerated scrounging.     

Exogenous androgen activates female behavior in noncopulating, prenatally stressed male rats

Male copulatory behavior was severely impaired in the male offspring of female rats stressed during pregnancy. This deficiency persisted even after castration and prolonged treatment with testosterone propionate and after exposure to electric skin shock. However, androgen treatment effectively activated female lordotic behavior in a large percentage of prenatally stressed males but not in any control animals and in only a negligible number of postnatally stressed males. Although prenatal stress demasculinizes and feminizes behavior, no modifications of reproductive morphology were detectable. It is postulated that prenatal stress alters normal sexual behavior differentiation by attenuating testosterone secretion from the fetal testes.     

Prenatal stress and risk for psychopathology: specific effects or induction of general susceptibility?

This review focuses on prenatal stress as a risk factor for psychopathology. Evidence from animal studies is summarized, and the relevance of prenatal stress models in animals for human studies is discussed. In the offspring of prenatally stressed animals, overactivity and impaired negative feedback regulation of the hypothalamic-pituitary-adrenal axis are consistent findings and may reflect a pathophysiological mechanism involved in the development of psychopathology. Reduced activity of the opioid GABA/benzodiazepine, serotonin, and dopamine systems and increased activity of the sympathico-adrenal system have been found as well. These alterations have been linked to a diverse spectrum of psychopathology. Therefore, the evidence supports the view that exposure to prenatal stress may result in a general susceptibility to psychopathology, rather than exerting a direct effect on a specific form of psychopathology.     

Affiliation and aggression as related to gender in domestic chicks (Gallus gallus).

Social discrimination in male and female domestic chicks (Gallus gallus) was investigated by using (a) latencies of approach response, (b) simultaneous free choice, and (c) intersubject aggressive-pecking tests. In approach-response tests, females showed shorter latencies when tested with cagemates than when tested with strangers, whereas males showed shorter latencies when tested with strangers than when tested with cagemates. In simultaneous-choice tests, females spent more time near a cagemate, whereas males spent more time near a strange chick. In aggressive-pecking tests, both sexes pecked more at strangers than at cagemates; aggressive pecking at strangers, however, was higher in males than in females. It is argued that gender effects in social discrimination can be accounted for in terms of stronger social attachment in females and aggressive responses in males.     

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.     

Infant Parasympathetic and Sympathetic Activity during Baseline,Stress and Recovery: Interactions with Prenatal Adversity Predict Physical Aggression in Toddlerhood

Exposure to prenatal adversity is associated with aggression later in life. Individual differences in autonomic nervous system (ANS) functioning, specifically nonreciprocal activation of the parasympathetic (PNS) and sympathetic (SNS) nervous systems, increase susceptibility to aggression, especially in the context of adversity. Previous work examining interactions between early adversity and ANS functioning in infancy is scarce and has not examined interaction between PNS and SNS. This study examined whether the PNS and SNS moderate the relation between cumulative prenatal risk and early physical aggression in 124 children (57% male). Cumulative risk (e.g., maternal psychiatric disorder, substance (ab)use, and social adversity) was assessed during pregnancy. Parasympathetic respiratory sinus arrhythmia (RSA) and sympathetic pre-ejection period (PEP) at baseline, in response to and during recovery from emotional challenge were measured at 6 months. Physical aggression and non-physical aggression/oppositional behavior were measured at 30 months. The results showed that cumulative prenatal risk predicted elevated physical aggression and non-physical aggression/oppositional behavior in toddlerhood; however, the effects on physical aggression were moderated by PNS and SNS functioning. Specifically, the effects of cumulative risk on physical aggression were particularly evident in children characterized by low baseline PNS activity and/or by nonreciprocal activity of the PNS and SNS, characterized by decreased activity (i.e., coinhibition) or increased activity (i.e., coactivation) of both systems at baseline and/or in response to emotional challenge. These findings extend our understanding of the interaction between perinatal risk and infant ANS functioning on developmental outcome.     

Enriched environment treatment restores impaired hippocampal synaptic plasticity and cognitive deficits induced by prenatal chronic stress

Prenatal stress can cause long-term effects on cognitive functions in offspring. Hippocampal synaptic plasticity, believed to be the mechanism underlying certain types of learning and memory, and known to be sensitive to behavioral stress, can be changed by prenatal stress. Whether enriched environment treatment (EE) in early postnatal periods can cause a recovery from these deficits is unknown. Experimental animals were Wistar rats. Prenatal stress was evoked by 10 foot shocks (0.8 mA for 1s, 2-3 min apart) in 30 min per day at gestational day 13-19. After weaning at postnatal day 22, experimental offspring were given the enriched environment treatment through all experiments until tested (older than 52 days age). Electrophysiological and Morris water maze testing was performed at 8 weeks of age. The results showed that prenatal stress impaired long-term potentiation (LTP) but facilitated long-term depression (LTD) in the hippocampal CA1 region in the slices. Furthermore, prenatal stress exacerbated the effects of acute stress on hippocampal LTP and LTD, and also impaired spatial learning and memory in the Morris water maze. However, all these deficits induced by prenatal stress were recovered by enriched environment treatment. This work observes a phenomenon that may contribute to the understanding of clinically important interactions among cognitive deficit, prenatal stress and enriched environment treatment. Enriched environment treatment on early postnatal periods may be one potentially important target for therapeutic interventions in preventing the prenatal stress-induced cognitive disorders.     

Altered grooming responses to stress in rats exposed prenatally to ethanol

The effects of prenatal alcohol exposure on grooming, locomotion, and rearing in response to stress were examined in adult rats whose mothers consumed a liquid diet containing 35% ethanol-derived calories (EDC). Offspring of both pair-fed 0% EDC mothers and ad libitum chow-fed mothers were included as controls. In Experiment 1, females groomed more than males following placement into a novel test chamber, but no differences due to prenatal treatment were observed. Ethanol-exposed animals groomed more than controls following the stress of a forced 1-min swim (Experiment 2), but when rats tested in Experiment 1 were observed again after forced swim stress (Experiment 3), no differences due to prenatal treatment or sex were observed. Experiment 4 examined the effects of pretreatment with 1 mg/kg naloxone on novelty-induced grooming and as in Experiment 1 prenatal treatment did not affect grooming responses. Females again groomed significantly more than males and naloxone reduced grooming equally for all groups. The results suggest that novelty-induced grooming is a sex-influenced behavior, with females grooming more than males, and that animals exposed prenatally to alcohol and tested as adults may have altered responses to certain stressors (i.e., forced swim) under specific conditions. The altered grooming response of alcohol-exposed rats to swim stress can be eliminated by preexposing them to novelty stress.     

Enhanced feminine sexual behavior and infertility in female rats prenatally treated with an antiestrogen

An attempt to elucidate the possible role of prenatal estrogen on the development of feminine sexual behavior and reproductive function was made by treating females with the antiestrogen CI628 prenatally on days 13-19. Control females were prenatally treated with saline or remained untreated. The animals were delivered by caesarian section on day 22 of pregnancy and placed with foster mothers whose newborn pups had been previously removed. Intact peripubertal females in each treatment group were observed for several reproductive measures, including the capacity to become pregnant. Other females were ovariectomized in adulthood and treated with estradiol benzoate (EB) (1, 1.5, 2 or 4 micro g/rat) and 0.5 mg progesterone and tested for receptivity, proceptivity and sexual partner preference. Two weeks after the completion of these tests, the females were injected daily for 7 days with 0.25 mg testosterone and tested for sexual partner preference and mounting behavior. The results obtained showed accelerated vaginal opening, and infertility in the antiestrogen-treated intact females and enhanced receptivity and proceptivity in response to 1 micro g EB in the antiestrogen ovariectomized females. Sexual partner preference and mounting behavior did not differ between groups. These results suggest an involvement of prenatal estrogen on the development of female reproductive function, but not on behavioral differentiation.     

Stress in cynomolgus monkeys (Macaca fascicularis) subjected to long-distance transport and simulated transport housing conditions

The stress associated with transportation of non-human primates used in scientific research is an important but almost unexplored part of laboratory animal husbandry. The procedures and routines concerning transport are not only important for the animals' physical health but also for their mental health as well. The transport stress in cynomolgus monkeys (Macaca fascicularis) was studied in two experiments. In Experiment 1, 25 adult female cynomolgus monkeys were divided into five groups of five animals each that received different diets during the transport phase of the experiment. All animals were transported in conventional single animal transport cages with no visual or tactile contact with conspecifics. The animals were transported by lorry for 24 h at ambient temperatures ranging between 20 degrees C and 35 degrees C. Urine produced before, during and after transport was collected and analysed for cortisol by enzyme-linked immunosorbent assay (ELISA). All monkeys exhibited a significant increase in cortisol excretion per time unit during the transport and on the first day following transport.Although anecdotal reports concerning diet during transport, including the provision of fruits and/or a tranquiliser, was thought likely to influence stress responses, these were not corrobated by the present study. In Experiment 2, behavioural data were collected from 18 cynomolgus macaques before and after transfer from group cages to either single or pair housing, and also before and after a simulated transport, in which the animals were housed in transport cages. The single housed monkeys were confined to single transport cages and the pair housed monkeys were kept in their pairs in double size cages. Both pair housed and singly housed monkeys showed clear behavioural signs of stress soon after their transfer out of their group cages.However, stress-associated behaviours were more prevalent in singly housed animals than in pair housed animals, and these behaviours persisted for a longer time after the simulated transport housing event than in the pair housed monkeys. Our data confirm that the transport of cynomolgus monkeys is stressful and suggest that it would be beneficial for the cynomolgus monkeys to be housed and transported in compatible pairs from the time they leave their group cages at the source country breeding facility until they arrive at their final laboratory destination in the country of use.     

Vasopressin, maternal behavior, and pup well-being

The brain peptide, vasopressin (VP), was studied with respect to its effects on maternal care in rearing natural and cross-fostered pups. Long-Evans (LE) rats synthesize hypothalamic VP; whereas, Brattleboro (DI) rats do not produce this peptide. Long-Evans dams exhibited superior maternal care when compared with DI dams when rearing their own as well as foster pups. This enhanced behavior was evidenced by the higher survival rate of pups reared by LE mothers compared to those reared by DI mothers. Later, when the offspring were subjected to the stress of 23 hours of food restriction each day, LE animals reared by their natural mothers survived for a significantly longer period of time and developed significantly less stomach pathology than DI animals reared by their natural mothers or LE foster mothers. The results demonstrated that the secondary factor of maternal care in the absence of VP was of little consequence in the characteristic difficulties observed in DI offspring.     

Vasopressin,maternal behavior,and pup well-being

The brain peptide, vasopressin (VP), was studied with respect to its effects on maternal care in rearing natural and cross-fostered pups. Long-Evans (LE) rats synthesize hypothalamic VP; whereas, Brattleboro (DI) rats do not produce this peptide. Long-Evans dams exhibited superior maternal care when compared with DI dams when rearing their own as well as foster pups. This enhanced behavior was evidenced by the higher survival rate of pups reared by LE mothers compared to those reared by DI mothers. Later, when the offspring were subjected to the stress of 23 hours of food restriction each day, LE animals reared by their natural mothers survived for a significantly longer period of time and developed significantly less stomach pathology than DI animals reared by their natural mothers or LE foster mothers. The results demonstrated that the secondary factor of maternal care in the absence of VP was of little consequence in the characteristic difficulties observed in DI offspring.     

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.     

Aggressive and affiliative behavior in green monkeys with differing housing complexity

Eleven green monkeys (Cercopithecus aethiops) were combined into three social groups (two heterosexual, one all-male) in enclosures with similar volume but different levels of environmental complexity (two or four compartments). Agonistic and affiliative interactions were recorded over a 21-week period. The two heterosexual groups had their environmental complexity reduced (number of compartments reduced by one-half and volume/floorspace reduced by one-third) for a 5-week period in the middle of the study. Rates of contact aggression were low throughout the study. In the group with complexity reduced to one compartment, rates of noncontact aggression and affiliative behavior increased, and remained high after complexity was restored. In the group reduced to two compartments, rates of affiliative behavior increased but rates of noncontact aggression decreased, trends which continued after complexity was restored. The all-male group exhibited low rates of affiliative behavior throughout. Two compartments appear to foster successful group formation, but any change in a group's enclosure can have long-term effects on rates of aggression. © 1992 Wiley-Liss, Inc.     

Cross-sectional and longitudinal observations of activity level and sustained attention in a normative sample

This study examined developmental changes in playroom observations of activity level and sustained attention among 47 elementary school-age boys. The boys were observed at two different times, approximately 2 years apart. The playroom observations consisted of two 15-minute periods, a relatively unstructured freeplay period and a structured restricted academic period. In general, both cross-sectional and longitudinal analyses suggested developmental improvements in the observed behaviors. Both gross and fine motor activity decreased with increasing age, while the time spent on task increased. Consistent with the selective attention literature, there appeared to be a dramatic increase in the boys' ability of focus attention at around age 11. Finally, most of the behaviors in the restricted academic period showed significant stability over time, whereas few of the free-play behaviors did so.This research was supported by NIH Grant No. 32992.     

Social and nonsocial behaviors of adult rhesus monkeys after amygdalectomy in infancy or adulthood.

At 6 yr of age six female rhesus monkeys that had sustained bilateral amygdalectomy in infancy, and five intact controls, were transferred to an observation cage where behaviors were recorded while the monkeys were (a) alone, (b) paired with unfamiliar stimulus animals, and (c) paired with familiar monkeys from the opposite experimental group. The five adult controls then underwent amygdalectomy, and all tests were repeated with the infant- and adult-operated animals. Infant-operated monkeys changed behaviors more rapidly than did intact controls in social and nonsocial situations, and their activity levels were less modified after a 24-hr period in the observation cage. They were subordinate to intact controls but expressed less fear than did controls when briefly placed with an unfamiliar aggressive animal. Adult amygdalectomy produced many changes in behavior, but these aberrations were identical to those observed in like-age monkeys that had been amygdalectomized in infancy. Infant-operated monkeys demonstrated more behavioral deficits at 6 yr than they had earlier in life.     

Variation in aggressive behavior and anatomo-physiological correlates generated by crowding without physical contact in the house mouse

Behavioral, physiological (i.e., endocrine), and anatomical consequences of crowding in mice were studied in a situation where animals were in auditory, visual, olfactory, and tactile contact but restrained from full physical interactions, to prevent overt aggression. Males that cohabited with females undisturbed by neighboring conspecifics showed greater propensity to attack same-sex intruders and had higher plasma testosterone levels than did their “crowded” counterparts, that is, males cohabiting with females and housed adjacent to other male/female pairs. In this respect, the latter animals resembled submissive males. However, a significant increase in weight of androgen-dependent target organs (i.e., seminal vesicles and preputial glands) was found in crowded males. These data indicate that despite the observed inhibition of social aggression these males are not physiologically comparable (homologous) to male mice that experienced defeat and the stress of submission during fighting. The intriguing possibility that different conversion pathway of testosterone are accelerated, as a result of social communication, in males living in these two environments and the behavioral implications of these possibilities are discussed. Finally, the parental behavior of crowded animals, although not freely interacting with each other, was disrupted, causing a marked decrease in reproductive success. In this situation a high incidence of infanticide of their offspring by both parents was observed, whereas this behavior was virtually absent in non-crowded male/female pairs.