Prenatal stress eliminates differential maternal attention to male offspring in Norway rats

Maternal licking behavior was observed in 20 Long-Evans rat dams on two consecutive days. Stimulus pups were male and female foster pups from dams that were either housed with 5 adult males during the last trimester of pregnancy (stressed) or housed alone (unstressed). Unstressed male pups received significantly more maternal licking than their female siblings, but prenatally stressed males and females received similar levels of maternal licking, comparable to that directed to unstressed females. In a second study, urine collected from prenatally stressed male pups elicited significantly less investigation from dams in a choice test than urine from age-matched unstressed males. It is concluded that the chemosignals which stimulate dams normally to provide more maternal attention to male than female neonates are deficient in prenatally stressed males. The results raise the possibility that differential maternal care may mediate some effects of prenatal stress on behavioral development in males.     

Uterine positions and schedules of urination: correlates of differential maternal anogenital stimulation

Lactating Mongolian gerbils, like lactating Norway rats, reliably lick some pups in their litters more than they lick others. Male gerbil pups are licked more by their dams than are their sisters and some males and some females within each litter are licked more often than are their sibs of the same sex. In the present article, we explore the characteristics of same-sex littermates that are correlated with elicitation of extreme amounts of maternal anogenital licking. We found that both the male pup and the female pup in a litter of gerbils that received the most maternal anogenital licking: (1) released greater quantities of urine and (2) exhibited longer latencies to begin to urinate in response to artificial anogenital stimulation than did the male pup and the female pup in a litter that received the least amount of maternal anogenital licking. We also found that foster mothers rearing Caesarean-delivered litters spent more time licking the anogenital areas of: (1) those male pups that, as fetuses, had occupied uterine locations adjacent to relatively few females and (2) those female pups that, as fetuses, had occupied uterine locations adjacent to relatively many males. We discuss implications of these findings for understanding of how maternal behavior may mediate hormonal effects on the development of young gerbils.     

Corpus callosum: interactive effects of infantile handling and testosterone in the rat

Previous research found that the corpus callosum of male rats is larger than that of females; handling rats in infancy enhances this sex difference; and female rat pups, when handled in infancy and given 1 injection of testosterone propionate (TP) on Day 4 of life, will have callosa as large as those of males. In 2 experiments, male pups were castrated on Day 1 or received sham surgery; female pups were injected with TP on Day 4 or received an oil injection. Litters were handled or nonhandled. The previous finding that females, when handled and given TP in infancy, have a larger callosum was confirmed; however, a TP effect when administered to nonhandled females was not found. Because handling is known to cause a corticosterone release, these findings were interpreted as evidence of a developmental interaction between adrenal and gonadal hormones at the cortical level.     

Sex differences and developmental effects of manipulations of oxytocin on alloparenting and anxiety in prairie voles

In adult animals, peptide hormones, including oxytocin and arginine vasopressin, have been implicated in both parental behavior and the modulation of anxiety. The purpose of this study was to examine the consequences of developmental manipulations of oxytocin for the later expression of alloparental behavior as well as behavioral responses to a novel environment, the elevated plus maze (EPM). Prairie voles (Microtus ochrogaster), a cooperatively breeding species, were selected for this study. On neonatal Day 1, pups received an ip injection of oxytocin or oxytocin antagonist, or were controls, receiving either saline or handling only. At 21 and approximately 60 days of age, each animal was tested for parental care toward novel stimulus pups. At approximately 67 days, an EPM test was administered. Control females at 60 days of age were more likely to attack pups and spent less time in the open arm of the EPM, both of which might reflect higher levels of anxiety in females than males. In males, neonatal treatment with oxytocin antagonist was associated with reductions in parental care, especially during the initial exposure to pups on Day 21. Female behavior was not significantly changed as a function of neonatal treatments. Findings to date implicate vasopressin in the behavioral changes in males, that in later life followed a single exposure to an oxytocin antagonist, and suggest caution in the clinical use of agents such as Atosiban, which may have the potential to influence infant development.     

Aggressive behaviors in adult SF-1 knockout mice that are not exposed to gonadal steroids during development

Sex hormones are a major factor responsible for the development of sex differences. Steroidogenic factor 1 (SF-1) is a key regulator of gonadal and adrenal development, and SF-1 knockout mice (SF-1 KO) are born without gonads and adrenal glands. Consequently, these mice are not exposed to gonadal sex steroids. SF-1 KO pups die shortly after birth due to adrenal deficiency. In the present study, SF-1 KO mice were rescued by neonatal corticosteroid injections followed by adrenal transplantations on day 7-8 postnatally. Control mice received corticosteroid injections and were gonadectomized prior to puberty. Mice were observed interacting with ovariectomized hormone primed females and gonad-intact males. In the absence of sex steroid replacement, adult SF-1 KO mice were significantly more aggressive than control mice in tests with stimulus females. After testosterone treatment, control males displayed significantly more aggression towards male intruders than control female mice, or male and female SF-1 KO mice, suggesting a developmental role of gonadal hormones in the expression of aggressive behavior and affirming SF-1 KO mice as a behavioral model to investigate affects of fetal gonad deficiency.     

Sex differences in the behavioral consequences of inescapable footshocks depend on time since shock

In two experiments, the effects of inescapable shock on subsequent shuttle-box escape performance were studied in male and female rats. Effects of treatment with short-duration shocks (2 s) were studied after 1- and 24-hour intervals (Experiment 1), and effects of long-duration shocks (6 s) were studied after 24- and 72-hour intervals (Experiment 2). Experience with inescapable shock resulted in a serious disruption of escape performance in both males and females. A large increment in escape latencies was found both during fixed ratio 1 and fixed ratio 2 escape training; however, effects of inescapable shock were more pronounced in males than in females. In Experiment 1, sex differences were most obvious after the short 1-hour interval whereas, in Experiment 2, sex differences were only present after 24 hours and not after 72 hours. Shuttle activity during 2-min adaptation prior to shock-escape training was reduced in both males and females treated with IS, and this effect was somewhat stronger in males than in females. The data of these experiments show that male rats are more sensitive to the consequences of exposure to inescapable aversive stimulation than female rats. It is proposed that the time-dependency of the sex differences in behavioral consequences of treatment with inescapable shock may be related to sex differences in transient neurochemical or hormonal changes induced by inescapable shock.     

Sex differences in the central nervous system actions of ethanol

For many years, researchers have avoided including females in their research because of the poorly understood influences of cycling hormones. However, we are becoming increasingly aware that sex matters, showing that it is important to conduct studies in females as well as males. This review will focus on the central nervous system (CNS) actions of alcohol (ethanol) because we have found significant sex differences in ethanol actions at the molecular as well as the behavioral level. Most recently, in our studies of ethanol dependence and withdrawal, we found that female rats displayed a shorter time for recovery from ethanol withdrawal, assessed by measuring seizure susceptibility. We now report that this finding was confirmed with a second convulsant agent. Moreover, GABAA receptor function was differentially altered in ethanol-withdrawn female compared to male rats. Studies by other investigators have reported additional significant sex differences in ethanol seeking and drinking behaviors and across several measures of ethanol dependence and withdrawal. We are gaining a better understanding of how the actions of ethanol in the CNS overlay sex differences in brain architecture and the hormonal milieu. Therefore, it is not surprising to observe sex-selective effects on cellular and behavioral outcomes from ethanol consumption. While current research is focused on characterizing sex differences in the actions of ethanol, it has not yet reached the point where we can integrate our findings into a unifying concept of how being female differentially regulates CNS responses to ethanol. This is likely a result of the complexity of ethanol actions, involving multiple neurotransmitter systems and responses covering the spectrum from drug seeking behaviors to neuropathological consequences of ethanol misuse. Regardless, the observed sex differences in ethanol withdrawal are noteworthy because they suggest that treatment of alcoholism should be managed differently in women than in men. Finally, it remains important to compare and contrast responses in males and females because recent studies of sex differences in basic physiology have made it clear that being female impacts health and disease.     

Intra-uterine nutrition and its effects on aggression

Prenatal zinc deficiency and prenatal undernutrition were found to have adverse effects on the food consumption and weight gain of pregnant dams and their offspring. Pups whose dams suffered prenatal zinc deficiency (ZD) consumed less food and gained less weight than pups whose dams suffered prenatal undernutrition (PF). The PF pups consumed less food and gained less weight than pups whose dams were normally fed (AL). The ZD females at age 75 days were significantly more aggressive than the PF females, while the PF females were more aggressive than the AL females. At age 105 days, ZD females were significantly more aggressive than the PF and AL females. There were no differences in aggression between the PF and AL females at 105 days. Among the ZD, PF, and AL male offspring, there were no differences in aggression at either age level except that the 75 day old PF males were significantly less aggressive than the AL males. Thus prenatal malnutrition, especially zinc deficiency, seems to have differential effects on the aggressive tendencies of female and male offspring.     

Postimplantation pregnancy disruptions in meadow voles: relationship to variation in male sexual and aggressive behavior

Previous research on Microtines indicates that the presence of new males may more effectively produce pregnancy disruptions than do pheromones alone. If the male's presence is important, behavioral differences among males may be related to the occurrence of disruptions. We observed female meadow voles (Microtus pennsylvanicus) interacting with new males twelve days after they had been paired with stud males. Behavioral interactions were recorded for one hour on each of Days 12-14. Timing of parturition and weight gain by Day 12 were used to assess whether a disruption had occurred. Females with disrupted pregnancies were frequently observed mating within an hour of being placed with the new male, whereas females that retained their original pregnancies rarely copulated with the new male. When pregnancies were disrupted, female-new male pairs fought more, but also engaged in more nonaggressive contact than when pregnancies were retained. Pup survival and male attendance of pups were lower when females retained litters, suggesting that females could successfully rear more pups if the original pregnancy was reabsorbed. However, relatively aggressive females paired with nonaggressive new males protected retained litters from new males. New males were tested for aggressive and pup care responses to an unrelated pup on the day before they were placed with the females. Males aggressive to unrelated pups in these tests were also more aggressive to females on Day 12. These data suggest that male aggressiveness may signal females when it would be advantageous to disrupt pregnancy.     

Development of sex differences in the response of spiny mouse pups to adult male odors

Using a three-choice preference test, olfactory-mediated investigatory activity in response to adult male urine odor was examined in a precocially active rodent, the spiny mouse (Acomys cahirinus) aged between 3-26 days. Temporally related sex differences were seen in the time spent in the presence of the odors of father's or unfamiliar adult male's urine, or distilled (control) water. Neither male nor female pups discriminated between odors from the father and strange adult males. After the first olfactory test, when the pups were aged between four and six days, male pups strongly preferred to stay in the vicinity of urine odors of adult males, whereas female pups avoided odors of adult males and remained in the enclosure with the control odor source. To our knowledge this is the first time that such a behavioral sex difference related to olfaction has been shown to occur in young rodent pups. We suggest that the sexually dimorphic response of the pups is associated with the development of later sex differences in behavior.     

Cohabitation impaired physiology, fitness and sex-related chemosignals in golden hamsters

This study investigated the impact of long-term paternal presence (cohabitation) on several physiological parameters such as body weight, adrenal weight, cortisol of parents, and the survival of pups compared with brief daily encounters (isolation) of male-female pairs in golden hamsters (Mesocricetus auratus). We showed that females were affected more by cohabitation as evidenced by increased body and adrenal weights, elevated cortisol concentrations, and heavier uteri and spleens as compared with cohabiting male and isolated females. Furthermore, we found that tetradecanoic and hexadecanoic acids of the flank glands were sexually dimorphic, for which they were putative female pheromones. These two compounds were suppressed in females and elevated in males by cohabitation, suggesting that cohabitation impaired sex chemosignals. Overall, we concluded that housing females and males together had deleterious effects on adults and the survival of their pups in the golden hamster.     

A comparison of cognitive and behavioral patterns in learning‐disabled children: Subtype and sex differences

A sample of 83 learning‐disabled (LD) females were individually matched to 83 LD males by age and Full Scale IQ and were compared on several cognitive and behavioral measures. Factor‐ and cluster‐analytic techniques were applied to the cognitive and behavioral data, and similar factor and profile structures were found for male and female LD children. The clusters and factors identified in the analyses demonstrated several significant relationships to performance on certain cognitive and behavioral measures, reading, and an attention‐impulsivity task for the combined male and female sample. Although statistically significant sex differences were found on measures suggesting that females were less impulsive and were better at reading comprehension than males, the study identified more similarities than differences among LD males and females.     

Intrauterine position,parenting, and nest-site attachment in male Mongolian gerbils

We housed male Mongolian gerbils, their mates, and foster litters of standardized size and sex ratio in enclosures that provided cover in two locations. Males had been gestated in known intrauterine positions: either between two females (2F males) or between two males (2M males). From Days 1 to 20 postpartum, we examined the frequency with which both males and females were in contact with the pups they were rearing. We found that 2F males spent more time with pups than did 2M males both during entire observation periods and when females were away from the nest. Further, when pups were moved from the nest site, 2M males spent more time than did 2F males in the vacated nest site. We concluded that 2F male gerbils spent more time with pups than 2M males not because of a greater attachment of 2F than 2M males to places of concealment, their mate, or their nest site. Rather, 2F males were more attracted to pups than were 2M males. © 1998 John Wiley & Sons, Inc. Dev Psychobiol 32: 177–181, 1998     

"Nice guys finish last": influence of mate choice on reproductive success in Long-Evans rats

The present study was designed to determine if male physiology and male reproductive behavior predict reproductive success in Long–Evans rats. Mating behavior was observed in sexually naïve, naturally cycling female rats during behavioral estrous that were given the opportunity to mate with two males simultaneously. DNA analysis of offspring born following these mating encounters was used to identify the paternity of each pup. In order to assess the effect of mate choice during these mating encounters on reproductive success, one male rat in each pair was categorized as the preferred mate if the female spent more time (> 50%) with him during the mating test of the present study. Furthermore, each male in the pairs was categorized as “attractive” or “non-attractive” by computing the number of females that preferred each male across many mating tests. Similar to results reported in Lovell et al. (2007), during 76% of these mating tests the same male rat in each pair was preferred by different female rats. Overall attractiveness of individual male rats predicted reproductive success in the present study. Interestingly, “attractive” males sired significantly FEWER pups than “non-attractive” males. Neither behavioral (e.g., latency to first sexual stimulation, number of sexual stimulations) nor physiological measures (e.g., body weight, urinary testosterone levels) of male rats predicted their reproductive success. In conclusion, the present results indicate that certain features of some males are more attractive to females, but attractive males are at a reproductive disadvantage (as measured by the number of pups sired). Although basal urinary testosterone levels did not differ between males that sired the majority of pups in a litter and males that sired few or none of the pups in a litter, aggression and/or other physiological measures of fertility (e.g., penile reflexes) may differ between males that are attractive to females and those that have a reproductive advantage.     

Within-litter variation in maternal care received by individual pups correlates with adolescent social play behavior in male rats

Maternal care represents an essential environmental factor during the first post-natal week(s) of rodents and is known to have lasting consequences for neuronal structure, brain function as well as behavioral outcome later in life, including social functions and reward-related processes. Previous experiments have shown that the amount of maternal care received by individual pups varies substantially, even within one litter. During adolescence, mammals display high levels of social play behavior, a rewarding form of social interaction that is of great importance for social and cognitive development. In order to investigate how maternal care influences adaptive social behavior later in life, we here examined whether individual differences in maternal licking and grooming (%LG) received during the first postnatal week affect social play behavior during adolescence. We observed that %LG received by male rats early in life correlates positively with the frequency and duration of pouncing and pinning, the two most characteristic behavioral expressions of social play behavior in rats. The latency to engage in social exploration also correlated with %LG. In female rats we observed no correlation between %LG and any social parameter. The data indicate that subtle variations in maternal care received early in life influence social interactions in male adolescent rats. These changes in social play likely have repercussions for the social development of male rats, suggesting that maternal care can have both direct and indirect effects on the behavioral development of the offspring.     

Effects of consanguinity, exposure to pregnant females, and stimulation from young on male gerbils' responses to pups.

In three experiments investigating variables affecting responses of male Mongolian gerbils to conspecific young, we compared the behavior directed towards pups of natural fathers, virgin foster fathers, and sexually experienced foster fathers (Experiment 1); males either previously exposed or not exposed to pregnant females (Experiment 2); and males provided or not provided with extra opportunities to huddle over pups (Experiment 3). We found no difference in responses to pups among natural fathers, virgin foster fathers, and foster fathers that had fathered litters. On the other hand, both a week of exposure to a pregnant female and opportunity to huddle over pups for an extra 15 min/day had significant effects on males' subsequent responses to conspecific young. We speculate on the reasons why a male's response to pups might be affected by his exposure to a pregnant female and stimuli from pups, but not by the probability that the pups were his own offspring.     

Effects of neonatal RU486 on adult sexual, parental, and fearful behaviors in rats

Exposure to gonadal hormones during perinatal life influences later behavior. The finding that sex differences exist in progestin receptor expression in the perinatal rat brain suggests differential sensitivity of male and female brains to progesterone (C. K. Wagner, A. N. Nakayama, & G. J. De Vries, 1998). Because these sex differences are in neural sites that influence sexually differentiated sexual, parental, and fearful behaviors in adults, this study examined the effects of administering the progestin receptor antagonist RU486 for the first 10 days after birth on these behaviors in adulthood. Neonatal RU486 significantly reduced sexual behavior in males but did not impair reproduction in females. Neonatal RU486 did not affect parental responses of virgin rats exposed to pups (sensitization) but reduced fear in the elevated plus-maze in both sexes. Treatment of pups with RU486 affected neither mother-litter interactions nor plasma testosterone levels in males during or after treatment. These results suggest that neonatal exposure to progesterone, in addition to androgens and estrogens, influences behavioral development in rats.     

Intrauterine position influences anatomy and behavior in domestic rabbits

In several rodent species, the sexual differentiation of a female offspring is known to be affected in utero by the testosterone produced in adjacent male littermates. The aim of this study was to investigate the effect of male neighbors on the sexual differentiation in domestic rabbits. For this, the intrauterine position (IUP) of a female offspring from unilaterally ovariectomized, multiparous mothers was determined by their birth order. Depending on the sex of the adjacent fetuses, pups were divided into 4 groups: 1. Males. 2. 2 M females (females with 2 adjacent males), 1 M females (females with 1 male neighbor), and 0 M females (females with zero adjacent male). Pups' anogenital distance (AGD) was measured at birth and on Day 180 postpartum, when spontaneous chin marking activity was also measured. Our results revealed that AGD was a reliable indicator of sex as male pups had larger AGD than females, both at birth and later on. Adjacent male fetuses had significant effect: the more adjacent male fetuses females have had the longer AGD they possessed. AGD at birth was a good predictor of AGD and behavior of adults, as 2 M does showed the longest AGD and the highest chin marking activity among females. We concluded that, similarly to rodents, proximity to males in utero affects both anatomy and behavior in rabbits.     

Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation

The widespread use of persistent organic polybrominated diphenyl ethers (PBDEs) as commercial flame retardants has raised concern about potential long-lived effects on human health. Epigenetic mechanisms, such as DNA methylation, are responsive to environmental influences and have long-lasting consequences. Autism spectrum disorders (ASDs) have complex neurodevelopmental origins whereby both genetic and environmental factors are implicated. Rett syndrome is an X-linked ASD caused by mutations in the epigenetic factor methyl-CpG binding protein 2 (MECP2). In this study, an Mecp2 truncation mutant mouse (Mecp2(308)) with social behavioral defects was used to explore the long-lasting effects of PBDE exposure in a genetically and epigenetically susceptible model. Mecp2(308/+) dams were perinatally exposed daily to 2,2',4,4'-tetrabromodiphenyl ether 47 (BDE-47) and bred to wild-type C57BL/6J males, and the offspring of each sex and genotype were examined for developmental, behavioral and epigenetic outcomes. Perinatal BDE-47 exposure negatively impacted fertility of Mecp2(308/+) dams and preweaning weights of females. Global hypomethylation of adult brain DNA was observed specifically in female offspring perinatally exposed to BDE-47 and it coincided with reduced sociability in a genotype-independent manner. A reversing interaction of Mecp2 genotype on BDE-47 exposure was observed in a short-term memory test of social novelty that corresponded to increased Dnmt3a levels specifically in BDE-47-exposed Mecp2(308/+) offspring. In contrast, learning and long-term memory in the Morris water maze was impaired by BDE-47 exposure in female Mecp2(308/+) offspring. These results demonstrate that a genetic and environmental interaction relevant to social and cognitive behaviors shows sexual dimorphism, epigenetic dysregulation, compensatory molecular mechanisms and specific behavioral deficits.     

The epigenetic environment: secondary sex ratio depends on differential survival in embryogenesis

Live human births are usually more than half male, in spite of excess losses of males throughout fetal development. These observations together demand an excess of males near the beginning of pregnancy greater than that seen at birth. Reductions of the usual excess of males among human live births have widely been considered to represent consequences of untoward circumstances surrounding conception. Repeated competent research efforts have found no evidence for any bias in gametogenesis or fertilization in favour of Y-bearing sperm. Male embryogenesis is faster and more efficient, leaving females in excess among failures before the fetal period. Sex differences in speed and efficiency of embryogenesis, dependent for example on epigenetic differences such as genomic imprinting, produce an excess of males at the transition from embryogenesis to clinical pregnancy, that will survive the male excess of losses throughout the fetal period, to yield an excess of males among live births. Changes in, or mediated by, the epigenetic environment of embryogenesis provide the most plausible prospects for causes of changes in secondary sex ratio.