The organizational–activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues

The 1959 publication of the paper by Phoenix et al. was a major turning point in the study of sexual differentiation of the brain. That study showed that sex differences in behavior, and by extension in the brain, were permanently sexually differentiated by testosterone, a testicular secretion, during an early critical period of development. The study placed the brain together in a class with other major sexually dimorphic tissues (external genitalia and genital tracts), and proposed an integrated hormonal theory of sexual differentiation for all of these non-gonadal tissues. Since 1959, the organizational–activational theory has been amended but survives as a central concept that explains many sex differences in phenotype, in diverse tissues and at all levels of analysis from the molecular to the behavioral. In the last two decades, however, sex differences have been found that are not explained by such gonadal hormonal effects, but rather because of the primary action of genes encoded on the sex chromosomes. To integrate the classic organizational and activational effects with the more recently discovered sex chromosome effects, we propose a unified theory of sexual differentiation that applies to all mammalian tissues.     

Mechanisms by which neonatal testosterone exposure mediates sex differences in impulsivity in prepubertal rats

Neonatal testosterone, either acting directly or through its conversion to estradiol, can exert organizational effects on the brain and behavior. The goal of the current study was to examine sex differences and determine the role of neonatal testosterone on prefrontal cortex-dependent impulsive choice behavior in prepubertal rats. Male and female prepubertal rats were tested on the delay-based impulsive choice task. Impulsive choice was defined as choosing an immediate small food reward over a delayed large reward. In a first experiment to examine sex differences, males made significantly more impulsive choices than did females. In a second experiment to examine the organizational effects of testosterone, females treated with neonatal testosterone made significantly more impulsive choices than did control females and their performance was indistinguishable from that of control males. In a third experiment to determine if the effect of testosterone on performance is due to the actions of androgens or estrogens through its conversion to estradiol, males treated neonatally with the aromatase inhibitor formestane, which blocks the conversion of testosterone to estradiol, females treated neonatally with the non-aromatizable androgen dihydrotestosterone, and females treated neonatally with estradiol made significantly more impulsive choices than did control females and their performance was indistinguishable from that of control males. Results indicate that male pubertal rats display increased impulsive choice behavior as compared to females, that this sex difference results from organizing actions of testosterone during the neonatal period, and that this effect can result from both androgenic and estrogenic actions.     

Sex allocation and dispersal in a heterogeneous two-patch environment

We investigate the evolution of sex allocation and dispersal in a two-habitat environment using a game theoretic analysis. One habitat is of better quality than the other and increased habitat quality influences the competitive ability of offspring in a sex-specific manner. Unlike previous work, we allow incomplete mixing of the population during mating. We discuss three special cases involving the evolution of sex allocation under fixed levels of dispersal between habitats. In these special cases, stable sex-allocation behaviors can be both biased and unbiased. When sex-allocation behavior and dispersal rates co-evolve we identify two basic outcomes. First-when sex-specific differences in the consequences of spatial heterogeneity are large-we predict the evolution of biased sex-allocation behavior in both habitats, with dispersal by males in one direction and dispersal by females in the other direction. Second-when sex-specific differences are small-unbiased sex-allocation is predicted with no dispersal between habitats.     

Sexual differentiation of motivation: A novel mechanism?

Sex differences in motivation are apparent for the motivation to engage in sexual behavior, the motivation to take drugs of abuse, and the motivation to engage in parental behavior. In both males and females there is an increase in NAcc DA associated with motivated behaviors. Here it proposed that sex differences in the regulation of DA activity in the ascending mesolimbic projections may underlie sex differences in motivation. In particular, sex differences in the neuroendocrine regulation of this brain system play a role in the expression of sex differences in motivated behaviors. Here it is proposed that sexual differentiation of motivation is mediated, at least in part, by a novel mechanism in which ovarian hormones secreted at puberty in the female actively feminize the DA system.     

Dominant-subordinate relationships in hamsters: sex differences in reactions to familiar opponents

In the majority of mammalian species, males are dominant over and more aggressive than females. In contrast, some reports suggest that female golden hamsters are more aggressive than males but systematic comparisons using the same methods for both sexes are rare. We observed same-sexed pairs of hamsters over repeated trials to assess whether sex differences existed in the level of agonistic behavior and in the development and maintenance of dominant-subordinate relationships with familiar partners. There were no sex differences in measures of agonistic behavior or fear responses (fleeing) during the initial series of three trials on the first day of testing. Following a four-day interval, males that had lost in session 1 showed fearful responses to a familiar dominant male and were not likely to engage in a fight with him. In contrast, females that lost the initial fights were not fearful and fought vigorously with the familiar winner in subsequent encounters. Although the amount of agonistic behavior engaged in by females did decrease over the course of the three sessions, females that lost did not demonstrate an increase in fear, as measured by the latency to flee. Males that lost fights did show increased fear during later trials and sessions. These results suggest that female hamsters are less affected by losing fights than males are and thus that females are less likely than males to develop highly polarized dominant-subordinate relationships. Further work is needed to understand the mechanisms underlying these sex differences.     

Japanese macaques (Macaca fuscata) social development: Sex differences in Juvenile behavior

We have quantitatively documented the development of sex differences in the behavior of juvenile Japanese macaques (1 to 2 years of age). Mothers treated their offspring differently by sex, i.e., mothers of males broke contact with them more frequently than did mothers of females. Juvenile males played more, and mounted other macaques more frequently; juvenile females groomed their mothers more and were also punished by other group members more frequently than were males. Males showed a pattern of decreasing interactions with their mothers, but females increased the frequency of their maternal interactions. These patterns appear to presage the life histories of the sexes. However, comparisons with other species of nonhuman primates indicate that although sex differences in behavior are common, the variability among species severely limits cross-specific generalizations.     

Chronic stress effects on memory: sex differences in performance and monoaminergic activity

Increasing evidence suggests that the time course of advantageous versus deleterious effects of stress on physiologic function is also apparent in some brain functions, including learning and memory. This article reviews the effects of chronic stress on behavioral performance and, more importantly, shows that sex of the subject, as well as duration and intensity of stress, is an important determinant of the functional/behavioral, neurochemical, and anatomical consequences of the stress. Following chronic stress (7-28 days of restraint, 6 h/day), male and female rats were tested on a visual memory task (object recognition) and two spatial memory tasks (object placement and radial arm maze). At 21 days, stress impaired males on all tasks while females were either enhanced (spatial memory tasks) or not impaired (nonspatial memory tasks). Additionally, the influence of the hypothalamic-pituitary-adrenocortical axis in mediating the sex-specific responses to stress is considered. Behavioral and neurochemical assessments following chronic stress in ovariectomized females, with and without estradiol, suggest that estrogen exerts both organizational and activational influences on the observed sex differences in response to stress. Furthermore, stress differentially affected central transmitter levels in the frontal cortex, hippocampus, and amygdala depending on sex. The possible role of these sex-specific changes in neurotransmitter levels in mediating behavioral differences in response to stress is discussed. While these results are thus far limited to a few studies and require both further investigation and verification, chronic stress appears to be associated with distinct, sex-differentiated behavioral/cognitive and neurochemical responses. We conclude that sex differences must be taken into account when investigating or describing stress and associated sequalae.     

Sex chromosome complement affects nociception in tests of acute and chronic exposure to morphine in mice

We tested the role of sex chromosome complement and gonadal hormones in sex differences in several different paradigms measuring nociception and opioid analgesia using "four core genotypes" C57BL/6J mice. The genotypes include XX and XY gonadal males, and XX and XY gonadal females. Adult mice were gonadectomized and tested 3-4 weeks later, so that differences between sexes (mice with testes vs. ovaries) were attributable mainly to organizational effects of gonadal hormones, whereas differences between XX and XY mice were attributable to their complement of sex chromosomes. In Experiment 1 (hotplate test of acute morphine analgesia), XX mice of both gonadal sexes had significantly shorter hotplate baseline latencies prior to morphine than XY mice. In Experiment 2 (test of development of tolerance to morphine), mice were injected twice daily with 10 mg/kg morphine or saline for 6 days. Saline or the competitive NMDA antagonist CPP (3-(2-carboxypiperazin-4yl) propyl-1-phosphonic acid) (10 mg/kg) was co-injected. On day 7, mice were tested for hotplate latencies before and after administration of a challenge dose of morphine (10 mg/kg). XX mice showed shorter hotplate latencies than XY mice at baseline, and the XX-XY difference was greater following morphine. In Experiment 3, mice were injected with morphine (10 mg/kg) or saline, 15 min before intraplantar injection of formalin (5%/25 microl). XX mice licked their hindpaw more than XY mice within 5 min of formalin injection. The results indicate that X- or Y-linked genes have direct effects, not mediated by gonadal secretions, on sex differences in two different types of acute nociception.     

Gonadal hormones and sex differences in nonreproductive behaviors in rodents: organizational and activational influences

Sex differences in many nonreproductive behaviors have been described in rodents. Among the behaviors that are sexually dimorphic in the rat are activity, aggression, pain, and taste sensitivity, food intake and body weight regulation, the learning and retention of certain kinds of mazes, avoidance responses, taste aversion, and performance on certain schedules of reinforcement. Gonadal hormones seem to be responsible, in part, for sex differences in these behaviors, but their contribution varies greatly with the behavior in question. Frequently, these sexually dimorphic behaviors are influenced both by organizational and activational actions of sex hormones. In other instances (e.g., maze learning and the acquisition of shuttle-box avoidance responses) organizational influences predominate. And while there is no sexually dimorphic behavior surveyed that can be shown to be influenced only by activational effects, wheel-running activity is clearly more strongly subject to activational than to organizational effects of the gonadal hormones. In general, only rudimentary information exists regarding the temporal limits of the period in development when organizational influences on nonsexual behaviors occur. The suggestion can be made that organizational influences often occur outside of the critical period for differentiation of the neuroendocrine system regulating cyclic release of gonadotrophins. Even for behaviors where organizational effects usually occur during a roughly delimited period of development, data for other behavioral systems suggest that the time limits during which organizational effects can occur are not rigidly fixed. Very little information exists regarding biochemical or neural mechanisms by which organizational or activational effects on sexually dimorphic nonreproductive behaviors are expressed. It is important to recognize for many of the sexually dimorphic behaviors in the rat that differences between the sexes are neither large nor absolute. This is especially true of several kinds of learning situations where groups of males and females typically differ in average levels of performance. Ostensibly minor variations in test procedure can abolish or accentuate the average difference in performance between the sexes. We are a long way from an adequate understanding of what factors are important, but such information could be quite helpful in estimating whether sex differences in certain laboratory learning tasks have any adaptive significance.Sex differences in nonreproductive behaviors may be influenced by many factors other than hormonal status. This greatly complicates a comparative analysis, but such an analysis will ultimately be necessary. What limited data exist on rodents suggest that: (1) Sexually dimorphic responses in the rat are often not similarly differentiated in the hamster, the gerbil, or the mouse; and (2) major differences exist among rodent species in hormonal effects on such responses.Over the last decade it has become clear that the behavioral effects of deliberate neurological insult are not necessarily the same in male and female rats (or in one case, in rhesus monkeys). Sex differences in the behavioral effects of ventromedial hypothalamic, lateral hypothalamic, septal, and striatal lesions in the rat and of orbital prefrontal cortex lesions in the monkey have been described. While information regarding hormonal modulation of these differences in response to brain damage is very limited, available data suggest both organizational and activational effects of sex hormones may be involved. It is too early to tell where this line of research may ultimately lead, but rather striking sex differences in the incidence of certain neurological disorders in humans suggest that further research may have both practical and theoretical significance.     

Sex differences in otoacoustic emissions measured in rhesus monkeys (Macaca mulatta)

Click-evoked otoacoustic emissions (CEOAEs) and distortion-product OAEs (DPOAEs) were measured in about 60 rhesus monkeys. CEOAE strength was substantially greater in females than in males, just as in humans. DPOAE strength was generally slightly stronger in females, just as in humans. In males, CEOAEs were weaker (more masculine) in the fall breeding season and in winter than in the summer. In females, CEOAEs were slightly stronger (more feminine) in the fall, when sex steroids are elevated in females (and males), than in the summer when rhesus monkeys are reproductively quiescent. Thus, the sex differences in CEOAEs were greater in the fall than in the summer. We presume that the seasonal fluctuations in OAEs reflect activational hormonal effects, while the basic sex differences in OAEs likely reflect organizational effects of prenatal androgen exposure. Some monkeys of both sexes had been treated with additional testosterone or the anti-androgen flutamide during prenatal development. In accord with expectations, prenatal androgen treatment weakened CEOAEs in females, and prenatal flutamide treatment strengthened CEOAEs in males. For DPOAEs, the differences between treated and untreated groups were mostly small and often inconsistent. Taken as a whole, the data from both rhesus monkeys and humans suggest that the linear, reflection-based mechanism of OAE production that underlies CEOAEs is more sensitive to prenatal androgenic processes than is the nonlinear distortion mechanism that underlies DPOAEs.     

Salivary testosterone does not predict mental rotation performance in men or women

Multiple studies report relationships between circulating androgens and performance on sexually differentiated spatial cognitive tasks in human adults, yet other studies find no such relationships. Relatively small sample sizes are a likely source of some of these discrepancies. The present study thus tests for activational effects of testosterone (T) using a within-participants design by examining relationships between diurnal fluctuations in salivary T and performance on a male-biased spatial cognitive task (Mental Rotation Task) in the largest sample yet collected: 160 women and 177 men. T concentrations were unrelated to within-sex variation in mental rotation performance in both sexes. Further, between-session learning-related changes in performance were unrelated to T levels, and circadian changes in T were unrelated to changes in spatial performance in either sex. These results suggest that circulating T does not contribute substantially to sex differences in spatial ability in young men and women. By elimination, the contribution of androgens to sex differences in human performance on these tasks may be limited to earlier, organizational periods.     

Organizational effects of maternal testosterone on reproductive behavior of adult house sparrows

Despite the well-known, long-term, organizational actions of sex steroids on phenotypic differences between the sexes, studies of maternal steroids in the vertebrate egg have mainly focused on effects seen in early life. Long-term organizational effects of yolk hormones on adult behavior and the underlying mechanisms that generate them have been largely ignored. Using an experiment in which hand-reared house sparrows (Passer domesticus) from testosterone- or control-treated eggs were kept under identical conditions, we show that testosterone treatment in the egg increased the frequency of aggressive, dominance, and sexual behavior of 1-year-old, reproductively competent house sparrows. We also show that circulating plasma levels of progesterone, testosterone, 5alpha-dihydrotestosterone, and 17beta-estradiol did not differ between treatment groups. Thus, a simple change in adult gonadal hormone secretion is not the primary physiological cause of long-term effects of maternal steroids on adult behavior. Rather, differences in adult behavior caused by exposure to yolk testosterone during embryonic development are likely generated by organizational modifications of brain function. Furthermore, our data provide evidence that hormone-mediated maternal effects are an epigenetic mechanism causing intra-sexual variation in adult behavioral phenotype.     

Do Sex Differences in the Brain Explain Sex Differences in the Hormonal Induction of Reproductive Behavior? What 25 Years of Research on the Japanese Quail Tells Us

Early workers interested in the mechanisms mediating sex differences in morphology and behavior assumed that differences in behavior that are commonly observed between males and females result from the sex specificity of androgens and estrogens. Androgens were thought to facilitate male-typical traits, and estrogens were thought to facilitate female-typical traits. By the mid-20th century, however, it was apparent that administering androgens to females or estrogens to males was not always effective in sex-reversing behavior and that in some cases a “female” hormone such as an estrogen could produce male-typical behavior and an androgen could induce female-typical behavior. These conceptual difficulties were resolved to a large extent by the seminal paper of C. H. Phoenix, R. W. Goy, A. A. Gerall, and W. C. Young in (1959,Endocrinology65, 369–382) that illustrated that several aspects of sexual behavior are different between males and females because the sexes have been exposed during their perinatal life to a different endocrine milieu that has irreversibly modified their response to steroids in adulthood. Phoenixet al.(1959) therefore formalized a clear dichotomy between the organizational and activational effects of sex steroid hormones. Since this paper, a substantial amount of research has been carried out in an attempt to identify the aspects of brain morphology or neurochemistry that differentiate under the embryonic/neonatal effects of steroids and are responsible for the different behavioral response of males and females to the activation by steroids in adulthood. During the past 25 years, research in behavioral neuroendocrinology has identified many sex differences in brain morphology or neurochemistry; however many of these sex differences disappear when male and female subjects are placed in similar endocrine conditions (e.g., are gonadectomized and treated with the same amount of steroids) so that these differences appear to be of an activational nature and cannot therefore explain sex differences in behavior that are still present in gonadectomized steroid-treated adults. This research has also revealed many aspects of brain morphology and chemistry that are markedly affected by steroids in adulthood and are thought to mediate the activation of behavior at the central level. It has been explicitly, or in some cases, implicitly assumed that the sexual differentiation of brain and behavior driven by early exposure to steroids concerns primarily those neuroanatomical/neurochemical characteristics that are altered by steroids in adulthood and presumably mediate the activation of behavior. Extensive efforts to identify these sexually differentiated brain characteristics over the past 20 years has only met with limited success, however. As regards reproductive behavior, in all model species that have been studied it is still impossible to identify satisfactorily brain characteristics that differentiate under early steroid action and explain the sex differences in behavioral activating effects of steroids. This problem is illustrated by research conducted on Japanese quail (Coturnix japonica), an avian model system that displays prominent sex differences in the sexual behavioral response to testosterone, and in which the endocrine mechanisms that control sexual differentiation of behavior have been clearly identified so that subjects with a fully sex-reversed behavioral phenotype can be easily produced. In this species, studies of sex differences in the neural substrate mediating the action of steroids in the brain, including the activity of the enzymes that metabolize steroids such as aromatase and the distribution of steroid hormone receptors as well as related neurotransmitter systems, did not result in a satisfactory explanation of sex differences in the behavioral effectiveness of testosterone. Possible explanations for the relative failure to identify the organized brain characteristics responsible for behavioral sex differences in the responsiveness to steroids are presented. It is argued that novel research strategies may have to be employed to successfully attack the fundamental question of the hormonal mechanisms regulating sex differences in behavior.     

Sex hormones, central nervous system and pain

The aim of the present review, which highlights some relationships between sex hormones, the CNS and pain, is to provide reference points for discussion on one of the most intriguing aspects of pain pathophysiology: the presence of sex differences in the response threshold to phasic painful stimuli and in the incidence of chronic pain syndromes. The first part of the review deals with sex steroids and their mechanisms of action. In the second part, the connections between sex steroids, the CNS and pain are illustrated to introduce possible areas of discussion in the study of sex differences in experimental and clinical pain.     

疼痛的性别差异

目前已有许多临床流行病学研究和实验研究证实了人类的疼痛存在性别差异。临床迹象表明疼痛存在性别差异,许多慢性疼痛疾病（偏头痛、颞下颌关节痛、纤维肌痛、风湿痛等）的发生率女性明显高于男性。女性对一些实验性疼痛（机械刺激痛、电刺激痛、热刺激痛等）更加敏感,痛阈和对疼痛的耐受性比男性低,而且女性月经周期与疼痛有关。啮齿动物实验研究也发现存在疼痛的性别差异。但是在不同动物研究或不同实验性疼痛刺激下雌雄性别的反应不完全相同,这些差异可能是由很多影响因素所导致的。目前许多研究对疼痛存在性别差异的解释也有所不同,机制尚不清楚,可能的因素包括：生物因素（性激素、内源性镇痛、基因等）、社会心理因素以及两者的相互作用等。     

两栖动物性染色体的多样性及其 进化机制的研究进展

两栖动物性别决定类型和性染色体具有多样性的特点。在已发现异形性染色体两栖动物中,大部分物种Y或W染色体大于其对应的X或Z染色体,少数物种具有高度分化的Y或W染色体。同时两栖动物类群内基因组大小差异大,性染色体间分子水平上也存在差异。高频转换、偶然重组和染色体重排可能是两栖动物性染色体进化过程中的关键机制。本综述通过对两栖动物性染色体进化的深入探讨,揭示其遗传性别决定的机理,有助于对两栖动物性别人工调控的进一步探索。     

The emergence of gonadal hormone influences on dopaminergic function during puberty

Adolescence is the developmental epoch during which children become adults—intellectually, physically, hormonally and socially. Brain development in critical areas is ongoing. Adolescents are risk-taking and novelty-seeking and they weigh positive experiences more heavily and negative experiences less than adults. This inherent behavioral bias can lead to risky behaviors like drug taking. Most drug addictions start during adolescence and early drug-taking is associated with an increased rate of drug abuse and dependence.The hormonal changes of puberty contribute to physical, emotional, intellectual and social changes during adolescence. These hormonal events do not just cause maturation of reproductive function and the emergence of secondary sex characteristics. They contribute to the appearance of sex differences in non-reproductive behaviors as well. Sex differences in drug use behaviors are among the latter. The male predominance in overall drug use appears by the end of adolescence, while girls develop the rapid progression from first use to dependence (telescoping) that represent a female-biased vulnerability. Sex differences in many behaviors including drug use have been attributed to social and cultural factors. A narrowing gap in drug use between adolescent boys and girls supports this thesis. However, some sex differences in addiction vulnerability reflect biologic differences in brain circuits involved in addiction. The purpose of this review is to summarize the contribution of sex differences in the function of ascending dopamine systems that are critical to reinforcement, to briefly summarize the behavioral, neurochemical and anatomical changes in brain dopaminergic functions related to addiction that occur during adolescence and to present new findings about the emergence of sex differences in dopaminergic function during adolescence.     

Towards meeting Tinbergen's challenge

In mammals, sex specialization is reflected by differences in brain anatomy and function. Measurable differences are documented in reproductive behavior, cognition, and emotion. We hypothesized that gonadotropin-releasing hormone (GnRH) plays a crucial role in controlling the extent of the brain's sex specificity and that changes in GnRH action during critical periods of brain development, such as puberty, will result in altered sex-specific behavioral and physiological patterns. We blocked puberty in half of the 48 same-sex Scottish mule Texel cross sheep twins with GnRH analog (GnRHa) goserelin acetate every 3 weeks, beginning just before puberty. To determine the effects of GnRHa treatment on sex-specific behavior and emotion regulation in different social contexts, we employed the food acquisition task (FAT) and measurement of heart rate variability (HRV). ANOVA revealed significant sex and sex × treatment interaction effects, suggesting that treated males were more likely to leave their companions to acquire food than untreated, while the opposite effect was observed in females. Concordant results were seen in HRV; treated males displayed higher HRV than untreated, while the reverse pattern was found in females, as shown by significant sex and sex × treatment interaction effects. We conclude that long-term prepubertal GnRHa treatment significantly affected sex-specific brain development, which impacted emotion and behavior regulation in sheep. These results suggest that GnRH is a modulator of cognitive function in the developing brain and that the sexes are differentially affected by GnRH modulation.     

Sex differences and ovarian hormones in animal models of drug dependence

Increasing evidence indicates the presence of sex differences in many aspects of drug abuse. Most studies reveal that females exceed males during the initiation, escalation, extinction, and reinstatement (relapse) of drug-seeking behavior, but males are more sensitive than females to the aversive effects of drugs such as drug withdrawal. Findings from human and animal research indicate that circulating levels of ovarian steroid hormones account for these sex differences. Estrogen (E) facilitates drug-seeking behavior, while progesterone (P) and its metabolite, allopregnanalone (ALLO), counteract the effects of E and reduce drug seeking. Estrogen and P influence other behaviors that are affiliated with drug abuse such as drug-induced locomotor sensitization and conditioned place preference. The enhanced vulnerability to drug seeking in females vs. males is also additive with the other risk factors for drug abuse (e.g., adolescence, sweet preference, novelty reactivity, and impulsivity). Finally, treatment studies using behavioral or pharmacological interventions, including P and ALLO, also indicate that females show greater treatment effectiveness during several phases of the addiction process. The neurobiological basis of sex differences in drug abuse appears to be genetic and involves the influence of ovarian hormones and their metabolites, the hypothalamic pituitary adrenal (HPA) axis, dopamine (DA), and gamma-hydroxy-butyric acid (GABA). Overall, sex and hormonal status along with other biological risk factors account for a continuum of addiction-prone and -resistant animal models that are valuable for studying drug abuse prevention and treatment strategies.     

Sex differences and developmental effects of oxytocin on aggression and social behavior in prairie voles (Microtus ochrogaster)

Various hormones, including sex steroids and neuropeptides, have been implicated in aggression. In this study we examined (1) sex differences in intrasexual aggression in na?ve prairie voles; (2) the effects of developmental manipulations of oxytocin on intrasexual aggression; and (3) changes in patterns of intrasexual aggression after brief exposure to an animal of the opposite sex. Within 24 h of birth, infants were randomly assigned to receive either an injection of oxytocin (OT) or oxytocin antagonist (OTA) or to one of two control (CTL) groups receiving either isotonic saline or handling without injection. As adults, animals were tested twice in a neutral arena; before (Test 1) and 24 h after (Test 2) a 4-h exposure to an animal of the opposite sex. In Test 1, CTL males were more likely to show aggressive and less likely to show social behavior than CTL females. No significant treatment differences were observed within either sex in Test 1. In Test 2, after brief exposure to a male, females treated with OT became more aggressive and less social than OTA or CTL females. Male aggressive behavior did not change after exposure to a female. An increase in aggression and decline in social behavior toward other females, seen here in OT-treated females, is typically observed only following several days of female-male cohabitation. These findings demonstrate a sex difference in intrasexual aggression and suggest that neonatal exposure to OT may facilitate the onset of the mate-guarding component of pair bonding in female prairie voles.