The Role of Androgens and Estrogens in Social Interactions and Social Cognition.

Gonadal hormones are becoming increasingly recognized for their effects on cognition. Estrogens, in particular, have received attention for their effects on learning and memory that rely upon the functioning of various brain regions. However, the impacts of androgens on cognition are relatively under investigated. Testosterone, as well as estrogens, have been shown to play a role in the modulation of different aspects of social cognition. This review explores the impact of testosterone and other androgens on various facets of social cognition including social recognition, social learning, social approach/avoidance, and aggression. We highlight the relevance of considering not only the actions of the most commonly studied steroids (i.e., testosterone, 17ß-estradiol, and dihydrotestosterone), but also that of their metabolites and precursors, which interact with a plethora of different receptors and signalling molecules, ultimately modulating behaviour. We point out that it is also essential to investigate the effects of androgens, their precursors and metabolites in females, as prior studies have mostly focused on males. Overall, a comprehensive analysis of the impact of steroids such as androgens on behaviour is fundamental for a full understanding of the neural mechanisms underlying social cognition, including that of humans.

Immune activation attenuates memory acquisition and consolidation of conditioned disgust (anticipatory nausea) in rats.

Anticipatory nausea is a classically conditioned response to cues (e.g. contexts) that have been previously paired with a nauseating stimulus, such as chemotherapy in humans. In rodents, anticipatory nausea can be modeled by pairing a novel context with lithium chloride (LiCl), which leads to conditioned disgust behaviours (such as gaping) when exposed to the context alone. Growing evidence suggests that selective immune activation attenuates various forms of learning and memory. The present study investigated the effects of the endotoxin lipopolysaccharide (LPS) on LiCl-induced anticipatory nausea across critical stages of associative memory including acquisition, consolidation, and extinction. Adult male Long Evans rats were subject to intraperitoneal (i.p.) LiCl (127 mg/kg) or vehicle control (NaCl) paired with a 30 min conditioning trial in a distinct context for a total of 4 trials. To study acquisition, rats were administered either LPS or NaCl (200 µg/kg, i.p.) 90 mins before the conditioning trials. To study consolidation, different rats were administered either LPS or NaCl (200 µg/kg, i.p.) immediately after the conditioning trials. These trials were followed by 4 drug-free extinction trials within the same context. LPS significantly reduced conditioned gaping behaviours by the 4th conditioning trial and on the 1st drug-free extinction trial when administered 90 mins before or immediately after the conditioning trials. LPS had no significant effect on extinction. The present study provides strong evidence for the attenuating effects of LPS exposure on the acquisition and consolidation of LiCl-induced anticipatory nausea.

Social factors and the neurobiology of pathogen avoidance.

Although the evolutionary causes and consequences of pathogen avoidance have been gaining increasing interest, there has been less attention paid to the proximate neurobiological mechanisms. Animals gauge the infection status of conspecifics and the threat they represent on the basis of various sensory and social cues. Here, we consider the neurobiology of pathogen detection and avoidance from a cognitive, motivational and affective state (disgust) perspective, focusing on the mechanisms associated with activating and directing parasite/pathogen avoidance. Drawing upon studies with laboratory rodents, we briefly discuss aspects of (i) olfactory-mediated recognition and avoidance of infected conspecifics; (ii) relationships between pathogen avoidance and various social factors (e.g. social vigilance, social distancing (approach/avoidance), social salience and social reward); (iii) the roles of various brain regions (in particular the amygdala and insular cortex) and neuromodulators (neurotransmitters, neuropeptides, steroidal hormones and immune components) in the regulation of pathogen avoidance. We propose that understanding the proximate neurobiological mechanisms can provide insights into the ecological and evolutionary consequences of the non-consumptive effects of pathogens and how, when and why females and males engage in pathogen avoidance.

Differential effects of progesterone on social recognition and the avoidance of pathogen threat by female mice.

Although pathogen threat affects social and sexual responses across species, relatively little is known about the underlying neuroendocrine mechanisms. Progesterone has been speculated to be involved in the mediation of pathogen disgust in women, though with mixed experimental support. Here we considered the effects of acute progesterone on the disgust-like avoidance responses of female mice to pathogen threat. Estrous female mice discriminated and avoided the urinary and associated odors of males subclinically infected with the murine nematode parasite, Heligmosomoides polygyrus. These avoidance responses were not significantly affected by pre-treatment with progesterone. Likewise, brief (1 min) exposure to the odors of infected males attenuated the subsequent responses of females to the odors of the normally preferred unfamiliar males and enhanced their preferences for familiar males. Neither progesterone nor allopregnanolone, a central neurosteroid metabolite of progesterone, had any significant effects on the avoidance of unfamiliar males elicited by pre-exposure to a parasitized male. Progesterone and allopregnanolone, did, however, significantly attenuate the typical preferences of estrous females for unfamiliar uninfected males, suggestive of effects on social recognition. These findings with mice indicate that progesterone may have minimal effects on the responses to specific parasite threat and the expression of pathogen disgust but may influence more general social recognition and preferences.

Pathogens, odors, and disgust in rodents.

All animals are under the constant threat of attack by parasites. The mere presence of parasite threat can alter behavior before infection takes place. These effects involve pathogen disgust, an evolutionarily conserved affective/emotional system that functions to detect cues associated with parasites and infection and facilitate avoidance behaviors. Animals gauge the infection status of conspecific and the salience of the threat they represent on the basis of various sensory cues. Odors in particular are a major source of social information about conspecifics and the infection threat they present. Here we briefly consider the origins, expression, and regulation of the fundamental features of odor mediated pathogen disgust in rodents. We briefly review aspects of: (1) the expression of affective states and emotions and in particular, disgust, in rodents; (2) olfactory mediated recognition and avoidance of potentially infected conspecifics and the impact of pathogen disgust and its' fundamental features on behavior; (3) pathogen disgust associated trade-offs; (4) the neurobiological mechanisms, and in particular the roles of the nonapeptide, oxytocin, and steroidal hormones, in the expression of pathogen disgust and the regulation of avoidance behaviors and concomitant trade-offs. Understanding the roles of pathogen disgust in rodents can provide insights into the regulation and expression of responses to pathogens and infection in humans.

Conspecific infection threat rapidly biases the social responses of female mice: Involvement of oxytocin.

Pathogen threat affects social preferences and responses across species. Here we examined the effects of social context and the infection status of conspecific females and males on the social and mate responses of female mice. The responses of female mice to males were rapidly affected by the presence of infected female conspecifics and infected males. In mice odor cues drive appetitive and aversive social and mate responses. Brief (1 min) exposure to the fresh urinary odors of females infected with the murine nematode parasite, Heligmosomoides polygyrus, attenuated the responses of other uninfected females to the odors of naturally preferred unfamiliar males and enhanced their preferences for familiar males. Likewise exposure to the odors of a male either infected with H. polygyrus or treated with the bacterial endotoxin, lipopolysaccharide, reduced the responses of females to the odors of unfamiliar males. In addition, females displayed an avoidance of, and discrimination against, male mice whose odors had been associated with that of an infected female ("guilt by association") and a preference for the odors associated with an uninfected female ("mate copying"). These shifts in preferences for female associated male odors were attenuated in a dose-related manner by pre-treatment with the oxytocin receptor antagonist, L-368,899. These findings show that social information associated with the infection status of conspecifics can rapidly bias the mate preferences of female mice in an oxytocin receptor dependent manner.

Social neuroscience of disgust.

Disgust can be thought of as an affective system that has evolved to detect signs of pathogens, parasite and toxins as well as to stimulate behaviors that reduce the risk of their acquisition. Disgust incorporates social cognitive mechanisms to regulate exposure to and, or anticipate and avoid exposure to pathogens and toxins. Social cognition entails the acquisition of social information about others (ie, social recognition) and from others (ie, social learning). This involves recognizing and assessing other individuals and the pathogen/parasite/contamination/toxin threat they pose and deciding about when and how to interact with and, or avoid them. Social cognition provides a frame-work for examining the expression of disgust and the associated neurobiological mechanisms. Here, we briefly consider the relations between social cognition and pathogen/parasite/toxin avoidance behaviors. We briefly discuss aspects of: (1) the odor mediated social recognition of actual and potentially infected individuals and the impact of parasite/pathogen threat on disgust mate and social partner choice; (2) the roles of "out-groups" (strangers, unfamiliar individuals) and "in-groups" (familiar individuals) in the expression of disgust and pathogen avoidance behaviors; (3) individual and social learning of disgust and empathy for disgust; (4) toxin elicited disgust and anticipatory disgust; (5) the neurobiological mechanisms, and in particular the roles of the nonapeptide, oxytocin and estrogenic mechanism associated with social cognition and the expression of disgust. These findings on the social neuroscience of disgust have a direct bearing on our understanding of the roles of disgust in shaping human and nonhuman social behavior.

Conditioned disgust in rats (anticipatory nausea) to a context paired with the effects of the toxin LiCl: Influence of sex and the estrous cycle.

The role of sex and estrous phase in the conditioning of toxin-induced disgust reactions (anticipatory nausea) to a novel context were examined in adult rats. Conditioned oral gaping responses have been shown to be a reliable index of nausea in rats. In Experiment 1 male and female rats were injected with LiCl (0, 64, 96, or 128 mg/kg) on each of 4 conditioning trials (72 h apart) and then placed in a novel context for 30 min. 72 h following the last conditioning trial each animal was re-exposed to this context in a toxin-free state for 10 min and disgust responses (gapes, forelimb flails, chin rubs, and paw treads) were scored from video records. A significant toxin dose-related monotonic increase in conditioned gaping showed a significantly greater increase in females, relative to males. In Experiment 2 female rats were conditioned, using the same paradigm, on either diestrus or proestrus days (trials 96 h apart) with LiCl (96 mg/kg) or saline control injections. Disgust responses were recorded on each of the 4 conditioning trials and a toxin-free test trial. Significant increases in conditioned disgust were obtained on proestrus relative to diestrus days on the toxin-free test trial. However no significant estrous cycle differences in disgust responding were obtained on the acquisition trials. The sex difference in conditioned gaping and the increased conditioned disgust responses in proestrus suggest that increased levels of estradiol likely enhance the strength of the association of the toxin-induced nausea with the novel context in rats.

Estrogen involvement in social behavior in rodents: Rapid and long-term actions.

This article is part of a Special Issue ("Estradiol and cognition"). Estrogens have repeatedly been shown to influence a wide array of social behaviors, which in rodents are predominantly olfactory-mediated. Estrogens are involved in social behavior at multiple levels of processing, from the detection and integration of socially relevant olfactory information to more complex social behaviors, including social preferences, aggression and dominance, and learning and memory for social stimuli (e.g. social recognition and social learning). Three estrogen receptors (ERs), ERα, ERß, and the G protein-coupled ER 1 (GPER1), differently affect these behaviors. Social recognition, territorial aggression, and sexual preferences and mate choice, all requiring the integration of socially related olfactory information, seem to primarily involve ERα, with ERß playing a lesser, modulatory role. In contrast, social learning consistently responds differently to estrogen manipulations than other social behaviors. This suggests differential ER involvement in brain regions important for specific social behaviors, such as the ventromedial and medial preoptic nuclei of the hypothalamus in social preferences and aggression, the medial amygdala and hippocampus in social recognition, and the prefrontal cortex and hippocampus in social learning. While the long-term effects of ERα and ERß on social behavior have been extensively investigated, our knowledge of the rapid, non-genomic, effects of estrogens is more limited and suggests that they may mediate some social behaviors (e.g. social learning) differently from long-term effects. Further research is required to compare ER involvement in regulating social behavior in male and female animals, and to further elucidate the roles of the more recently described G protein-coupled ERs, both the GPER1 and the Gq-mER.

Male risk taking, female odors, and the role of estrogen receptors.

Male risk-taking and decision making are affected by sex-related cues, with men making riskier choices and decisions after exposure to either women or stimuli associated with women. In non-human species females and, or their cues can also increase male risk taking. Under the ecologically relevant condition of predation threat, brief exposure of male mice to the odors of a sexually receptive novel female reduces the avoidance of, and aversive responses to, a predator. We briefly review evidence showing that estrogen receptors (ERs), ERα and ERß, are associated with the mediation of these risk taking responses. We show that ERs influence the production of the female odors that affect male risk taking, with the odors of wild type (ERαWT, ERßWT), oxytocin (OT) wildtype (OTWT), gene-deleted 'knock-out' ERß (ERßKO), but not ERαKO or oxytocin (OT) OTKO or ovariectomized (OVX) female mice reducing the avoidance responses of male mice to cat odor. We further show that administration of specific ERα and ERß agonists to OVX females results in their odors increasing male risk taking and boldness towards a predator. We also review evidence that ERs are involved in the mediation of the responses of males to female cues, with ERα being associated with the sexual and both ERß and ERα with the sexual and social mechanisms underlying the effects of female cues on male risk taking. The implications and relations of these findings with rodents to ERs and the regulation of human risk taking are briefly considered.

Estrogenic involvement in social learning, social recognition and pathogen avoidance.

Sociality comes with specific cognitive skills that allow the proper processing of information about others (social recognition), as well as of information originating from others (social learning). Because sociality and social interactions can also facilitate the spread of infection among individuals the ability to recognize and avoid pathogen threat is also essential. We review here various studies primarily from the rodent literature supporting estrogenic involvement in the regulation of social recognition, social learning (socially acquired food preferences and mate choice copying) and the recognition and avoidance of infected and potentially infected individuals. We consider both genomic and rapid estrogenic effects involving estrogen receptors α and ß, and G-protein coupled estrogen receptor 1, along with their interactions with neuropeptide systems in the processing of social stimuli and the regulation and expression of these various socially relevant behaviors.

Interplay of oxytocin, vasopressin, and sex hormones in the regulation of social recognition.

Social Recognition is a fundamental skill that forms the basis of behaviors essential to the proper functioning of pair or group living in most social species. We review here various neurobiological and genetic studies that point to an interplay of oxytocin (OT), arginine-vasopressin (AVP), and the gonadal hormones, estrogens and testosterone, in the mediation of social recognition. Results of a number of studies have shown that OT and its actions at the medial amygdala seem to be essential for social recognition in both sexes. Estrogens facilitate social recognition, possibly by regulating OT production in the hypothalamus and the OT receptors at the medial amygdala. Estrogens also affect social recognition on a rapid time scale, likely through nongenomic actions. The mechanisms of these rapid effects are currently unknown but available evidence points at the hippocampus as the possible site of action. Male rodents seem to be more dependent on AVP acting at the level of the lateral septum for social recognition than female rodents. Results of various studies suggest that testosterone and its metabolites (including estradiol) influence social recognition in males primarily through the AVP V1a receptor. Overall, it appears that gonadal hormone modulation of OT and AVP regulates and fine tunes social recognition and those behaviors that depend upon it (e.g., social bonds, social hierarchies) in a sex specific manner. This points at an important role for these neuroendocrine systems in the regulation of the sex differences that are evident in social behavior and of sociality as a whole.

Tamoxifen produces conditioned taste avoidance in male rats: an analysis of microstructural licking patterns and taste reactivity.

Estrogen receptor activation has been shown to reduce body weight and produce a conditioned reduction in food intake in male rats that is putatively mediated by estradiol's suggested aversive effects. Evidence has shown that the selective estrogen receptor modulator tamoxifen used in the prevention and treatment of breast cancer may also produce changes in food intake and body weight, which are known to impact cancer development and survival. The purpose of the present study was to examine whether tamoxifen produces a conditioned reduction in intake similar to estradiol by producing a conditioned aversion. A one bottle lickometer test was used to examine conditioned changes in sucrose drinking, while the taste reactivity test was used to measure rejection reactions, which serve to index aversion in rats. A backward conditioning procedure that consisted of 3 conditioning days and one vehicle test day was used to examine conditioned changes in 0.3 M sucrose intake and taste reactivity. Our results show that tamoxifen produced a conditioned reduction in sucrose drinking in a one bottle fluid intake test that was similar to the effects produced by estradiol (positive control); however, no active rejection reactions were produced by either tamoxifen (1 and 10 mg/kg) or estradiol. The present results suggest that tamoxifen, at the doses used in the present study, acts as an estrogen receptor agonist to regulate food intake and that the conditioned reduction in intake produced by tamoxifen and estradiol reflects conditioned taste avoidance rather than conditioned taste aversion.

Neuroendocrinology of social information processing in rats and mice.

We reviewed oxytocin (OT), arginine-vasopressin (AVP) and gonadal hormone involvement in various modes of social information processing in mice and rats. Gonadal hormones regulate OT and AVP mediation of social recognition and social learning. Estrogens foster OT-mediated social recognition and the recognition and avoidance of parasitized conspecifics via estrogen receptor (ER) alpha (ERalpha) and ERbeta. Testosterone and its metabolites, including estrogens, regulate social recognition in males predominantly via the AVP V1a receptor. Both OT and AVP are involved in the social transmission of food preferences and ERalpha has inhibitory, while ERbeta has enhancing, roles. OT also enhances mate copying by females. ERalpha mediates the sexual, and ERbeta the recognition, aspects of the risk-taking enhancing effects of females on males. Thus, androgens and estrogens control social information processing by regulating OT and AVP. This control is finely tuned for different forms of social information processing.

Tamoxifen and raloxifene produce conditioned taste avoidance in female rats: a microstructural analysis of licking patterns.

AIMS: Estrogen receptor activation has been shown to reduce body weight and produce conditioned taste avoidance (CTA) when estradiol administration is paired with a novel tastant. This study determined if the selective estrogen receptor modulators tamoxifen and raloxifene, which effectively prevent and treat breast cancer, can induce a CTA and alter body weight in ovariectomized (OVX)-female rats. MAIN METHODS: During conditioning, OVX-female rats were injected with tamoxifen, raloxifene, 17beta-estradiol or vehicle, or were uninjected, prior to drinking 0.3 M sucrose in a lickometer. Immediately following sucrose access, alterations in locomotor activity and thigmotaxis (anxiety) were assessed in an open field apparatus. Conditioned drug effects on drinking, locomotor activity and anxiety were examined on a separate test day. KEY FINDINGS: Our results suggest that both tamoxifen and raloxifene produce CTA that is similar to that produced by estradiol. Both the number and size of bursts of licking were significantly reduced, as well as body weight gain, in OVX-female rats treated with tamoxifen or raloxifene. SIGNIFICANCE: The results of the present study suggest that tamoxifen and raloxifene may have the potential to produce CTA in breast cancer patients receiving chemoprevention care.

Steroidal/neuropeptide interactions in hypothalamus and amygdala related to social anxiety.

Oestrogens (E) influence the activity of oxytocin (OT) producing neurons and heighten the rate of transcription of the oxytocin receptor (OTR) gene. Working through synergistic activities of two different oestrogen receptors (ERs), likely gene duplication products, in the hypothalamus and amygdala, E supports social recognition by mice. As part of social recognition and approach, it is important for mice to assess the risks of social interactions, thus to reduce the social anxiety. Here we argue that hyperactivity in ascending central nervous system arousal systems would work in the opposite direction: increasing social anxiety by potentiating fear-related mechanisms in the amygdala. In humans, such increased social anxiety might account for some features of autism.

Estrogen receptor beta agonists in neurobehavioral investigations.

Neurobehavioral investigations into the functions of estrogen receptor (ER)alpha and ERbeta have utilized 'knockout' mice, phytoestrogens and, more recently, ER-specific agonists. Feeding, sexual, aggressive and social behavior, anxiety, depression, drug abuse, pain perception, and learning (and associated synaptic plasticity) are affected by ERalpha and ERbeta in a manner that is dependent upon the specific behavior studied, gender and developmental stage. Overall, ERalpha and ERbeta appear to function together to foster sociosexual behavior while inhibiting behaviors that, if occurring at the time of behavioral estrous, may compete with reproduction (eg, feeding). Recently developed pharmacological tools have limited selectivity and availability to the research community at large, as they are not commercially available. The development of highly selective, commercially available ERbeta-specific antagonists would greatly benefit preclinical and applied research.

Estrogen receptors alpha and beta mediate different aspects of the facilitatory effects of female cues on male risk taking.

Male risk taking and decision making are affected by sex-related cues, with men making poorer and riskier decisions in the presence of females and, or their cues. In non-human species, female cues can also increase male risk taking, reducing their responses to predator threat. As estrogen receptors alpha and beta (ERalpha and ERbeta) are involved in the mediation of social and sexual responses, we investigated their roles in determining the effects of female-associated cues on male risk taking. We examined the effects of brief pre-exposure to the odors of either a novel or familiar estrous female on the avoidance of, and aversive responses to, predator threat (cat odor) in ERalpha and ERbeta wild type (alphaERWT, betaERWT) and gene-deleted (knockout, alphaERKO, betaERKO) male mice. Exposure of alphaERWT and betaERWT males to the odors of a novel, but not a familiar, estrous female mouse resulted in enhanced risk taking with the males displaying reduced avoidance of, and analgesic responses to, cat odor. In contrast, alphaERKO male mice failed to show any changes in risk taking, while betaERKO males, although displaying greater risk taking, did not distinguish between novel and familiar females, displaying similarly reduced avoidance responses to cat odor after exposure to either a novel or familiar female odor. These findings indicate that the gene for ERalpha is associated with the sexual mechanisms (response to estrous female) and the genes for ERbeta and ERalpha with the social (recognition of novel female) mechanisms underlying the effects of female cues on male risk taking.

The rate of behavioral tolerance development to repeated lipopolysaccharide treatments depends upon the time of injection during the light-dark cycle: a multivariable examination of locomotor activity.

Recent evidence suggests that sickness behaviors following lipopolysaccharide (LPS)-treatment may be modulated by environmental factors such as the light-dark (LD) cycle. The present study characterized LPS-induced hypoactivity and behavioral tolerance development across individual phases of the light-dark cycle and the transitions between phases. On days 1, 4 and 7, male rats were treated with LPS (200microg/kg i.p.) or saline 30min prior to the onset of either the dark period (dark-tested group) or the light period (light-tested group). Following treatment, rats were placed in non-novel automated open-fields where various aspects of locomotor activity were monitored for 16h. On day 1, LPS-treated rats in both the dark and light tested groups showed significant hypoactivity. However, temporal differences in the onset of hypoactivity were observed between the groups. In dark tested animals significant hypoactivity started 60min after LPS treatment and continued until the light period when hypoactivity was diminished. In contrast, the light tested LPS-treated animals did not exhibit a prolonged period of hypoactivity until the transition between the light and dark periods, 750min following LPS injection. On days 4 and 7, light tested animals showed complete tolerance to LPS as evidenced by the absence of significant activity reductions, whereas dark tested animals continued to show significant periods of hypoactivity. These results indicate that there are day-night differences in both the initial LPS-induced hypoactivity response as well as behavioral tolerance development. The rate of tolerance development to LPS may be a critical factor to survival and the prevention of sepsis, as organisms are repeatedly exposed to pathogens across the life cycle.