Elena Choleris

An estrogen-dependent four-gene micronet regulating social recognition: A study with oxytocin and estrogen receptor-α and -β knockout mice

Estrogens control many physiological and behavioral processes, some of which are connected to reproduction. These include sexual and other social behaviors. Here we implicate four gene products in a micronet required for mammalian social recognition, through which an individual learns to recognize other individuals. Female mice whose genes for the neuropeptide oxytocin (OT) or the estrogen receptor (ER)-β or ER-α had been selectively “knocked out” were deficient specifically in social recognition and social anxiety. There was a remarkable parallelism among results from three separate gene knockouts. The data strongly suggest the involvement in social recognition of the four genes coding for ER-α, ER-β, OT, and the OT receptor. We thus propose here a four-gene micronet, which links hypothalamic and limbic forebrain neurons in the estrogen control over the OT regulation of social recognition. In our model, estrogens act on the OT system at two levels: through ER-β, they regulate the production of OT in the hypothalamic paraventricular nucleus, and through ER-α, they drive the transcription of the OT receptor in the amygdala. The proper operation of a social recognition mechanism allows for the expression of appropriate social behaviors, aggressive or affiliative.

Microparticle-based delivery of oxytocin receptor antisense DNA in the medial amygdala blocks social recognition in female mice.

Social recognition constitutes the basis of social life. In male mice and rats, social recognition is known to be governed by the neuropeptide oxytocin (OT) through its action on OT receptors (OTRs) in the medial amygdala. In female rats and mice, which have sociosexual behaviors controlling substantial investment in reproduction, an important role for OT in sociosexual behaviors has also been shown. However, the site in the female brain for OT action on social recognition is still unknown. Here we used a customized, controlled release system of biodegradable polymeric microparticles to deliver, in the medial amygdala of female mice, “locked nucleic acid” antisense (AS) oligonucleotides with sequences specific for the mRNA of the OTR gene. We found that single bilateral intraamygdala injections of OTR AS locked nucleic acid oligonucleotides several days before behavioral testing reduced social recognition. Thus, we showed that gene expression for OTR specifically in the amygdala is required for normal social recognition in female mice. Importantly, during the same experiment, we performed a detailed ethological analysis of mouse behavior revealing that OTR AS-treated mice underwent an initial increase in ambivalent risk-assessment behavior. Other behaviors were not affected, thus revealing specific roles for amygdala OTR in female social recognition potentially mediated by anxiety in a social context. Understanding the functional genomics of OT and OTR in social recognition should help elucidate the neurobiological bases of human disorders of social behavior (e.g., autism).

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.

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.

Olfactory-mediated parasite recognition and avoidance: linking genes to behavior.

A major cost of social behavior is the increased risk of exposure to parasites and infection. Animals utilize social information, including chemical signals, to recognize and avoid conspecifics infected with either endoparasites or ectoparasites. Here, we briefly discuss the relations among odors, parasite recognition, and avoidance, and consider some of the associated hormonal, neural, and genomic mechanisms. In rodents, odor cues mediate sexual and competitive interactions and are of major importance in individual recognition and mate detection and choice. Female mice distinguish between infected and uninfected males by urinary odors, displaying aversive response to, and avoidance of, the odors of infected individuals. This reduces both the likelihood of the transmission of parasites to themselves and allows females to select for parasite-free males. This set of olfactory and mate choice responses can be further modulated by social factors such as previous experience and exposure to infected males and the mate choices of other females. Male mice, who also face the threat of infection, similarly distinguish and avoid parasitized individuals by odor, thus reducing their likelihood of infection. This recognition and avoidance of the odors of infected individuals involves genes for the neuropeptide, oxytocin (OT), and estrogenic mechanisms. Mice with deletions of the oxytocin gene [OT knockout mice (OTKO)] and mice whose genes for estrogen receptor (ER)-alpha or ER-beta have been disrupted [ER knockout mice (ERKO), alpha-ERKO and beta-ERKO] are specifically impaired in their recognition of, aversion to, and memory of the odors of infected individuals. These findings reveal some of the genes involved in the mediation of social recognition in the ecologically relevant context of parasite recognition and avoidance.

Estradiol differentially regulates lipocalin-type prostaglandin D synthase transcript levels in the rodent brain: Evidence from high-density oligonucleotide arrays and in situ hybridization

Microarrays comprise an efficient approach to discovering large numbers of differentially expressed mRNA transcripts in the CNS resulting from changes in hormonal milieu. We used high-density oligonucleotide microarrays to examine the short- and long-term actions of estradiol (E2) on the transcriptomes from the medial basal hypothalamus and other brain regions of E2-treated (10 μg) adult female mice. Our results have revealed several unanticipated gene regulations. Most striking is lipocalin prostaglandin D2 synthase (L-PGDS), which catalyzes the conversion of prostaglandin (PG) H2 to PGD2, a neuromodulator involved in a variety of functions, including sleep, pain, and odor responses. In situ hybridization revealed significant increases in L-PGDS expression in the arcuate and ventromedial nucleus of the medial basal hypothalamus compared with vehicle controls. The magnitude of these changes is ≈2-fold and suggests a modulatory role for PGD2 in E2-controlled neuroendocrine secretions and behaviors. Surprisingly, L-PGDS gene expression is reduced 2-fold after E2 treatment in the ventrolateral preoptic area (VLPO), the suspected site of action for the sleep-promoting effects of PGD2. Finally, whereas L-PGDS has been reported to be expressed primarily in oligodendrocytes of the adult rodent brain, we demonstrate, immunocytochemically, that L-PGDS is also expressed in a population of VLPO neurons. Thus, our data suggest the intriguing possibility that E2 modulation of L-PGDS plays a role in the regulation of sleep–wake states through hitherto unknown mechanisms in VLPO neurons and through hormone-dependent neuronal-glial cooperation.

Recognition and avoidance of the odors of parasitized conspecifics and predators: Differential genomic correlates

In many species of animals chemical stimuli are an important source of information about the threats and dangers present in the social and non-social world. Olfactory cues play a fundamental role in modulating social recognition and interactions in a wide variety of mammals. Rodents, in particular, utilize chemical signals, to recognize and avoid conspecifics infected with parasites and other pathogens. Animals also respond to, and utilize, predator odor related information to assess and minimize their risk of predation. In this review, we briefly focus on the relations between odors, parasite recognition and avoidance and consider some of the associated hormonal, neural and genomic mechanisms. We describe how both male and female rodents distinguish between infected and uninfected males on the basis of odors, displaying aversive response to, and avoidance of, the urine odors of infected individuals. We further describe how the recognition and avoidance of the odors of infected individuals involves genes for the neuropeptide, oxytocin, (OT), and estrogenic mechanisms. We show that mice with deletions of the oxytocin gene (OT knockout mice (OTKO)) and mice whose genes for estrogen receptor (ER)-alpha or ER-beta [ER knockout mice (ERKO), alphaERKO and betaERKO] have been disrupted are specifically impaired in their recognition, avoidance, and memory of the odors of infected individuals. We contrast this with the recognition and display of aversive responses to predator (cat) odor that are insensitive to these genetic manipulations. These findings reveal some of the mechanisms associated with the olfactory mediated recognition of parasitized individuals and predators.

Brief exposure to female odors Emboldens male mice by reducing predator-induced behavioral and hormonal responses

In rodents, where chemical signals play a particularly important role in determining intersexual interactions, various studies have shown that male behavior and physiology is sensitive to female odor cues. Here we examined the effects of brief (1 min) and more prolonged (60 min) preexposure to the odors of a novel estrous female on the behavioral and hormonal responses of sexually experienced and inexperienced male mice, Mus musculus, to subsequent predator (cat and weasel) odor exposure and potential predator risk. Brief, but not prolonged, preexposure to the odors of an estrous female decreased the aversion and avoidance responses of male mice to cat odor in a Y-maze preference test, with the extent of responses being affected by a males prior sexual experience. Similarly, brief, but not prolonged, preexposure to female odors markedly attenuated the analgesic responses elicited in male mice by weasel odor. Brief exposure to a novel estrous female by itself had no significant immediate effects on either corticosterone or testosterone levels in the males. However, brief, but not prolonged, preexposure to the odors of an estrous female attenuated the marked increase in corticosterone and decrease in testosterone that were induced in males by exposure to weasel odor. The decreases in aversive responses to, and effects of, predator odor exposure that are induced by brief exposure to a novel estrous female may reflect a greater risk taking and boldness in males that could directly facilitate access to an immediately, and possibly transiently, available novel sexually receptive female.

Low doses of 17β-estradiol rapidly improve learning and increase hippocampal dendritic spines.

While a great deal of research has been performed on the long-term genomic actions of estrogens, their rapid effects and implications for learning and memory are less well characterized. The often conflicting results of estrogenic effects on learning and memory may be due to complex and little understood interactions between genomic and rapid effects. Here, we investigated the effects of low, physiologically relevant, doses of 17β-estradiol on three different learning paradigms that assess social and non-social aspects of recognition memory and spatial memory, during a transcription independent period of memory maintenance. Ovariectomized female CD1 mice were subcutaneously administered vehicle, 1.5 μg/kg, 2 μg/kg, or 3 μg/kg of 17β-estradiol 15 minutes before social recognition, object recognition, or object placement learning. These paradigms were designed to allow the testing of learning effects within 40 min of hormone administration. In addition, using a different set of ovariectomized mice, we examined the rapid effects of 1.5 μg/kg, 2 μg/kg, or 3 μg/kg of 17β-estradiol on CA1 hippocampal dendritic spines. All 17β-estradiol doses tested impacted learning, memory, and CA1 hippocampal spines. 17β-Estradiol improved both social and object recognition, and may facilitate object placement learning and memory. In addition, 17β-estradiol increased dendritic spine density in the stratum radiatum subregion of the CA1 hippocampus, but did not affect dendritic spines in the lacunosum-moleculare, within 40 min of administration. These results demonstrate that the rapid actions of 17β-estradiol have important implications for general learning and memory processes that are not specific for a particular type of learning paradigm. These effects may be mediated by the rapid formation of new dendritic spines in the hippocampus.

Impaired discrimination of and aversion to parasitized male odors by female oxytocin knockout mice

A major cost of social behavior is the increased risk of exposure to parasites, with animals utilizing social information to recognize and avoid infected conspecifics. In mice, females can discriminate between infected and uninfected males on the basis of social cues, displaying aversive responses to the odors of infected males. In the present study, using female mice whose gene for oxytocin (OT) has been selectively deleted (OT knockout mice (OTKO)), we show that at least one normal allele for OT is required for the mediation of the recognition and avoidance of parasitized males. Female wild type (OTWT) and heterozygous (OTHZ) mice distinguished between the odors of individual males infected with the louse, Polyplax serrata, and uninfected males while the KO mice did not. Exposure to the odors of infected males induced analgesia in OTWT and OTHZ females, with OTKO females displaying attenuated analgesia. OTWT and OTHZ females, but not the OTKO females, also distinguished between the odors of novel and familiar infected males and modulated their analgesic responses on the basis of prior familiarity. In an odor choice test, OTWT and OTHZ females displayed a marked initial choice for the odors of uninfected males, whereas the OTKO females showed no consistent choice. This impairment was specific to the odors of infected males. OTKO females displayed normal analgesic responses to another aversive social odor, that of a stressed male, and an aversive non‐social odor, that of a cat. The OTKOs had normal non‐social olfactory memory, but were impaired in their social odor memory. These findings indicate that a normal OT gene comprises an essential part of the central recognition mechanism whereby females can both reduce the transmission of parasites to themselves and select for parasite‐free males.