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Neuroendocrine control of vocalizations in rodents
Abstract
The neuroendocrine control of ultrasonic vocalizations (USVs) in rodents is a relatively understudied field; nonetheless, interesting findings regarding hormone-behavior relationships have emerged. Here, we focus on five rodent species in which most of this work has been done: golden hamsters (Mesocricetus auratus), house mice (Mus musculus), California mice (Peromyscus californicus), Alston’s singing mice (Scotinomys teguina), and rats (Rattus norvegicus). Many studies focus on sociosexual behavior and sex steroid hormones, however, there is a growing body of literature that probes other aspects of the impacts of neuroendocrine systems on rodent USVs. Using a comparative approach, we identify five major hormone-behavior concepts that are supported in the literature by at least one rodent species. Notably, the production of USVs in rodents can occur in the absence or presence of another individual and is particularly sensitive to social context. This leads us to ask whether (1) social context is critical for identifying sex steroid hormonal effects on USVs and whether (2) the internal energetic state, as represented by hunger hormones, is associated with changes in USVs. (3) We also review evidence for rapid effects of steroid hormone compounds on USVs and (4) research examining USVs as indicators of positive and negative affective states through the lens of hormones and neuroendocrine compounds. (5) Finally, because of the well-known effects of vasopressin and oxytocin on many social behaviors, including vocalizations, we examine the relationship of USV production to these neuropeptide hormones. Overall, there is a relative dearth of information on the function of many of the rodent USVs, with the exception of mate attraction, making it difficult to identify whether the effects of neuroendocrine compounds on USVs have an impact on social interactions, but emerging technology and call analysis tools are expected to advance our knowledge in this area. Through a comparative approach, this review highlights both common themes and a diversity of functions that arise from neuroendocrine influences on USV production.
... In rodents, the neural circuitry of vocal behaviour is organized during neonatal development and activated later in adulthood by gonadal hormones (see reviews Fern andez-Vargas, 2018b;Marler & Monari, 2021). Gonadal hormones can affect vocal behaviour by modulating activity in different brain regions (e.g. ...
... Gonadal hormones can affect vocal behaviour by modulating activity in different brain regions (e.g. limbic system, the midbrain periaqueductal grey (PAG)) or by affecting peripheral tissue structure such as mechanical properties or shape and size of the vocal organ (Adkins-Regan, 2005;Aufdemorte et al., 1983;Fern andez-Vargas, 2018b;Marler & Monari, 2021;Rosenfeld & Hoffmann, 2020). More recently, endocrine disruptor chemicals have also been found to affect acoustic properties in California mice, like call duration in males and vocal activity in females (Marshall et al., 2019). ...
... Beyond barks, California mice produce a variety of ultrasonic vocalizations (USVs) 39 important for communication and behavioral coordination 56 . Because barks are only typically produced when aggressive physical contact is made 16 and were not produced by mice in this study, two call types, sustained vocalizations (SVs) and sweeps, were analyzed, because they may play a role in pair bond formation and maintenance 48,57,58 . SVs are low-bandwidth calls with low modulation, a peak frequency of 20 kHz and a duration of 100 to 500 ms for each individual syllable (Fig. 1B). ...
... IN-OT likely induced coordination of behavior beyond bonding, as evidenced by the increase in time IN-OT pairs spent jointly approaching the stimulus, but not jointly avoiding. Further evidence is suggested by the vocalization data: In this study we tracked two call types, sustained vocalizations (SVs) and sweeps, because they may play a role in pair bond formation and maintenance 58 . While mismatched pairs produced a higher proportion of sustained vocalizations, indicating a potential behavioral mechanism underlying this coordination, IN-OT drove a negative correlation between SV proportion and time spent together in the approach chamber, suggesting that OT may be involved in the relationship between decreased SV production and behavioral convergence. ...
Coordinated responses to challenge are essential to survival for bonded monogamous animals and may depend on behavioral compatibility. Oxytocin (OT) context-dependently regulates social affiliation and vocal communication, but its role in pair members’ decision to jointly respond to challenge is unclear. To test for OT effects, California mouse females received an intranasal dose of OT (IN-OT) or saline after bonding with males either matched or mismatched in their approach response to an aggressive vocal challenge. Pair mates were re-tested jointly for approach response, time spent together, and vocalizations. Females and males converged in their approach after pairing, but mismatched pairs with females given a single dose of IN-OT displayed a greater convergence that resulted from behavioral changes by both pair members. Unpaired females given IN-OT did not change their approach, indicating a social partner was necessary for effects to emerge. Moreover, IN-OT increased time spent approaching together, suggesting behavioral coordination beyond a further increase in bonding. This OT-induced increase in joint approach was associated with a decrease in the proportion of sustained vocalizations, a type of vocalization that can be associated with intra-pair conflict. Our results expand OT’s effects on behavioral coordination and underscore the importance of emergent social context.
... In rodents, the neural circuitry of vocal behaviour is organized during neonatal development and activated later in adulthood by gonadal hormones (see reviews Fern andez-Vargas, 2018b;Marler & Monari, 2021). Gonadal hormones can affect vocal behaviour by modulating activity in different brain regions (e.g. ...
... Gonadal hormones can affect vocal behaviour by modulating activity in different brain regions (e.g. limbic system, the midbrain periaqueductal grey (PAG)) or by affecting peripheral tissue structure such as mechanical properties or shape and size of the vocal organ (Adkins-Regan, 2005;Aufdemorte et al., 1983;Fern andez-Vargas, 2018b;Marler & Monari, 2021;Rosenfeld & Hoffmann, 2020). More recently, endocrine disruptor chemicals have also been found to affect acoustic properties in California mice, like call duration in males and vocal activity in females (Marshall et al., 2019). ...
Like passerines among birds, rodents among mammals have experienced an enormous radiation. Similar to songbirds, this radiation is associated with the evolution of a critical innovation in how vocal signals are produced. Recent studies on the anatomical and physiological bases of vocal production provide an opportunity to understand how proximate mechanisms shape acoustic variation to influence signal function and evolution. Acoustic variation ranges from subtle changes within individuals in different social contexts to extreme divergence among closely related species. Despite increased appreciation of this modality, relatively few studies have assessed variability of acoustic features within individuals over time and/or the consequences of such variation. Moreover, our understanding of the mechanisms that promote and constrain acoustic variation is limited. Herein, we review ontogenetic, social and endocrine factors associated with intraspecific acoustic signal variation in murid and cricetid rodents, summarize the functional consequences of such variation and describe morphological and physiological adaptations underlying vocal displays. We then suggest a framework for developing mutually informative mechanistic and functional studies to explore the evolution of signal elaboration. Clarifying the causes and consequences of interspecific and intraspecific acoustic variation is critical to understanding the evolution and function of vocalizations in the largest radiation of mammals.
... Additionally, T-males did not increase USVs associated with courtship (sweeps) that unpaired males express at high levels toward unfamiliar females (sweeps; Pultorak et al., 2015), as would be expected from courting an unfamiliar female (although these are more difficult to detect with our field set-up). This lack of increased sexual behavior to unfamiliar females is also consistent with the finding that the administration of a single T-pulse caused paired but not unpaired male California mice to decrease sweep USVs to unfamiliar females in the laboratory (Pultorak et al., 2015), suggesting a dampening of the classical increase in vocalizations that occurs in response to the combined stimulus of T and the presence of a female in rodents (review by Marler and Monari, 2021). In the context of the nest site, there was no evidence in the current study that T-pulses increased aggression (see laboratory studies focused on male-male interactions; Marler and Trainor, 2020), as evidenced by lack of injuries (all animals tested were trapped post experiment with no visible injuries) or increase in aggressive barks or shortening of SV calls (Supplementary file 1G; see Pultorak et al., 2018, for evidence that barks can be produced in male-female interactions). ...
Changing social environments such as the birth of young or aggressive encounters present a need to adjust behavior. Previous research examined how long-term changes in steroid hormones mediate these adjustments. We tested the novel concept that the rewarding effects of transient testosterone pulses (T-pulses) in males after social encounters alters their spatial distribution on a territory. In free-living monogamous California mice ( Peromyscus californicus ), males administered three T-injections at the nest spent more time at the nest than males treated with placebo injections. This mimics T-induced place preferences in the laboratory. Female mates of T-treated males spent less time at the nest but the pair produced more vocalizations and call types than controls. Traditionally, transient T-changes were thought to have transient behavioral effects. Our work demonstrates that in the wild, when T-pulses occur in a salient context such as a territory, the behavioral effects last days after T-levels return to baseline.
... In support of the social salience theory [87][88][89][90][91], IN OXT amplified the effect of the tactile pup experience, leading to an increase above and beyond the observed increase in control mothers during the habituation phase (and a trend in reunion phase). To our knowledge, this is the first study reporting context-dependent IN OXT-moderated changes in USV production that were associated with physical access to a social stimulus [92]. ...
Maternal-offspring communication and care are essential for offspring survival. Oxytocin (OXT) is known for its role in initiation of maternal care, but whether OXT can rapidly influence maternal behavior or ultrasonic vocalizations (USVs; above 50 kHz) has not been examined. To test for rapid effects of OXT, California mouse mothers were administered an acute intranasal (IN) dose of OXT (0.8 IU/kg) or saline followed by a separation test with three phases: habituation with pups in a new testing chamber, separation via a wire mesh, and finally reunion with pups. We measured maternal care, maternal USVs, and pup USVs. In mothers, we primarily observed simple sweep USVs, a short downward sweeping call around 50 kHz, and in pups we only observed pup whines, a long call with multiple harmonics ranging from 20 kHz to 50 kHz. We found that IN OXT rapidly and selectively enhanced the normal increase in maternal simple sweep USVs when mothers had physical access to pups (habituation and reunion), but not when mothers were physically separated from pups. Frequency of mothers’ and pups’ USVs were correlated upon reunion, but IN OXT did not influence this correlation. Finally, mothers given IN OXT showed more efficient pup retrieval/carrying and greater total maternal care upon reunion. Behavioral changes were specific to maternal behaviors (e.g. retrievals) as mothers given IN OXT did not differ from controls in stress-related behaviors (e.g. freezing). Overall, these findings highlight the rapid effects and context-dependent effect a single treatment with IN OXT has on both maternal USV production and offspring care.
Monogamous, pair-bonded animals coordinate intra-pair behavior for spatially separated challenges including territorial defense and nest attendance. Paired California mice, a monogamous, territorial and biparental species, approach intruders together or separately, but often express behavioral convergence across intruder challenges. To gain a more systems-wide perspective of potential mechanisms contributing to behavioral convergence across two conspecific intruder challenges, we conducted an exploratory study correlating behavior and receptor mRNA (Days 10 and 17 post-pairing). We examined associations between convergence variability in pair time for intruder-oriented behaviors with a pair mRNA index for oxytocin (OXTR), androgen (AR), and estrogen alpha (ERα) receptors within the medial amygdala (MeA) and the anterior olfactory nucleus (AON), brain regions associated with social behavior. An intruder behavior index revealed a bimodal distribution of intruder-related behaviors in Challenge 1 and a unimodal distribution in Challenge 2, suggesting population behavioral convergence, but no significant correlations with neuroendocrine measures. However, OXTR, AR, and ERα mRNA in the MeA were positively associated with convergence in individual intruder-related behaviors, suggesting multiple mechanisms may influence convergence. Mice could also occupy the nest during intruder challenges and convergence in nest attendance was positively correlated with MeA OXTR. At an individual level, nest attendance was positively associated with MeA ERα. Vocalizations were positively associated with AR and ERα mRNA. No positive associations were found in the AON. Overall, neuroendocrine receptors were implicated in convergence of a monogamous pair's defense behavior, highlighting the potential importance of the MeA as part of a circuit underlying convergence.
Animals vocalize only in certain behavioral contexts, but the circuits and synapses through which forebrain neurons trigger or suppress vocalization remain unknown. Here we used transsynaptic tracing to identify two populations of inhibitory neurons that lie upstream of neurons in the periaqueductal gray that gate the production of ultrasonic vocalizations in mice (i.e., PAG-USV neurons). Activating PAG-projecting neurons in the preoptic hypothalamus (POA PAG neurons) elicited USV production in the absence of social cues. In contrast, activating PAG-projecting neurons in the central-medial boundary zone of the amygdala (Amg C/M-PAG neurons) transiently suppressed USV production without disrupting non-vocal social behavior. Optogenetics-assisted circuit mapping in brain slices revealed that POA PAG neurons directly inhibit PAG interneurons, which in turn inhibit PAG-USV neurons, whereas Amg C/M-PAG neurons directly inhibit PAG-USV neurons. These experiments identify two major forebrain inputs to the PAG that trigger and suppress vocalization, respectively, while also establishing the synaptic mechanisms through which these neurons exert opposing behavioral effects.
The Norway rat has important impacts on our life. They are amongst the most used research subjects, resulting in groundbreaking advances. At the same time, wild rats live in close association with us, leading to various adverse interactions. In face of this relevance, it is surprising how little is known about their natural behaviour. While recent laboratory studies revealed their complex social skills, little is known about their social behaviour in the wild. An integration of these different scientific approaches is crucial to understand their social life, which will enable us to design more valid research paradigms, develop more effective management strategies, and to provide better welfare standards. Hence, I first summarise the literature on their natural social behaviour. Second, I provide an overview of recent developments concerning their social cognition. Third, I illustrate why an integration of these areas would be beneficial to optimise our interactions with them.
The neuromodulator oxytocin, since its first synthesis by du Vigneaud in 1953, has mainly been associated with beneficial physiological effects, as well as positive social and emotional behaviors. This overall positive picture of oxytocin as the "love-, cuddle-, or bonding-hormone" has repeatedly been challenged since then. Oxytocin-induced effects that would be perceived as negative by the individual, such as increased anxiety or potentiation of stress-induced ACTH release, as well as the regulation of negative approach-related emotions, such as envy and schadenfreude (gloating) have been described. The general consent is that oxytocin, instead of acting unidirectional, induces changes in the salience network to shift the emphasis of emotional contexts, and therefore can, e.g., produce both anxiolytic as well as anxiogenic behavioral outcomes. However, the underlying mechanisms leading to alterations in the salience network are still unclear. With the aim to understand the manifold effects of oxytocin on a cellular/molecular level, a set of oxytocin receptor-coupled signaling cascades and downstream effectors regulating transcription and translation has been identified. Those oxytocin-driven effectors, such as MEF2 and CREB, are known modulators of the neuronal and glial cytoarchitecture. We hypothesize that, by determining cellular morphology and connectivity, MEF2 is one of the key factors that might contribute to the diverse behavioral effects of oxytocin.
Background:
Courtship vocalizations are used by males of many species to attract and influence the behavior of potential mating partners. Our aim here was to investigate the modulation and reproductive consequences of courtship ultrasonic vocalizations (USVs) in wild-derived house mice (Mus musculus musculus). The courtship USVs of male mice are surprisingly complex and are composed of a variety of different syllable types. Our specific aims were to test whether (1) the emission of courtship USVs depends upon the kinship of a potential mating partner, and (2) whether USV emission during courtship affects the pairs' subsequent reproductive success.
Results:
We experimentally presented males with an unfamiliar female that was either genetically related or unrelated, and we recorded USV emission, first while the sexes were separated by a perforated partition and then during direct interactions, after removing the partition. USVs were detected by the Automatic Mouse Ultrasound Detector (A-MUD) and manually classified into 15 syllable types. The mice were kept together to test whether and how courtship vocalizations predict their subsequent reproductive success. We found that the mice significantly increased their amount of vocalizations (vocal performance) and number of syllable types (vocal repertoire) after the partition was removed and they began interacting directly. We show that unrelated pairs emitted longer and more complex USVs compared to related pairs during direct interactions. Unrelated pairs also had a greater reproductive success compared to related pairs, and in addition we found a negative correlation between the mean length and amount of vocalizations with the latency to their first litter.
Conclusion:
Our study provides evidence that house mice modulate the emission of courtship USVs depending upon the kinship of potential mating partners, and that courtship USVs correlate with reproductive success.
The neuropeptide arginine-vasopressin (AVP) has long been implicated in the regulation of social behavior and communication in diverse taxa, often through its actions on the V1a receptor (V1aR) and in a sex-different and steroid-dependent way. One source of sex-different brain AVP is the steroid-sensitive and sexually-dimorphic AVP neurons in the bed nucleus of the stria terminalis (BNST), a cell population that regulates social behavior in a sex-dependent manner. Potential targets of these BNST-AVP cells include the lateral habenula (LHb) and dorsal raphe (DR), areas known to be important for social behavior, yet few studies have investigated AVP action within these regions. Consequently, to test if V1aR action in the LHb or DR controls social behavior in a sexually dimorphic manner, we administered a highly-specific V1aR antagonist (or saline vehicle) in the LHb or DR of C57BL/6 male and female mice and tested its effects on social investigation, social communication (urine marking, ultrasonic vocalizations), and territorial aggression. V1aR antagonism of the LHb or DR decreased male urine marking toward unfamiliar males, but not toward unfamiliar females. Additionally, V1aR blockade of the LHb decreased ultrasonic vocalizations generated in the presence of females. Social investigation, locomotion and aggressive behavior were not altered by V1aR antagonism in either area. Blocking V1aR in the LHb or DR of females had no effect, indicating V1aR action in the DR and LHb drives sex differences in social communication.
In a short time, oxytocin has progressed from being a regular hormone involved in parturition and breastfeeding to be possibly the neuromodulator that has gathered the most attention. Attributed many positive roles in the modulation of different aspects of social behavior, such as bonding, empathy, cooperation, trust, and generosity, as well as roles as a natural anxiolytic and antidepressant, the expectations on oxytocin becoming a treatment for a number of disorders with associated social deficits have dramatically raised over the last years. However, despite the field has been investigating oxytocin’s role in social behavior for over twenty years, there are still many unknowns on oxytocin’s mechanisms of action and efficiency and the increasing number of clinical trials administering oxytocin to different clinical groups seem to disagree in its properties and report in most cases conflicting results. This has led to some disappointment among researchers and clinicians as oxytocin might not be the miraculous molecule that works in a “one size fits all” fashion initially considered. Conversely, this down-side of oxytocin might merely reflect the complexity of its neurotransmission system. The current reality is that, although oxytocin seems to have potential therapeutic value, there are key questions that remain unanswered as to decide the optimal target groups and treatment course. Here, we present an overview on critical points regarding the oxytocin system in health and disease that need to be better understood to establish its therapeutic properties and to decide who could benefit the most from its treatment.
Vocalization is an ancient vertebrate trait essential to many forms of communication, ranging from courtship calls to free verse. Vocalizations may be entirely innate and evoked by sexual cues or emotional state, as with many types of calls made in primates, rodents and birds; volitional, as with innate calls that, following extensive training, can be evoked by arbitrary sensory cues in non-human primates and corvid songbirds; or learned, acoustically flexible and complex, as with human speech and the courtship songs of oscine songbirds. This review compares and contrasts the neural mechanisms underlying innate, volitional and learned vocalizations, with an emphasis on functional studies in primates, rodents and songbirds. This comparison reveals both highly conserved and convergent mechanisms of vocal production in these different groups, despite their often vast phylogenetic separation. This similarity of central mechanisms for different forms of vocal production presents experimentalists with useful avenues for gaining detailed mechanistic insight into how vocalizations are employed for social and sexual signalling, and how they can be modified through experience to yield new vocal repertoires customized to the individual's social group.
This article is part of the theme issue ‘What can animal communication teach us about human language?’
It is currently unclear whether mice use their ultrasonic vocalizations (USVs) for communication purposes. It is also unknown whether mice require previous experience with USVs to understand conspecifics. There is some evidence that experience changes the perception of juvenile USVs; however, it is unclear whether similar plasticity also occurs for adult USVs. To examine whether social exposure or deprivation throughout development leads to changes in USV perception, eleven female CBA/CaJ mice were trained to discriminate between 18 USVs of three different categories using operant conditioning procedures. Mice were group housed with four females or housed individually from weaning for the duration of the experiment. Socially housed and isolated mice differed in initial training times on pure tones, suggesting isolated mice had a more difficult time learning the task. Both groups completed USV discrimination conditions quicker at the end of the testing phases relative to the beginning. The overall discrimination of USVs did not differ between the two housing conditions, but a multidimensional scaling analysis revealed that socially experienced and isolated mice perceive some USVs differently, illustrated by differences in locations of USVs on the scaling maps from the two groups. Finally, a negative correlation was found between spectrotemporal similarity and percent discrimination, and analyses support the idea that mice may show categorical perception of at least two of the three USV categories. Thus, experience with USVs changes USV perception.
Social hierarchies emerge when animals compete for access to resources such as food, mates or physical space. Wild and laboratory male mice have been shown to develop linear hierarchies, however, less is known regarding whether female mice have sufficient intrasexual competition to establish significant social dominance relationships. In this study, we examined whether groups of outbred CD-1 virgin female mice housed in a large vivaria formed social hierarchies. We show that females use fighting, chasing and mounting behaviors to rapidly establish highly directionally consistent social relationships. Notably, these female hierarchies are less linear, steep and despotic compared to male hierarchies. Female estrus state was not found to have a significant effect on aggressive behavior, though dominant females had elongated estrus cycles (due to increased time in estrus) compared to subordinate females. Plasma estradiol levels were equivalent between dominant and subordinate females. Subordinate females had significantly higher levels of basal corticosterone compared to dominant females. Analyses of gene expression in the ventromedial hypothalamus indicated that subordinate females have elevated ERα, ERβ and OTR mRNA compared to dominant females. This study provides a methodological framework for the study of the neuroendocrine basis of female social aggression and dominance in laboratory mice.
The neuropeptide arginine vasopressin (AVP) has long been implicated in the regulation of social behavior and communication, but precisely which AVP cell groups are involved is largely unknown. To address whether the sexually dimorphic AVP cell group in the bed nucleus of the stria terminalis (BNST) is important for social communication, we deleted BNST AVP cells by viral delivery of a Cre-dependent caspase-3 cell-death construct in AVP-iCre-positive mice using AVP-iCre negative littermate as controls, and assessed social, sexual, aggressive and anxiety-related behaviors. In males, lesioning BNST AVP cells reduced social investigation of other males and increased urine marking (UM) in the presence of a live female, without altering ultrasonic vocalizations (USVs), resident-intruder aggression, copulatory behavior, anxiety, or investigation of females or their odor cues. In females, which have significantly fewer AVP cells in the BNST, these injections influenced copulatory behavior but otherwise had minimal effects on social behavior and communication, indicating that these cells contribute to sex differences in social behavioral function.
Rodents engage in social communication through a rich repertoire of ultrasonic vocalizations (USVs). Recording and analysis of USVs has broad utility during diverse behavioral tests and can be performed noninvasively in almost any rodent behavioral model to provide rich insights into the emotional state and motor function of the test animal. Despite strong evidence that USVs serve an array of communicative functions, technical and financial limitations have been barriers for most laboratories to adopt vocalization analysis. Recently, deep learning has revolutionized the field of machine hearing and vision, by allowing computers to perform human-like activities including seeing, listening, and speaking. Such systems are constructed from biomimetic, “deep”, artificial neural networks. Here, we present DeepSqueak, a USV detection and analysis software suite that can perform human quality USV detection and classification automatically, rapidly, and reliably using cutting-edge regional convolutional neural network architecture (Faster-RCNN). DeepSqueak was engineered to allow non-experts easy entry into USV detection and analysis yet is flexible and adaptable with a graphical user interface and offers access to numerous input and analysis features. Compared to other modern programs and manual analysis, DeepSqueak was able to reduce false positives, increase detection recall, dramatically reduce analysis time, optimize automatic syllable classification, and perform automatic syntax analysis on arbitrarily large numbers of syllables, all while maintaining manual selection review and supervised classification. DeepSqueak allows USV recording and analysis to be added easily to existing rodent behavioral procedures, hopefully revealing a wide range of innate responses to provide another dimension of insights into behavior when combined with conventional outcome measures.
An ongoing question related to the evolution of monogamy is how behavioral traits that characterize individuals in monogamous species evolve, and whether monogamy influences the evolution of these traits. One of the most important models for the study of monogamy in mammals is the California mouse (Peromyscus californicus) that uses ultrasonic vocalizations (USVs) in multiple behavioral contexts, including pair-bonding and courtship. Because the genus Peromyscus has many species that both use USVs and express a variety of mating systems, we were able to examine the relationship among USVs, and other ecological (e.g., xeric habitat), physiological (testosterone), and behavioral (e.g., boldness) traits across species. We measured USVs from seven species at the Peromyscus Genetic Stock Center and derived character traits associated with the species' ecology, physiology, and behavior from published studies, including those that had used stocks from the Peromyscus Genetic Stock Center. We determined whether there were USV traits that were particular to monogamous species or whether traits other than mating system best predicted USVs. The trait that best predicted USVs was not related to mating system, but rather, species boldness. Bold species produced few aggressive barks (likely a defensive agonistic USV type) at a higher mean fundamental frequency than less bold species. In relation to mating system, the barks in monogamous species were shorter in duration than the barks in non-monogamous species. Our results suggest that boldness of a species has a higher selection on USVs than the species mating system, ecology, or physiology and that selection has acted on agonistic acoustic signals. Because another type of USV, the sustained vocalization or SV type, did not differ among species in spite of mating system differences, and because all species produced bark types, we suggest that the USVs in rodents evolved as general signals that have generally been co-opted for particular functions within the mating system context that differs across species, as opposed to signals that have been shaped by mating system type.
House mice, like many tetrapods, produce multielement calls consisting of individual vocalizations repeated in rhythmic series. In this study, we examine the multielement ultrasonic vocalizations (USVs) of adult male C57Bl/6J mice and specifically assess their temporal properties and organization. We found that male mice produce two classes of USVs which display unique temporal features and arise from discrete respiratory patterns. We also observed that nearly all USVs were produced in repetitive series exhibiting a hierarchical organization and a stereotyped rhythmic structure. Furthermore, series rhythmicity alone was determined to be sufficient for the mathematical discrimination of USVs produced by adult males, adult females, and pups, underscoring the known importance of call timing in USV perception. Finally, the gross spectrotemporal features of male USVs were found to develop continuously from birth and stabilize by P50, suggesting that USV production in infants and adults relies on common biological mechanisms. In conclusion, we demonstrate that the temporal organization of multielement mouse USVs is both stable and informative, and we propose that call timing be explicitly assessed when examining mouse USV production. Furthermore, this is the first report of putative USV classes arising from distinct articulatory patterns in mice, and is the first to empirically define multielement USV series and provide a detailed description of their temporal structure and development. This study therefore represents an important point of reference for the analysis of mouse USVs, a commonly used metric of social behavior in mouse models of human disease, and furthers the understanding of vocalization production in an accessible mammalian species.
Different rat and mouse models are used in studies of social interactions. Simple behavioral measures, which are commonly used in the laboratory, allow to perform relatively short experiments and use multiple brain manipulation techniques. However, too much focus on the simplest behavioral models generates a serious risk of reducing ecological validity or even studying phenomena which would never happen outside of the laboratory. In this review, we discuss the suitability of mice and rats as model organisms for studying social behaviors, with focus on social transmission of fear paradigms. First, we briefly introduce the concept of domestication and what impact it had on laboratory rodents. Then we present two aspects of social behaviors, sociability and dominance, which are crucial for social organization in these species. Finally, we present experimental models used for studying how animals transmit information about danger between each other, and how these models may reflect what happens in the natural environment. We discuss the difficulties that arise from our limited knowledge of rat and mouse ecology, especially their social life. We also explore the subject of balancing ecological validity and controllability in rodent models of social behaviors, the latter being particularly important for studying brain activity. Though it is very challenging, an efficient program for social neuroscience research should, in our opinion, aim at bridging the gap between laboratory and field studies.
Despite recent exciting research about pair bonding, little is known about how mammalian vocalizations change with the initiation and maintenance of pair bonding in monogamous species. Moreover, even less is known about the significance of pair bond resilience in the face of social challenges. In the strictly monogamous California mouse (Peromyscus californicus), we measured changes in ultrasonic vocalizations (USV) and other behaviors within male-female dyads over the course of pair bonding and characterized associations of USVs with affiliation and aggression. After 1 week of cohabitation, pairs exhibited decreased aggression and “bark” USVs, and increased “simple sweep” and “sustained vocalization” (SV) USV types. Accordingly, the number of barks was associated with aggression, whereas the number of simple sweeps and the number, call duration and bout size of SVs corresponded with affiliation. We then experimentally assessed the impact of an infidelity challenge (1 week cohabitation with an unfamiliar, opposite-sex, extra-pair individual) for both sexes on pair social behavior, acoustic behavior, and reproductive success. The infidelity challenge temporarily disrupted pair bond interactions during pair reunion, independent of which sex experienced the infidelity challenge, via both increases in aggression and barks, and a stunting of affiliation and SVs, compared to control pairs. Pair reproductive success, in the form of birth latency, litter size, pup survival and birth weight, did not differ between infidelity challenge pairs and controls. The quality of pair interactions, however, was associated with reproductive success: aggression during pair reunion across all pairs was associated with a lower likelihood of successfully producing a litter. Similarly, among infidelity challenge pairs, but not the controls, there was a positive association between pair affiliation and paternal care, and a negative association between pair aggression and paternal care. Overall, the infidelity challenge revealed a weak negative effect on reproductive success, but we speculate, based on our results, that greater resiliency of a pair bond can moderate negative effects of a social challenge.
Mice produce various sounds within the ultrasonic range in social contexts. Although these sounds are often used as an index of sociability in biomedical research, their biological significance remains poorly understood. We previously showed that mice repeatedly produced calls in a sequence (i.e. calling bout), which can vary in their structure, such as Simple, Complex or Harmonics. In this study, we investigated the use of the three types of calling bouts in different sociosexual interactions, including both same- and opposite-sex contexts. In same-sex contexts, males typically produced a Simple calling bout, whereas females mostly produced a Complex one. By contrast, in the opposite-sex context, they produced all the three types of calling bouts, but the use of each calling type varied according to the progress and mode of sociosexual interaction (e.g. Harmonic calling bout was specifically produced during reproductive behaviour). These results indicate that mice change the structure of calling bout according to sociosexual contexts, suggesting the presence of multiple functional signals in their ultrasonic communication.
Rodent pups use vocalizations to communicate with one or both parents in biparental species, such as California mice (Peromyscus californicus). Previous studies have shown California mice developmentally exposed to endocrine disrupting chemicals, bisphenol A (BPA) or ethinyl estradiol (EE), demonstrate later compromised parental behaviors. Reductions in F1 parental behaviors might also be due to decreased emissions of F2 pup vocalizations. Thus, vocalizations of F2 male and female California mice pups born to F1 parents developmentally exposed to BPA, EE, or controls were examined. Postnatal days (PND) 2–4 were considered early postnatal period, PND 7 and 14 were defined as mid-postnatal period, and PND 21 and 28 were classified as late postnatal period. EE pups showed increased latency to emit the first syllable compared to controls. BPA female pups had decreased syllable duration compared to control and EE female pups during the early postnatal period but enhanced responses compared to controls at late postnatal period; whereas, male BPA and EE pups showed greater syllable duration compared to controls during early postnatal period. In mid-postnatal period, F2 BPA and EE pups emitted greater number of phrases than F2 control pups. Results indicate aspects of vocalizations were disrupted in F2 pups born to F1 parents developmentally exposed to BPA or EE, but their responses were not always identical, suggesting BPA might not activate estrogen receptors to the same extent as EE. Changes in vocalization patterns by F2 pups may be due to multigenerational exposure to BPA or EE and/or reduced parental care received.
Adult rats spontaneously vocalize in ultrasonic frequencies. Although these ultrasonic vocalizations (USVs) have been described as by-products of locomotor activity or social signals, accumulating evidence suggests that they may also index anticipatory affective states. Converging ethological, pharmacological, and brain stimulation research indicates that whereas long low-frequency (> 0.3-s, ∼22-kHz) USVs occur during anticipation of punishment or avoidance behavior, short, high-frequency (< 0.3-s, ∼50-kHz) USVs typically occur during anticipation of reward or approach behavior. Thus, long 22-kHz USVs may index a state of negative activation, whereas short, 50-kHz USVs may instead index a state of positive activation. This hypothesis has theoretical implications for understanding the brain circuitry underlying mammalian affective states and clinical applicability for modeling hedonic properties of different psychotropic compounds.
Advertisement displays often seem extravagant and expensive, and are thought to depend on the body condition of a signaller. Nevertheless, we know little about how signallers adjust effort based on condition, and few studies find a strong relationship between natural variation in condition and display. To examine the relationship between body condition and signal elaboration more fully, we characterized physiological condition and acoustic displays in a wild rodent with elaborate vocalizations, Alston's singing mouse, Scotinomys teguina We found two major axes of variation in condition-one defined by short-term fluctuations in caloric nutrients, and a second by longer-term variation in adiposity. Among acoustic parameters, song effort was characterized by high rates of display and longer songs. Song effort was highly correlated with measures of adiposity. We found that leptin was a particularly strong predictor of display effort. Leptin is known to influence investment in other costly traits, such as immune function and reproduction. Plasma hormone levels convey somatic state to a variety of tissues, and may govern trait investment across vertebrates. Such measures offer new insights into how animals translate body condition into behavioural and life-history decisions.
Background
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by two core symptoms: impaired social interaction and communication, and restricted, repetitive behaviors and interests. The pathophysiology of ASD is not yet fully understood, due to a plethora of genetic and environmental risk factors that might be associated with or causal for ASD. Recent findings suggest that one putative convergent pathway for some forms of ASD might be the downregulation of the calcium-binding protein parvalbumin (PV). PV-deficient mice (PV−/−, PV+/−), as well as Shank1−/−, Shank3−/−, and VPA mice, which show behavioral deficits relevant to all human ASD core symptoms, are all characterized by lower PV expression levels. Methods
Based on the hypothesis that PV expression might be increased by 17-β estradiol (E2), PV+/− mice were treated with E2 from postnatal days 5–15 and ASD-related behavior was tested between postnatal days 25 and 31. ResultsPV expression levels were significantly increased after E2 treatment and, concomitantly, sociability deficits in PV+/− mice in the direct reciprocal social interaction and the 3-chamber social approach assay, as well as repetitive behaviors, were attenuated. E2 treatment of PV+/+ mice did not increase PV levels and had detrimental effects on sociability and repetitive behavior. In PV−/− mice, E2 obviously did not affect PV levels; tested behaviors were not different from the ones in vehicle-treated PV−/− mice. Conclusion
Our results suggest that the E2-linked amelioration of ASD-like behaviors is specifically occurring in PV+/− mice, indicating that PV upregulation is required for the E2-mediated rescue of ASD-relevant behavioral impairments.
Acoustic communication is vital to complex social behaviours such as territorial defence. The use of ultrasonic vocalizations, particularly in territorial defence by monogamous species and females, remains understudied. We studied ultrasonic vocalization production and associated aggression in the monogamous, biparental and territorial California mouse, Peromyscus californicus, in which both males and females were found to display similar levels of physical aggression against same-sex intruders. We identified specific ultrasonic vocalization calls that are modulated based on social context: (1) sustained vocalizations, which are long, low-bandwidth calls ranging from 22 to 25 kHz, and (2) barks, which are short, high-intensity calls beginning and ending in the audible range. Despite similarities in physical aggression, sex differences emerged in vocal communication. Only resident males, and not females, produced sustained vocalizations prior to the onset of physical aggression, and were found to shorten the duration of individual sustained vocalization calls over both the course of the pre-encounter phase and from the pre-encounter to encounter phase. In addition, the degree of sustained vocalization shortening in males predicted offensive aggression of the resident. Males exhibited shorter sustained vocalization calls during encounters than females. Barks occurred more frequently during female–female physical aggression than in male–male encounters, and correlated highly with defensive aggression by intruders. Finally, a newly identified highly complex call, sweep phrases, was recorded in a subset of both sexes in the pre- and post-encounter phases. The overall results indicate that ultrasonic vocalizations may play an important role in territorial defence during both territorial advertisement and aggression in a monogamous rodent. Overall, this monogamous species showed sex similarities in physical aggression but sex differences in vocal communication and a more sophisticated function for sustained vocalizations than previously recognized.
Communication consists of social interaction, recognition, and information transmission. Communication ability is the most affected component in children with autism spectrum disorder (ASD). Recently, we reported that the CD157/BST1 gene is associated with ASD, and that CD157 knockout (Cd157−/−) mice display severe impairments in social behavior that are improved by oxytocin (OXT) treatment. Here, we sought to determine whether Cd157−/− mice can be used as a suitable model for communication deficits by measuring ultrasonic vocalizations (USVs), especially in the early developmental stage. Call number produced in pups due to isolation from dams was higher at postnatal day (PND) 3 in knockout pups than wild-type mice, but was lower at PNDs 7 and 10. Pups of both genotypes had similarly limited voice repertoires at PND 3. Later on, at PNDs 7 and 10, while wild-type pups emitted USVs consisting of six different syllable types, knockout pups vocalized with only two types. This developmental impairment in USV emission was rescued within 30 min by intraperitoneal OXT treatment, but quickly returned to control levels after 120 min, showing a transient effect of OXT. USV impairment was partially observed in Cd157+/− heterozygous mice, but not in Cd157−/− adult male mice examined while under courtship. These results demonstrate that CD157 gene deletion results in social communication insufficiencies, and suggests that CD157 is likely involved in acoustic communication. This unique OXT-sensitive developmental delay in Cd157−/− pups may be a useful model of communicative interaction impairment in ASD.
Male house mice (Mus musculus) emit ultrasonic vocalizations (USVs) during courtship, which attract females, and we aimed to test whether females use these vocalizations for species or subspecies recognition of potential mates. We recorded courtship USVs of males from different Mus species, Mus musculus subspecies, and populations (F1 offspring of wild-caught Mus musculus musculus, Mus musculus domesticus (and F1 hybrid crosses), and Mus spicilegus), and we conducted playback experiments to measure female preferences for male USVs. Male vocalizations contained at least seven distinct syllable types, whose frequency of occurrence varied among species, subspecies, and populations. Detailed analyses of multiple common syllable types indicated that Mus musculus and Mus spicilegus could be discriminated based on spectral and temporal characteristics of their vocalizations, and populations of Mus musculus were also distinctive regardless of the classification model used. Females were able to discriminate USVs from different species, and showed assortative preferences for conspecific males. We found no evidence that females discriminate USVs of males from a different subspecies or separate populations of the same species, even though our spectral analyses identified acoustic features that differ between species, subspecies, and populations of the same species. Our results provide the first comparison of USVs between Mus species or between Mus musculus subspecies, and the first evidence that male USVs potentially facilitate species recognition.
This study tested the effects of long-term estradiol (E2) replacement on social behavior and gene expression in brain nuclei involved in the regulation of these social behaviors in adult female rats. We developed an ultrasonic vocalization (USV) test and a sociability test to examine communications, social interactions, and social preference, using young adult female cagemates. All rats were ovariectomized (OVX) and implanted with a Silastic capsule containing E2 or vehicle, and housed in same-treatment pairs for a 3-month period. Then, rats were behaviorally tested, euthanized, and 5 nuclei in the brain's social decision-making circuit selected for neuromolecular profiling by a multiplex qPCR method. Our novel USV test proved to be a robust tool to measure numbers and types of calls emitted by cagemates that had been reintroduced after a 1-week separation. Results also showed that E2-treated OVX rats had profoundly decreased numbers of USV calls compared to vehicle-treated OVX rats. In a test of sociability, in which a female was allowed to choose between her cagemate or a same-treatment novel rat, we found few effects of E2 compared to vehicle, although interestingly, rats chose the cagemate over an unfamiliar conspecific. Gene expression results revealed that the supraoptic nucleus had the greatest number of gene changes caused by E2: Oxt, Oxtr and Avp were increased, and Drd2, Htr1a, Grin2b, and Gabbr1 were decreased, by E2. No genes were affected in the prefrontal cortex, and 1–4 genes were changed in paraventricular nucleus (Pgr), bed nucleus of the stria terminalis (Oxtr, Esr2, Dnmt3a), and medial amygdala (Oxtr, Ar, Foxp1, Tac3). Thus, E2 changes communicative interactions between adult female rats, together with selected expression of genes in the brain, especially in the supraoptic nucleus.
Over the past 3 decades, a large body of evidence has accumulated demonstrating that the neuropeptide arginine vasopressin (AVP) plays a critical role in regulating social behavior. The overwhelming majority of this evidence comes from adults, leaving a gap in our understanding of the role of AVP during development. Here, we investigated the effect of chronic AVP deficiency on a suite of juvenile social behaviors using Brattleboro rats, which lack AVP due to a mutation in the Avp gene. Social play behavior, huddling, social investigation & allogrooming, and ultrasonic vocalizations (USVs) of male and female rats homozygous for the Brattleboro mutation (Hom) were compared with their wild-type (WT) and heterozygous (Het) littermates during same-sex, same-genotype social interactions. Male and female Hom juveniles exhibited less social play than their Het and WT littermates throughout the rise, peak, and decline of the developmental profile of play. Hom juveniles also emitted fewer prosocial 50 kHz USVs, and spectrotemporal characteristics (call frequency and call duration) of individual call types differed from those of WT and Het juveniles. However, huddling behavior was increased in Hom juveniles, and social investigation and 22 kHz USVs did not differ across genotypes, demonstrating that not all social interactions were affected in the same manner. Collectively, these data suggest that the Avp gene plays a critical role in juvenile social development.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder estimated by the World Health Organization to occur in one of 160 children worldwide. No pharmaceutical treatments are available to improve the deficits in social communication that are common symptoms of ASD. Recent clinical trials have focused on the nasal application of oxytocin, a neuronal peptide known to regulate a variety of social behaviors. However, the effect of oxytocin on this deficit is inconclusive. In contrast, evidence from ASD animal model studies indicates that when animals are treated with oxytocin during early development, improvements in social deficits are observed in adulthood. Thus, it is necessary to examine the effect of therapeutic target medication prescribed in early development. Mice prenatally exposed to valproic acid (VPA) are widely used as an animal model of ASD. However, many behavioral studies have been conducted during adulthood rather than early development. To establish a screening system to identify therapeutic drugs that are effective when delivered during the early postnatal period, it is important to examine the early developmental changes in their communicative behaviors. Here, we examined the ultrasonic vocalization (USV) of VPA‐exposed mice pups during their early postnatal developmental days. USV rates were comparable to those of the controls until the first week of their life but declined more on postnatal day 11. We checked the expression of oxytocin system in the hypothalamus and found the downregulation of oxytocin and CD38, and upregulation of oxytocin receptor in the VPA pups. Acute administration of oxytocin on postnatal day 11 increased the call rate of VPA pups. Taken together, we demonstrated there was a deficiency in the oxytocinergic signaling in the VPA pups and showed the existence of time periods that are effective to screen the therapeutic drugs.
Territoriality is an adaptive behavioral trait that is important for animal's fitness and there still remains much to learn about the proximate mechanisms underlying the development of territoriality. We speculate that the formation of a conditioned place preference (CPP), an increased time allocation to the environment where a rewarding experience occurred, contributes to territoriality. Testosterone (T) plays an important role in modulating territorial behaviors and T pulses can induce a CPP. We confirmed previous findings in California mice (Peromyscus californicus) that T pulses can induce a CPP in singly-housed, but not group-housed males. Housing singly may be similar enough to dispersal in nature to initiate similar hormonal and neuroanatomical changes needed for the development of territoriality. We further revealed that T pulses interact with the single housing experience and appear to enhance the motivation to be aggressive towards a stimulus male. On a neural level, being singly housed upregulated levels of androgen receptors in the preoptic area, which positively correlated with the strength of the CPP. We speculate that this change in androgen sensitivity in the preoptic area is characteristic of males that have dispersed, making them more sensitive to T pulses. Also, single housing increased markers of synaptic plasticity in the nucleus accumbens, ventral and dorsal hippocampus, neural changes that may be associated with dispersal, reproduction and territory establishment. These behavioral and neural changes may reflect the life history transition from residing in the natal territory to dispersing and establishing a new territory.
Turn-taking in singing mice
The ability to take turns is a hallmark of social interaction among animals. It occurs in many different species, from dueting birds to frogs, and is a notable part of human speech. Such rapid response requires a complex cascade of sensory and motor actions that has been difficult to characterize. Okobi et al. examined turn-taking in tropical singing mice, in which males interrupt, and alter, each other's songs (see the Perspective by Hage). They describe an orofacial motor cortex that mediates rapid transition from the motor cortex to the vocal motor apparatus and facilitates rapid vocal interactions.
Science , this issue p. 983 see also p. 926
Fifty-kHz ultrasonic vocalizations (USVs) are emitted by adult rats during appetitive phases of behavior in response to stimuli thought to be associated with a positive affective state. In particular, 50-kHz USVs with rapid frequency oscillations, known as trills and flat-trills, in which these oscillations are flanked by a monotonic portion, are together positively correlated with appetitive behaviors such as rough and tumble play, drug and natural reward, and mating. Female rats produce 50-kHz USVs during a variety of sexual contexts, yet data are still vague as female sexual behavior is seldom studied on its own. Distributed clitoral stimulation (CLS) offers a unique approach to investigating female 50-kHz USVs as it mimics stimulation received during mating. Although CLS induces a sexual reward state, it is unknown whether CLS elicits trills and flat-trills. We addressed this question using eight ovariectomized rats, we investigated whether ovarian hormones augmented these call subtypes in response to CLS. The combined and separate effects of estradiol benzoate (EB) and progesterone (P), and oil vehicle were assessed through comparison of these call subtypes between CLS and inter-CLS interval. We found that CLS with EB + P significantly increased call duration and rate, lowered peak frequency, and widened the bandwidth of trills. Flat-trills showed a similar pattern except for call duration. Call distribution during the CLS and inter-CLS interval suggest that trill and flat-trills may be indicative of both anticipatory and sexual reward.
Rodents emit ultrasonic vocalizations (USVs) to communicate the presence of positive or negative emotional states and to coordinate social interactions. On this basis, USVs are increasingly being used as a behavioral readout in rodent studies of affect, motivation and social behavior. Notably, several investigations have demonstrated that rodents emit USVs when tested in experimental paradigms that are used in preclinical studies of psychiatric and neurological diseases. Moreover, it has been shown that calling behavior may be influenced by genetic and/or environmental factors (i.e., stress), early rearing conditions that have been implicated in brain disease, as well as psychoactive drugs. Hence, measuring USV emissions has emerged as a useful tool in studying the mechanisms that underlie the emotional disturbances featuring certain brain diseases, as well as in the development of suited pharmacological therapies. This review provides an overview of the behavioral significance of USV emissions and describes the contexts that promote calling behavior in rats and mice. Moreover, the review summarizes the current evidence concerning the use of USVs as a marker of affect in rat and mouse models of sociability, psychiatric diseases and neurological diseases, and discusses the strengths and current limitations of using USVs as a behavioral readout in rodent studies of emotional behavior.
Modulation of baseline testosterone (T) via long‐lasting T implants alters territorial, sexual, and social behavior of animals in the field. Transient T increases occur in numerous species after social interactions, but these transient increases in T have not been manipulated in the field. In the laboratory, these T increases can influence future behavior for days, causing changes in social behavior and inducing preferences for specific locations. We manipulated transient increases in T in the field at the nests of the monogamous and territorial California mouse (Peromyscus californicus) to examine long‐term (>24 hr) changes in ultrasonic vocalizations (USVs). Males of bonded male–female dyads (=pair) were administered a T injection (vs. saline) three times over seven days and USVs of the male–female dyad were measured for three days after the last injection. At T nests, the male–female dyad produced significantly more 1SV (one call SV: an SV is a sustained vocalization that is long in duration and low in modulation) and 4SV (four call SV) type USVs than controls, but no significant changes in aggressive barks. Overall, male–female dyad mice at T nests produced a greater diversity in call types such that 1SV, 4SV, 5SV, and a complex sweep were produced at T nests but not control nests. There were significantly more USVs produced at T nests on night 2 after the final injection. There were no differences in spectral characteristics of SV calls or aggressive barks between T and control nests. The function of the changes that occurred is unknown, but is consistent with increased long‐term changes in behavioral interactions with nest mates and may reflect T‐induced conditioned place preferences to the nest site. Significantly, transient increases in T influence future acoustic communication under field conditions with competing biotic and abiotic stimuli.
Exposures to endocrine-disrupting chemicals (EDCs) affect the development of hormone-sensitive neural circuits, the proper organization of which are necessary for the manifestation of appropriate adult social and sexual behaviors. We examined whether prenatal exposure to polychlorinated biphenyls (PCBs), a family of ubiquitous industrial contaminants detectable in virtually all humans and wildlife, caused changes in sexually-dimorphic social interactions and communications, and profiled the underlying neuromolecular phenotype. Rats were treated with a PCB commercial mixture, Aroclor 1221 (A1221), estradiol benzoate (EB) as a positive control for estrogenic effects of A1221, or the vehicle (4% DMSO), on embryonic day (E) 16 and 18. In adult F1 offspring, we first conducted tests of ultrasonic vocalization (USV) calls in a sociosexual context as a measure of motivated communications. Numbers of certain USV call types were significantly increased by prenatal treatment with A1221 in males, and decreased by EB in females. In a test of sociosexual preference for a hormone-vs. a non-hormone-primed opposite sex conspecific, male (but not female) nose-touching with opposite-sex rats was significantly diminished by EDCs. Gene expression profiling was conducted in two brain regions that are part of the social decision-making network in the brain: the medial preoptic nucleus (MPN) and the ventromedial nucleus (VMN). In both regions, many more genes were affected by A1221 or EB in females than males. In female MPN, A1221 changed expression of steroid hormone receptor and neuropeptides (e.g., Ar, Esr1, Esr2,andKiss1). In male MPN, only Per2 was affected by A1221. The VMN had a number of genes affected by EB (females: Kiss1, Kiss1r, Pgr; males: Crh) but not A1221. These differences between EB and A1221 indicate that the mechanism of action of A1221 goes beyond estrogenic pathways. These data show sex-specific effects of prenatal PCBs on adult behaviors and the neuromolecular phenotype.
Context adds meaning to vocal communication. For an individual that is encountering conspecifics, sensitivity to factors such as the identity of a social partner and presence of eavesdroppers (the external scene) or reproductive state and experience (the internal scene) may be essential for effective communication. Although the external and internal scenes are often categorized as separate, they are functionally entangled because they often interact to influence communication and they converge at the physiological level. The external and internal scenes have well-documented effects on both vocal production by signalers and the responses to vocal signals by receivers. This commonality supports a view of context as an emergent phenomenon with individuals acting as both senders and receivers during a communication event and contributing to the tone of the interaction via feedback to social partners. Amid this complexity, an operational view defines context as the set of factors that influences communication within a given interaction. This definition can be used as a simplifying tool for exploring both the functions and mechanisms of context sensitivity. Since both the external and internal scenes affect physiological systems involved in the internal representations of qualities such as stress, reward, and positive or negative valence, an integrated concept of context also unites ecological and biomedical perspectives.
Background:
Adolescent and adult rats emit 50-kHz ultrasonic vocalizations (USVs) to communicate the appetitive arousal and the presence of positive emotional states to conspecifics.
New method:
Based on its communicative function, emission of 50-kHz USVs is increasingly being evaluated in preclinical studies of affective behavior, motivation and social behavior.
Results:
Emission of 50-kHz USVs is initiated by the activation of dopamine receptors in the shell subregion of the nucleus accumbens. However, several lines of evidence show that non-dopaminergic receptors may influence the numbers of 50-kHz USVs that are emitted, as well as the acoustic parameters of calls.
Comparison with existing methods:
Emission of 50-kHz USVs is a non-invasive method that may be used to study reward and motivation without the need for extensive training and complex animal manipulations. Moreover, emission of 50-kHz USVs can be used alone or combined with other well-standardized behavioral paradigms (e.g., conditioned place preference, self-administration).
Conclusions:
This review summarizes the current evidence concerning molecular mechanisms that regulate the emission of 50-kHz USVs. Moreover, the review discusses the usefulness of 50-kHz USVs as an experimental tool to investigate how different neurotransmitter systems regulate the manifestations of positive emotional states, and also use of this tool in preclinical modeling of psychiatric diseases.
Rat pup ultrasonic vocalizations (USV) are usually studied in outbred rats belonging to either Long‐Evans, Sprague–Dawley, or Wistar stocks, but these were not compared so far. We therefore performed a stock comparison and analyzed USV of male pups (postnatal day 11) belonging to these three stocks. Pups of all three stocks showed substantial isolation‐induced USV, but differed in various call features, like call numbers, peak frequency, and frequency modulation. Also, three different call types were identified by means of a quantitative approach based on peak frequency and frequency modulation, and it was found that their proportions differed between stocks. These results are discussed with respect to functional aspects of pup USV.
The effects of exogenous opioids on 50-kHz ultrasonic vocalizations (USVs) depend on their affinity to specific opioid receptors and a schedule of administration. Acute administration of morphine inhibits the emission of 50-kHz USVs, but repeated morphine administration reduces this suppressive effect and might even increase the occurrence of this type of calls. During the withdrawal period after chronic administration of morphine, animals produce context-induced conditioned 50-kHz USVs associated with the rewarding effects of morphine. Administration of the κ-opioid receptor antagonist increases and the agonist inhibits the number of 50-kHz USV episodes. This effect might be associated with the negative feedback mechanism involving the endogenic dynorphin system. The effects of acute stimulation of the opioid system result in the suppression of 22-kHz calls. This phenomenon could be attributed mainly to the anxiolytic and analgesic properties of those agents. Withdrawal from prolonged opioid exposure causes an increase in 22-kHz USV production, probably by induction of anhedonia.
Postnatal development includes dramatic changes in gonadal hormones and the many social behaviors they help regulate, both in rodents and humans. Parental care-seeking is the most salient social interaction in neonates and infants, play and pro-social behaviors are commonly studied in juveniles, and the development of aggression and sexual behavior begins in peripubertal stages but continues through late adolescence into adulthood. While parental behaviors are shown after reproductive success in adulthood, alloparenting behaviors are actually high in juveniles as well. These behaviors are sensitive to both early life organizational effects of gonadal hormones and later life activational regulation. However, changes in circulating gonadal hormones and the display of the above behaviors over development differs between rats, mice and humans. These endpoints are of interest to endocrinologist, toxicologists, neuroscientists because of their relevance to mental health disorders and their vulnerability to effects of endocrine disrupting chemical exposure. As such, the goal of this minireview is to succinctly describe and relate the postnatal development of gonadal hormones and social behaviors to each other, over time and across animal models. Ideally, this will help identify appropriate animal models and age ranges for continued study of both normative development and in contexts of environmental disruption.
Adolescent and adult rats emit ultrasonic vocalizations (USVs) for communication with conspecifics. These USVs can be broadly divided into two subgroups that possess distinct acoustic features and have different behavioral significance: the 22-kHz USVs, emitted in aversive situations, and the 50-kHz USVs, emitted in appetitive situations. These USVs communicate the aversive or appetitive arousal to the conspecifics. USVs in either of the subgroups can influence the emotional state of the recipient rats and guide their behavior accordingly. Therefore, USVs are instrumental in maintaining the social structure and particularly the affiliative and collaborative forms of behavior that are characteristic of the rat species. This chapter provides an overview of the qualitative and quantitative features of the USVs emitted by adolescent and adult rats and of the situations that are associated with the emission of these vocalizations.
Ultrasonic vocalizations (USV) are widely studied in mice and rats, and in case of rats, the bulk of empirical evidence is based on outbred rats, which in most studies belong to either Long Evans, Sprague-Dawley or Wistar stocks. It is known that these stocks can differ in terms of specific brain variables and also behaviorally, but there is only few evidence so far showing whether these stocks behave in similar or substantially different ways in paradigms which are often used to study USV. Therefore, we have started a larger series of comparative studies, where we analyzed different classes of USV in rats from these three stocks spanning from pups to adults. Here, we report our findings in juvenile and adult male Long Evans, Sprague-Dawley and Wistar rats, which we tested as juveniles for appetitive 50-kHz calls during a so-called cage test or when being tickled by an experimenter, and later as adults for 22-kHz calls in a fear conditioning paradigm. In general, all three stocks showed the expected USV responses, indicating that they are all feasible for this kind of research. In detail, however, there were various quantitative differences between stocks both, in terms of specific USV features (like call rates, call durations etc.) as well as visible behavior, like spontaneous locomotor activity and shock-induced immobility. These findings are discussed in the context of the relevant, but somewhat equivocal literature on these stocks, including factors which might contribute to such variability, like breeding, housing, or details of the given test.
Steroid hormones, such as estrogens, were once thought to be exclusively synthesized in the ovaries and enact transcriptional changes over the course of hours to days. However, estrogens are also locally synthesized within neural circuits, wherein they rapidly (within minutes) modulate a range of behaviors, including spatial cognition and communication. Here, we review the role of brain-derived estrogens (neuroestrogens) as modulators within sensory circuits in songbirds. We first present songbirds as an attractive model to explore how neuroestrogens in auditory cortex modulate vocal communication processing and learning. Further, we examine how estrogens may enhance vocal learning and auditory memory consolidation in sensory cortex via mechanisms similar to those found in the hippocampus of rodents and birds. Finally, we propose future directions for investigation, including: 1) the extent of developmental and hemispheric shifts in aromatase and membrane estrogen receptor expression in auditory circuits; 2) how neuroestrogens may impact inhibitory interneurons to regulate audition and critical period plasticity; and, 3) dendritic spine plasticity as a candidate mechanism mediating estrogen-dependent effects on vocal learning. Together, this perspective of estrogens as neuromodulators in the vertebrate brain has opened new avenues in understanding sensory plasticity, including how hormones can act on communication circuits to influence behaviors in other vocal learning species, such as in language acquisition and speech processing in humans.
This chapter discusses anatomical, physiological, and functional aspects of circuits associated with four major neuromodulators: acetylcholine, serotonin, noradrenaline, and dopamine. These neuromodulators occur in nearly all auditory structures from the cochlea of the inner ear to the cortex of the brain. A review of the anatomy is focused on the origins of modulatory inputs to auditory structures and the patterns of termination in those areas. Sources of the modulatory inputs include widely recognized cell groups in the basal forebrain and pontomesencephalic tegmentum (for acetylcholine), raphe nuclei (for serotonin), locus coeruleus (for noradrenaline), and ventral tegmental area (for dopamine), as well as smaller cell groups in the brainstem. In addition, there are numerous examples of cells within the auditory system that release one or more of these neuromodulators. Physiology and function are discussed from several perspectives, starting with a brief overview of methods used for assessing modulatory function. Neuromodulators are directly involved in regulating auditory processing according to both internal state and stimulus salience. Many mechanisms are likely involved. Neuromodulators can reconfigure auditory circuitry through multiple receptor types and in multiple auditory regions. Furthermore, multiple neuromodulators may converge at the level of single neuron types. This makes the effects of neuromodulators complex but confers the ability to produce a range of behaviorally appropriate outputs from auditory circuitry. In addition, neuromodulators facilitate long-term plasticity. Such plasticity plays a role in many adaptive responses, including numerous changes that may play a role in the auditory dysfunction that follows hearing loss.
Significance
When compared with humans, nonhuman primates have small vocal repertoires that show little acoustic modification during development. These limitations pose a dilemma for those interested in the evolution of language. Recent research, however, suggests that monkeys and apes show an extensive ability to modify their use of calls in different social contexts. Many vocalizations function to facilitate social interaction by reducing the uncertainty about the signaler’s intentions and likely behavior. Such interactions help to establish and maintain the social bonds that increase reproductive success. For scientists interested in the evolutionary transition from nonlinguistic communication to language, a logical starting point should be social interactions between long-lived individuals who interact repeatedly and for whom long-term social bonds are of paramount importance.
Sexual attraction has two components: Emission of sexually attractive stimuli and responsiveness to these stimuli. In rodents, olfactory stimuli are necessary but not sufficient for attraction. We argue that body odors are far superior to odors from excreta (urine, feces) as sexual attractants. Body odors are produced by sebaceous glands all over the body surface and in specialized glands. In primates, visual stimuli, for example the sexual skin, are more important than olfactory. The role of gonadal hormones for the production of and responsiveness to odorants is well established. Both the androgen and the estrogen receptor α are important in male as well as in female rodents. Also in primates, gonadal hormones are necessary for the responsiveness to sexual attractants. In males, the androgen receptor is sufficient for sustaining responsiveness. In female non-human primates, estrogens are needed, whereas androgens seem to contribute to responsiveness in women.
This study tested the effects of timing and duration of estradiol (E2) treatment, factors that are clinically relevant to hormone replacement in perimenopausal women, on social behavior and expression of genes in brain regions that regulate these behaviors. Female rats were ovariectomized (OVX) at 1year of age, roughly equivalent to middle-age in women, and given E2 or vehicle for different durations (3 or 6months) and timing (immediately or after a 3-month delay) relative to OVX. Social and ultrasonic vocalization (USV) behaviors were assessed at the 3 and 6month timepoints, and the rats' brains were then used for gene expression profiling in hypothalamus (supraoptic nucleus, paraventricular nucleus), bed nucleus of the stria terminalis, medial amygdala, and prefrontal cortex using a 48-gene qPCR platform. At the 3-month post-OVX testing period, E2 treatment significantly decreased the number of frequency-modulated USVs emitted. No effects of hormone were found at the 6-month testing period. There were few effects of timing and duration of E2 in a test of social preference of a rat given a choice between her same-sex cagemate and a novel conspecific. For gene expression, effects of timing and duration of E2 were region-specific, with the majority of changes found for genes involved in regulating social behavior such as neuropeptides (Oxt, Oxtr &Avp), neurotransmitters (Drd1, Drd2, Htr2a, Grin2d &Gabbr1), and steroid hormone receptors (Esr2, Ar, Pgr). These data suggest that the mode of E2 treatment has specific effects on social behavior and expression of target genes involved in the regulation of these behaviors.
Context is critical to the adaptive value of communication. Sensory systems such as the auditory system represent an important juncture at which information on physiological state or social valence can be added to communicative information. However, the neural pathways that convey context to the auditory system are not well understood. The serotonergic system offers an excellent model to address these types of questions. Serotonin fluctuates in the mouse inferior colliculus (IC), an auditory midbrain region important for species-specific vocalizations, during specific social and non-social contexts. Furthermore, serotonin is an indicator of the valence of event-based changes within individual social interactions. We propose a model in which the brain's social behavior network serves as an afferent effector of the serotonergic dorsal raphe nucleus in order to gate contextual release of serotonin in the IC. Specifically, discrete vasopressinergic nuclei within the hypothalamus and extended amygdala that project to the dorsal raphe are functionally engaged during contexts in which serotonin fluctuates in the IC. Since serotonin strongly influences the responses of IC neurons to social vocalizations, this pathway could serve as a feedback loop whereby integrative social centers modulate their own sources of input. The end result of this feedback would be to produce a process that is geared, from sensory input to motor output, toward responding appropriately to a dynamic external world.
To reduce errors in species recognition and the probability of interbreeding that lowers fitness, individuals within sympatric zones shift the signals to differentiate from those of other species. In the present study, the differences of the acoustic features of ultrasounds (courtship calls during hetero-sexual encounters) and audible calls (distress calls during tail-clamp stress) are compared among three sympatric Rattus species (Rattus andamanensis, R. norvegicus, and R. losea). Results showed that the three species have significantly different call parameters, including call duration, peak frequency, bandwidth, pitch, goodness of pitch, frequency modulation, and Wiener entropy. This study provides quantitative evidence for character displacement in the acoustic signals of closely related sympatric Rattus species. Results indicate that the divergence of acoustic signal have arrived at the quite meticulous degree of evolution. Therefore, the acoustic signal trait is likely involved in the evolution of species diversity in rodents.
Most studies examining rodent ultrasonic vocalizations (USVs) have investigated pericopulatory vocal behaviour in polygynous rodents, while vocalizations related to pair bond maintenance in monogamous rodents remain unexplored. In the monogamous California mouse, Peromyscus californicus, we used ultrasonic playbacks and post-playback social interactions to assess possible functions of USVs. We found that females responded with approach towards USVs of an unfamiliar male (bonded male from another pair) compared to a noise control, but displayed no difference in response to calls of their partner versus noise. Responsiveness to unfamiliar males does not appear to reflect an interest in extrapair copulations because during post-playback social interactions, females displayed more agonistic behaviours and fewer affiliative behaviours towards unfamiliar, sexually naïve ‘stranger’ males than towards their partners. We speculate that approach to unfamiliar male USVs instead may be related to territorial defence. We further explored associations within the data set. Interestingly, female affiliation with her partner was predicted by USV output, particularly a higher number and proportion of complex call types, produced during the male partner USV elicitation phase. Female approach towards USVs was related to syllable duration of one call type in partner USVs (not in unfamiliar USVs) but no other features, and sufficient variation exists in syllable duration to allow females to theoretically distinguish between individuals based on this measure. Similarly, while pregnancy state did not influence female social behaviour, it decreased approach to playback of partner USVs but not to that of unfamiliar USVs. Overall, our results illuminate concepts about vocal communication in monogamous rodent species with strong pair bonds and suggest that functions of USVs in rodents can extend beyond mate choice.
Despite extensive research revealing the occurrence of testosterone (T) pulses following social encounters, it is unclear how they lead to varied behavioral responses. We investigated the influence of residency (home versus unfamiliar environment) and social/sexual experience (pair-bonded, isolated or housed with siblings) on the plasticity of T's rewarding effects by measuring the development of conditioned place preferences (CPPs), a classical paradigm used to measure the rewarding properties of drugs. For pair-bonded males, T-induced CPPs were only produced in the environment wherein the social/sexual experience was accrued and residency status had been achieved. For isolated males, the T-induced CPPs only occurred when the environment was unfamiliar. For males housed with a male sibling, the T-induced CPPs were prevented in both the home and unfamiliar chambers. Our results reveal the plasticity of T's rewarding effects, and suggest that the behavioral functions of T-pulses can vary based on social/sexual experience and the environment in which residency was established. The formation of CPPs or reward-like properties of drugs and natural compounds can therefore exhibit malleability based on past experience and the current environment.