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Variation in the mutual responsiveness of social partners to each other can be reflected in behavioral suites that covary with neural activity in ways that track the salience or valence of interactions. Juvenile social isolation alters social behavior and neural activity during social interaction, but whether and how it alters the covariation between behavior and neural activity has not been as well explored. To address this issue, four classes of experimental subjects: isolated males, socially housed males, isolated females, and socially housed females, were paired with an opposite-sex social partner that had been socially housed. Social behaviors and c-Fos expression in the serotonergic dorsal raphe nucleus (DRN) were then measured in subjects following the social interactions. Relative to social housing, postweaning isolation led to a decrease in the density of neurons double-labeled for tryptophan hydroxylase and c-Fos in the dorsomedial subdivision of the DRN, regardless of sex. Vocal and non-vocal behaviors were also affected by isolation. In interactions with isolated males, both ultrasonic vocalization (USVs) and broadband vocalizations (squeaks) increased in conjunction with greater male investigation of females. Neural and behavioral measures also correlated with each other. In the isolated male group, the density of double-labeled neurons in the dorsomedial DRN was negatively correlated with USV production and positively correlated with a principal component of non-vocal behavior corresponding to greater defensive kicking by females and less investigation and mounting behavior. This correlation was reversed in direction for socially housed males, and for isolated males versus isolated females. These findings confirm that the dynamics of social interactions are reflected in c-Fos activation in the dorsomedial DRN, and suggest an altered responsiveness of serotonergic neurons to social interaction following social isolation in males, in parallel with an altered male response to female cues. 

The context surrounding vocal communication can have a strong influence on how vocal signals are perceived. The serotonergic system is well-positioned for modulating the perception of communication signals according to context, because serotonergic neurons are responsive to social context, influence social behavior, and innervate auditory regions. Animals like lab mice can be excellent models for exploring how serotonin affects the primary neural systems involved in vocal perception, including within central auditory regions like the inferior colliculus (IC). Within the IC, serotonergic activity reflects not only the presence of a conspecific, but also the valence of a given social interaction. To assess whether serotonin can influence the perception of vocal signals in male mice, we manipulated serotonin systemically with an injection of its precursor 5-HTP, and locally in the IC with an infusion of fenfluramine, a serotonin reuptake blocker. Mice then participated in a behavioral assay in which males suppress their ultrasonic vocalizations (USVs) in response to the playback of female broadband vocalizations (BBVs), used in defensive aggression by females when interacting with males. Both 5-HTP and fenfluramine increased the suppression of USVs during BBV playback relative to controls. 5-HTP additionally decreased the baseline production of a specific type of USV and male investigation, but neither drug treatment strongly affected male digging or grooming. These findings show that serotonin modifies behavioral responses to vocal signals in mice, in part by acting in auditory brain regions, and suggest that mouse vocal behavior can serve as a useful model for exploring the mechanisms of context in human communication. 

Although male vocalizations during opposite- sex interaction have been heavily studied as sexually selected signals, the understanding of the roles of female vocal signals produced in this context is more limited. During intersexual interactions between mice, males produce a majority of ultrasonic vocalizations (USVs), while females produce a majority of human-audible squeaks, also called broadband vocalizations (BBVs). BBVs may be produced in conjunction with defensive aggression, making it difficult to assess whether males respond to BBVs themselves. To assess the direct effect of BBVs on male behavior, we used a split-cage paradigm in which high rates of male USVs were elicited by female presence on the other side of a barrier, but which precluded extensive male-female contact and the spontaneous production of BBVs. In this paradigm, playback of female BBVs decreased USV production, which recovered after the playback period. Trials in which female vocalizations were prevented by the use of female bedding alone or of anesthetized females as stimuli also showed a decrease in response to BBV playback. No non-vocal behaviors declined during playback, although digging behavior increased. Similar to BBVs, WNs also robustly suppressed USV production, albeit to a significantly larger extent. USVs suppression had two distinct temporal components. When grouped in 5-second bins, USVs interleaved with bursts of stimulus BBVs. USV suppression also adapted to BBV playback on the order of minutes. Adaptation occurred more rapidly in males that were housed individually as opposed to socially for a week prior to testing, suggesting that the adaptation trajectory is sensitive to social experience. These findings suggest the possibility that vocal interaction between male and female mice, with males suppressing USVs in response to BBVs, may influence the dynamics of communicative behavior. 

Abstract Juvenile social experience, such as social isolation, has profound effects on communicative behavior, including signal production and reception. In the current study, we explored responsiveness to the neuromodulator serotonin as a potential mechanistic link between early life social isolation and auditory processing. The serotonergic system is sensitive to social isolation in many brain regions including the inferior colliculus (IC), an auditory midbrain nucleus. We investigated the effects of social experience on serotonergic responsiveness by measuring cFos, an immediate early gene product, in the IC of female mice. Serotonin was manipulated pharmacologically by administering fenfluramine, pCPA, or saline to mice that had undergone an extreme dichotomy in social experience after weaning: being housed in social groups versus individually. These mice were exposed to a 60-min recording of vocalizations from an opposite-sex interaction and perfused. Using immunohistochemistry, we measured the density of cFos-positive (cFos+) nuclei in the major subdivisions of the IC. Housing condition, drug treatment, and IC subregion all had a significant effect on cFos+ density. The central IC showed the highest density of cFos+ cells and also the most pronounced effects of housing condition and drug treatment. In the central IC, cFos+ density was higher following fenfluramine treatment than saline, and lower following pCPA treatment than fenfluramine. Individually housed mice showed a higher cFos+ density than socially housed mice in both of the pharmacological treatment groups, but not in the saline group. Drug treatment but not housing condition had strong effects on the behaviors of grooming, digging, rearing, and movement. Once the effects of drug condition were controlled, there were no across-individual correlations between cFos+ densities and behaviors. These findings suggest that the responses of auditory neurons to neuromodulation by serotonin are influenced by early life experience. 

For social animals that communicate acoustically, hearing loss and social isolation are factors that independently influence social behavior. In human subjects, hearing loss may also contribute to objective and subjective measures of social isolation. Although the behavioral relationship between hearing loss and social isolation is evident, there is little understanding of their interdependence at the level of neural systems. Separate lines of research have shown that social isolation and hearing loss independently target the serotonergic system in the rodent brain. These two factors affect both presynaptic and postsynaptic measures of serotonergic anatomy and function, highlighting the sensitivity of serotonergic pathways to both types of insult. The effects of deficits in both acoustic and social inputs are seen not only within the auditory system, but also in other brain regions, suggesting relatively extensive effects of these deficits on serotonergic regulatory systems. Serotonin plays a much-studied role in depression and anxiety, and may also influence several aspects of auditory cognition, including auditory attention and understanding speech in challenging listening conditions. These commonalities suggest that serotonergic pathways are worthy of further exploration as potential intervening mechanisms between the related conditions of hearing loss and social isolation, and the affective and cognitive dysfunctions that follow. 

The serotonergic system has been widely studied across animal taxa and different functional networks. This modulatory system is therefore well positioned to compare the consequences of neuromodulation for sensory processing across species and modalities at multiple levels of sensory organization. Serotonergic neurons that innervate sensory networks often bidirectionally exchange information with these networks but also receive input representative of motor events or motivational state. This convergence of information supports serotonin’s capacity for contextualizing sensory information according to the animal’s physiological state and external events. At the level of sensory circuitry, serotonin can have variable effects due to differential projections across specific sensory subregions, as well as differential serotonin receptor type expression within those subregions. Functionally, this infrastructure may gate or filter sensory inputs to emphasize specific stimulus features or select among different streams of information. The near-ubiquitous presence of serotonin and other neuromodulators within sensory regions, coupled with their strong effects on stimulus representation, suggests that these signaling pathways should be considered integral components of sensory systems. 

Past social experience and current social context shape the responses of animals to social signals. The serotonergic system is one potential mechanism by which both experiential and contextual factors could be conveyed to sensory systems, such as the auditory system, for multiple reasons. 1) Many features of the serotonergic system are sensitive to social experience. 2) Elevations in serotonergic activity are triggered by social partners, and variations in socially triggered serotonergic responses reflect behavioral differences among social encounters. 3) Serotonin is an auditory neuromodulator, altering how auditory neurons respond to sounds including conspecific vocalizations. In this study, we tested how social experience influences the socially triggered serotonergic response in the inferior colliculus, an auditory midbrain region with an important role in vocalization processing. We used carbon fiber voltammetry to measure serotonin during social interactions of male mice ( Mus musculus) from different social backgrounds: 4 weeks of grouped or individual housing. When paired with an unfamiliar male, both group-housed and individually housed males demonstrated elevations in serotonin; however, individually housed males exhibited socially triggered serotonergic responses with delayed time courses compared with the group-housed males. Furthermore, group-housed males displayed previously described correlations between the socially triggered serotonergic response and behaviors such as social investigation. In contrast, individually housed males did not show these serotonin-behavior relationships. These results suggest that social experience gained via social housing may shape the ability of the central serotonergic system to encode social context in sensory regions. NEW & NOTEWORTHY We demonstrate that past social experience influences the fidelity with which the serotonergic system represents social context in an auditory region. Social experience altered the time course of socially triggered serotonergic responses and changed how the serotonergic system reflects behavioral variations among social encounters of the same context. These findings are significant to the study of communication, suggesting that centralized neuromodulatory systems potentially convey integrated information regarding past experience and current context to primary sensory regions.