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1. Postweaning Isolation Alters the Responses of Auditory Neurons to Serotonergic Modulation

   https://doi.org/10.1093/icb/icab051  

   Davis, Sarah E; Sansone, Jack M; Hurley, Laura M (May 2021, Integrative and Comparative Biology)

   null (Ed.)

   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. 

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2. Listening to your partner: serotonin increases male responsiveness to female vocal signals in mice

   https://doi.org/10.3389/fnhum.2023.1304653  

   Hood, Kayleigh E; Hurley, Laura M (January 2024, Frontiers in Human Neuroscience)

   Nagarajan, SS; Turner, JA (Ed.)

   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. 

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3. Solitude and serotonin: juvenile isolation alters the covariation between social behavior and cFos expression by serotonergic neurons

   https://doi.org/10.3389/fnins.2024.1446866  

   Hutchens, Sarah_E D; Khurram, Izza; Hurley, Laura M (October 2024, Frontiers in Neuroscience)

   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. 

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4. Silence, Solitude, and Serotonin: Neural Mechanisms Linking Hearing Loss and Social Isolation

   https://doi.org/10.3390/brainsci10060367  

   Keesom, Sarah M.; Hurley, Laura M. (June 2020, Brain Sciences)

   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. 

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5. Social experience and pheromone receptor activity reprogram gene expression in sensory neurons

   https://doi.org/10.1093/g3journal/jkad072  

   Deanhardt, Bryson; Duan, Qichen; Du, Chengcheng; Soeder, Charles; Morlote, Alec; Garg, Deeya; Saha, Aishani; Jones, Corbin D; Volkan, Pelin Cayirlioglu (March 2023, G3 Genes|Genomes|Genetics)

   Ramaswami, Mani (Ed.)

   Abstract Social experience and pheromone signaling in olfactory neurons affect neuronal responses and male courtship behaviors in Drosophila. We previously showed that social experience and pheromone signaling modulate chromatin around behavioral switch gene fruitless, which encodes a transcription factor necessary and sufficient for male sexual behaviors. Fruitless drives social experience-dependent modulation of courtship behaviors and physiological sensory neuron responses to pheromone; however, the molecular mechanisms underlying this modulation of neural responses remain less clear. To identify the molecular mechanisms driving social experience-dependent changes in neuronal responses, we performed RNA-seq from antennal samples of mutants in pheromone receptors and fruitless, as well as grouped or isolated wild-type males. Genes affecting neuronal physiology and function, such as neurotransmitter receptors, ion channels, ion and membrane transporters, and odorant binding proteins are differentially regulated by social context and pheromone signaling. While we found that loss of pheromone detection only has small effects on differential promoter and exon usage within fruitless gene, many of the differentially regulated genes have Fruitless binding sites or are bound by Fruitless in the nervous system. Recent studies showed that social experience and juvenile hormone signaling co-regulate fruitless chromatin to modify pheromone responses in olfactory neurons. Interestingly, genes involved in juvenile hormone metabolism are also misregulated in different social contexts and mutant backgrounds. Our results suggest that modulation of neuronal activity and behaviors in response to social experience and pheromone signaling likely arise due to large-scale changes in transcriptional programs for neuronal function downstream of behavioral switch gene function. 

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