Predictive Mouse Ultrasonic Vocalization Sequences: Uncovering Behavioral Significance, Auditory Cortex Neuronal Preferences, and Social-Experience-Driven Plasticity.

Mouse ultrasonic vocalizations (USVs) contain predictable sequential structures like bird songs and speech. Neural representation of USVs in the mouse primary auditory cortex (Au1) and its plasticity with experience has been largely studied with single-syllables or dyads, without using the predictability in USV sequences. Studies using playback of USV sequences have used randomly selected sequences from numerous possibilities. The current study uses mutual information to obtain context-specific natural sequences (NSeqs) of USV syllables capturing the observed predictability in male USVs in different contexts of social interaction with females. Behavioral and physiological significance of NSeqs over random sequences (RSeqs) lacking predictability were examined. Female mice, never having the social experience of being exposed to males, showed higher selectivity for NSeqs behaviorally and at cellular levels probed by expression of immediate early gene c-fos in Au1. The Au1 supragranular single units also showed higher selectivity to NSeqs over RSeqs. Social-experience-driven plasticity in encoding NSeqs and RSeqs in adult females was probed by examining neural selectivities to the same sequences before and after the above social experience. Single units showed enhanced selectivity for NSeqs over RSeqs after the social experience. Further, using two-photon Ca2+ imaging, we observed social experience-dependent changes in the selectivity of sequences of excitatory and somatostatin-positive inhibitory neurons but not parvalbumin-positive inhibitory neurons of Au1. Using optogenetics, somatostatin-positive neurons were identified as a possible mediator of the observed social-experience-driven plasticity. Our study uncovers the importance of predictive sequences and introduces mouse USVs as a promising model to study context-dependent speech like communications.SIGNIFICANCE STATEMENT Humans need to detect patterns in the sensory world. For instance, speech is meaningful sequences of acoustic tokens easily differentiated from random ordered tokens. The structure derives from the predictability of the tokens. Similarly, mouse vocalization sequences have predictability and undergo context-dependent modulation. Our work investigated whether mice differentiate such informative predictable sequences (NSeqs) of communicative significance from RSeqs at the behavioral, molecular, and neuronal levels. Following a social experience in which NSeqs occur as a crucial component, mouse auditory cortical neurons become more sensitive to differences between NSeqs and RSeqs, although preference for individual tokens is unchanged. Thus, speech-like communication and its dysfunction may be studied in circuit, cellular, and molecular levels in mice.