Of Mice, Birds, and Men: The Mouse Ultrasonic Song System and Vocal Behavior

Abstract

<p>Mice produce many ultrasonic vocalizations (USVs) in the 30 - 100 kHz range including pup isolation calls and adult male songs. These USVs are often used as behavioral readouts of internal states, to measure effects of social and pharmacological manipulations, and for behavioral phenotyping of mouse models for neuropsychiatric and neurodegenerative disorders; however, little is known about the biophysical and neurophysiological mechanisms of USV production in rodents. This lack of knowledge restricts the interpretation of data from vocalization-related experiments on mouse models of communication disorders and vocal medical conditions. Meanwhile, there has been increased interest in the social communication aspect of neural disorders such as autism, in addition to the common disorders involving motor control of the larynx: stroke, Parkinson's disease, laryngeal tremor, and spasmodic dysphonia. Therefore, it is timely and critical to begin assessing the neural substrate of vocal production in order to better understand the neuro-laryngeal deficits underlying communication problems.</p><p>Additionally, mouse models may generate new insight into the molecular basis of vocal learning. Traditionally, songbirds have been used as a model for speech learning in humans; however, the model is strongly limited by a lack of techniques for manipulating avian genetics. Accordingly, there has long been strong interest in finding a mammalian model for vocal learning studies. The characteristic features of accepted vocal learning species include programming of phonation by forebrain motor areas, a direct cortical projection to brainstem vocal motoneurons, and dependence on auditory feedback to develop and maintain vocalizations. Unfortunately, these features have not been observed in non-human primates or in birds that do not learn songs. Thus, in addition to elucidating vocal brain pathways it is also critical to determine the extent of any vocal learning capabilities present in the mouse USV system.</p><p>It is generally assumed that mice lack a forebrain system for vocal modification and that their USVs are innate; however, these basic assumptions have not been experimentally tested. I investigated the mouse song system to determine if male mouse song behavior and the supporting brain circuits resemble those of known vocal learning species. By visualizing activity-dependent immediate early gene expression as a marker of global activity patterns, I discovered that the song system includes motor cortex and striatal regions active during singing. Retrograde and anterograde tracing with pseudorabies virus and biodextran amines, respectively, revealed that the motor cortical region projects directly to the brainstem phonatory motor nucleus ambiguus. Chemical lesions in this region showed that it is not critical for producing innate templates of song syllables, but is required for producing more stereotyped acoustic features of syllables. To test for the basic components of adaptive learning I recorded the songs of mechanically and genetically deaf mice and found that male mice depend on auditory feedback to develop and maintain normal ultrasonic songs. Moreover, male mice that display natural strain specific song features may use auditory experience to copy the pitch of another strain when housed together and stimulated to compete sexually. I conclude that male mice have neuroanatomical and behavioral features thought to be unique to humans and song learning birds, suggesting that mice are capable of adaptive modification of the spectral features of their songs.</p>