Ultrasonic vocalizations in mouse models for speech and socio-cognitive disorders: insights into the evolution of vocal communication

Abstract

Comparative analyses used to reconstruct the evolution of traits associated with the human language faculty, including its socio-cognitive underpinnings, highlight the importance of evolutionary constraints limiting vocal learning in non-human primates. After a brief overview of this field of research and the neural basis of primate vocalizations, we review studies that have addressed the genetic basis of usage and structure of ultrasonic communication in mice, with a focus on the gene FOXP2 involved in specific language impairments and neuroligin genes (NL-3 and NL-4) involved in autism spectrum disorders. Knockout of FoxP2 leads to reduced vocal behavior and eventually premature death. Introducing the human variant of FoxP2 protein into mice, in contrast, results in shifts in frequency and modulation of pup ultrasonic vocalizations. Knockout of NL-3 and NL-4 in mice diminishes social behavior and vocalizations. Although such studies may provide insights into the molecular and neural basis of social and communicative behavior, the structure of mouse vocalizations is largely innate, limiting the suitability of the mouse model to study human speech, a learned mode of production. Although knockout or replacement of single genes has perceptible effects on behavior, these genes are part of larger networks whose functions remain poorly understood. In humans, for instance, deficiencies in NL-4 can lead to a broad spectrum of disorders, suggesting that further factors (experiential and/or genetic) contribute to the variation in clinical symptoms. The precise nature as well as the interaction of these factors is yet to be determined.

Figure 1. Playback experiments with mice

(a) Sketch of place preference design. LS = loudspeaker. In the two trials, females were presented with songs from different males, all of which were unfamiliar. (b) Spectrograms of playback sounds. (c) Percentage of time the females spent in the chamber with the playback sound (mean ± SEM). Line indicates chance level. Filled squares = first presentation, open squares = second presentation (N = 32) (figure adapted from Hammerschmidt et al. 2009).

Figure 2. Characterization of pup isolation calls

(a) Spectrograms of the three major call types. (b) Scattergram derived from a discriminant function analysis that depicts the categorization of call types. Discriminant function 1 (DF1) is mainly correlated with maximum pitch jump, DF2 with call duration. The discriminant function was calculated based on data published in Enard et al. (2009). (c) Acoustic differences in relation to genotype for short whistles (SW) and long whistles (LW). The p start, p max and p mean = start, maximum and mean of the peak frequency. In whistle-like calls, the peak frequency corresponds to fundamental frequency whereas the harmonics have such low amplitude that they are often not visible. (d) Acoustic differences related to genotype for whistles with pitch jump (PJW). P maxloc = location of maximum peak frequency in relation to call duration, calculated as coefficient ranging between 0 and 1. Jumploc = location of the highest change in peak frequency, also measured in relation to call duration (N: FoxP2^WT/WT = 39; FoxP2^hum/hum = 32). (c) and (d) are redrawn from Enard et al. (2009).

Figure 3. Differences in the ultrasound vocalization of NL-3 and NL-4 KO mice

(a) Differences in number of calls and latency to call of male mice courtship vocalizations (N: NL-3WT = 25; KO = 5; NL-4WT = 20; KO = 16). Figure compiled from data presented in (Jamain et al. 2008; Radyushkin et al. 2009). (b) Frequency spectrogram demonstrating the possibility to produce similar call types, WT = wild-type male, KO = NL-4KO male.