Ultrasonic vocalization in murine experimental stroke: A mechanistic model of aphasia.

Abstract

Approximately one-fourth of stroke survivors are aphasic. Speech therapy is the main treatment approach but leaves most patients with chronic disability. Attempts to improve this situation are hampered by a lack of mechanistic understanding of the disability and treatments, reflecting the neglect of this impairment modality in pre-clinical research. Accordingly, we devised a novel murine model of speech-related impairment after stroke to investigate the role of language- and plasticity-associated molecules. Rodents communicate socially with ultrasonic vocalizations (USVs), conveying semantic and semiotic information with complex frequency modulated "songs" and alarm calls. Transient focal cerebral ischemia was induced in male C57BL6 mice via either 30 or 45 minutes of reversible right MCAO using the intraluminal filament technique. Nine days post-operatively brains are stained with TTC and analyzed for infarct volume. For behavioral measures health scores are taken (days 1-4), cylinder tests and USV recordings performed at days 3 and 7 post operatively. Real time PCR was performed at 24 and 48 hour and 7 day time points to quantify mRNA expression of communication-related genes (Foxp2, Foxp1, Srpx2, Cntnap2 and Gapdh). Immunohistochemistry was performed to localize FOXP2 protein. After middle cerebral artery occlusion of either 30 or 45 minutes duration, mice demonstrate profoundly impaired socially evoked USVs. In addition, there is suppression of the language-associated transcription factor, Forkhead box protein 2 (Foxp2), and its downstream binding partner, contactin-associated protein 2 (Cntnap2). These findings set a foundation for further studies of mechanisms and novel treatment strategies for post-stroke vocalization impairments.