Rhythmic auditory stimulation rescues cognitive flexibility in mutant mice with impaired gamma synchrony

Neural synchronization at gamma ([~]40 Hz) frequencies is believed to contribute to brain function and be deficient in disorders including Alzheimers disease and schizophrenia. Gamma-frequency sensory stimulation has been proposed as a non-invasive treatment for deficient gamma synchrony and associated cognitive deficits, and has been shown to be effective in mouse models of Alzheimers disease. However, both the mechanism and applicability of this approach remain unclear. Here we tested this approach using mutant (Dlx5/6+/-) mice which have deficits in gamma synchrony and the ability to learn to shift between rules which use different types of cues to indicate reward locations. 40 Hz auditory stimulation rescues rule shifting in Dlx5/6+/- mice. However, this improvement does not outlast the period of stimulation, and is not associated with normalized gamma synchrony, measured using genetically encoded voltage indicators. These results show how gamma-frequency sensory stimulation may improve behavior without fully restoring normal circuit function.