Function of cortical NDNF interneurons in sound frequency discrimination

A growing understanding of cortical interneuron circuits has highlighted the role of specific inhibitory interneurons in shaping sensory tuning and discrimination acuity. In auditory cortex, neuron-derived neurotrophic factor-expressing interneurons (NDNF-INs) reside in layer 1 where they receive tonotopic projections from the auditory thalamus. In turn, they inhibit the dendrites of out-of-column excitatory pyramidal neurons while disinhibiting within-column neurons via descending projections to parvalbumin-positive interneurons. This circuitry suggests that NDNF-INs are well-poised to modulate cortical gain in a sound frequency-dependent manner, but their function in sensory tuning has not yet been explored. To establish the contribution of NDNF-INs to frequency tuning, we first characterized their frequency response properties using two-photon calcium imaging in awake mice. We found that NDNF-INs exhibit frequency tuning comparable to excitatory neurons but show greater intensity tuning, suggesting that their network effects may be greatest at near-threshold intensities. We next developed a behavioral frequency discrimination paradigm in which mice distinguish trains of repeating pure tones from alternating tones. Prior to training, a greater proportion of individual NDNF-INs were capable of discriminating between these stimuli than pyramidal neurons. Following training, both NDNF-INs and pyramidal neurons displayed a preference for alternating tones, demonstrating learning-dependent plasticity that may be facilitated by NDNF-IN activity. Finally, ongoing experiments are combining holographic optogenetic stimulation with multiplane imaging to activate subsets of NDNF-INs, such as those with overlapping receptive fields, while recording from pyramidal neurons in behaving mice. This strategy will allow us to assess the influence of NDNF-INs on network activity during both passive listening and behavior. This work will establish the function of NDNF-INs in frequency discrimination and further elucidate the contribution of specific inhibitory cortical circuits to sound processing.