Corticothalamic circuits for active listening

Abstract

Layer 6 corticothalamic neurons (L6 CTs) are the largest component of the corticofugal projection system and one of the largest classes of projection neuron in the brain. However, the contribution of L6 CTs to brain function and behavior has remained a mystery since the time of Ramon y Cajal. The advent of optogenetic approaches to activate and silence genetically targeted L6 CTs in Ntsr1-Cre transgenic mice has reinvigorated research on corticothalamic circuits and inspired new hypotheses about their role in sensory gain control and predictive coding. Optogenetic activation of L6 CTs can alternately suppress or enhance evoked responses in thalamic and cortical neurons, depending on the timing and frequency of L6 CT spiking relative to sensory stimulation. In this dissertation, we tested whether auditory L6 CTs were naturally recruited before expected sounds according to the behavioral goals of an animal, rather than the artificial flash of a laser. In our first experiments, we developed three distinct, but interrelated, auditory psychophysical tasks in head-fixed mice where the timing of a target sound was predicted by a visual, auditory or motor cue, respectively. We found that mice could use predictive cues to enhance auditory perception, but that the precise effect of each cue varied based on modality and timing relative to target sounds. Next, to directly address the hypothesis that L6 CTs might be activated by extrasensory inputs before expected sounds, we performed targeted recordings from L6 CTs while animals were engaged in a simplistic active listening task. Using two-photon calcium imaging and antidromic phototagging, we found that L6 CTs were activated hundreds of milliseconds prior to orofacial movements that predicted sound and reward, but not before other movements like locomotion, which were not linked to an explicit behavioral task. Finally, we show that the motor-related activity we observe in L6 CTs may be mediated by monosynaptic inputs from the basal ganglia. In summary, this dissertation describes a role for L6 CTs in active listening and suggests new directions for future research on corticothalamic circuits.