PROJECT SUMMARY The goal of this project is to investigate how the deepest layer in the neocortex can modulate sensory perception through a unique type of inhibitory interneuron. Almost all sensory information proceeds through the thalamus en route to the neocortex. Layer 6 (L6) corticothalamic (CT) neurons send massive feedback projections to the thalamus, and they also send ascending collaterals capable of strongly modulating the cortex itself. Recent indirect evidence suggests this modulation may occur through a distinct type of fast-spiking (FS), parvalbumin- expressing inhibitory interneuron that resides in upper L6 and uniquely sends axons into the upper layers where they presumably impart strong translaminar inhibition. Because the primary sensory pathway from the thalamus enters cortex most prominently in these zones, this wiring is suggestive of strong modulatory effects on sensory inputs and influence on perceptual processing. FS interneurons are critically involved in gamma oscillations and have been implicated in cognitive deficits (Carlen et al., 2012; Korotkova et al., 2010) and schizophrenia (Lewis et al., 2012). L6-CT cells have also been implicated in these disorders. The role of FS cells in gamma rhythms suggests that the L6 CT→FS connectivity may modulate the cortex by imposing synchrony on sensory input layers to influence perceptual processing. The central goal of this proposal is to determine how modulation of sensory information is implemented by intracortical L6-CT circuits, and how this inhibitory pathway participates in the perception of stimuli. Aim 1 is to determine the anatomical circuits by which CT cells can modulate sensory processing within cortex. Specifically, I will systematically determine the frequency and strength by which L6-FS interneurons connect to known neuron types across the layers of a cortical column. I will test the hypothesis that upper L6-FS cells form strong connections with specific neuronal subsets in the overlying cortical column, such as pyramidal cells in L2/3, 4, and 5, as well as L4-FS cells, and whether their extrinsic connectivity rules further distinguish this class from other FS cells. Aim 2 will test whether distinct groups of interneurons can coordinate rhythms in the overlying column. Specifically, this will test the hypotheses that translaminar FS cells of upper L6 contain unique intrinsic physiological properties that support the coordination of fast oscillatory rhythms, and mediates the network rhythmic activity observed in LFPs during CT-evoked gamma in vitro. Aim 3 will test the role of putative upper L6-FS cells in detection task performance and oscillatory activity in the awake behaving animal. This proposed investigation will illuminate important functions of a unique circuit, and in doing so will provide the applicant significant training in several critical in vitro and in vivo techniques. The valuable training provided by two Co-Sponsors with complementary expertise will...