Project Summary To perceive real-world objects and environments, animals must be able to combine sensory and contextual information. For mammals, the integration of sensory and contextual signals depends upon computations performed in the neocortex, a layered structure principally comprised of excitatory pyramidal cells and GABAergic inhibitory interneurons. Sensory processing in the neocortex is hierarchical and begins at primary sensory areas. Neocortical layer 4 receives input directly from the sensory thalamus, while layer 1 receives contextual input from a diversity of regions, including cortical areas processing different sensory modalities, higher-order thalamic nuclei, callosal input, neuromodulatory sources, and high-order cortical areas. Pyramidal cells, the main output cells of the neocortex, have two input zones: the basal dendrites, which eventually receive thalamic-driven sensory information, and the tuft dendrites, which project to layer 1. Neocortical layer 1 is unique among the cortical layers in that it exclusively contains GABAergic interneurons and no excitatory cells. Because they are positioned among the tuft dendrites of pyramidal cells and axonal projections carrying contextual information, the interneurons of L1 are ideal candidates to regulate the integration of sensory and contextual signals. Moreover, the functional importance of L1 interneurons in mediating the integration of contextual and sensory information has been demonstrated by recent studies. One such study has shown that L1 interneurons are critically important for the cross-modal adjustment of sensory signals in primary sensory cortices. However, the identity of interneurons in L1 is poorly understood, so their precise role in cross-modal neocortical circuits remains a mystery. My research has demonstrated that L1 contains four distinct subtypes of interneurons, each with a means of being targeted using transgenic mouse lines. With this knowledge, the purpose of this research is to discover cellular and circuit mechanisms that mediate cross-modal modulation of sensory processing in the neocortex. This goal will be achieved in two aims: (1) using optogenetics and electrophysiological recordings in brain slices, the subtypes of interneurons in L1 that receive cross-modal input and the roles those interneurons play in their local circuit will be determined; (2) using electrophysiological recordings in awake, head-fixed mice while manipulating the activity of interneurons in L1, the circuit mechanisms that regulate the cross-modal modulation of sensory processing will be determined. Results from these experiments will benefit our understanding of contextual processing in the neocortex and may shed light on the origins of deficits in sensory integration found in psychiatric disorders.