PROJECT SUMMARY A major unresolved question in systems neuroscience is whether specialized anatomical structures support specific functions in behavior. Therefore, this proposal will bridge the gap between anatomical circuit diagrams and their predicted functional roles. Specifically, it will address the functional consequences of the patch/matrix-like “modular” anatomical organization that has recently been characterized in the inferior colliculus. This acoustico-motor nucleus can be subdivided into modular regions, characterized by high density staining for GAD67 and other neurochemical markers, and extramodular regions that express calretinin. These neurochemical divisions also correlate with differences in connectivity; for example, modular regions of the lateral cortex receive input from somatosensory and motor structures, such as the dorsal column nuclei and somatosensory and motor cortices, while extramodular areas receive auditory inputs from the auditory cortex and other regions of the inferior colliculus. It is presently unknown whether this structural compartmentalization gives rise to segregated streams for distinct types of information processing, as is seen in the patch/matrix system in the striatum. Therefore, the goal of this proposal is to determine whether the modularity of the lateral cortex is conserved at the functional level, thus giving rise to complementary processing zones with distinct roles in acoustico-motor behavior. Two main hypotheses will be explored: 1) that auditory and somato-motor signals activate distinct populations of cells in the lateral cortex, and 2) that modular zones serve as somatosensory-driven gating regions for auditory information. These hypotheses will be tested using a combination of two-photon calcium imaging, clustering analysis, optogenetics, and behavior. Cells in modular and extramodular regions of the lateral cortex will be imaged in response to acoustic or somato-motor stimuli, and clustering analysis will be used to determine whether the populations of neurons activated by each modality form distinct groups. To determine whether somatosensory-recipient cells in modular regions of the lateral cortex gate auditory responses, this pathway will be selectively manipulated while mice perform a two- alternative unforced-choice sound localization task. The effect of optical activation and inhibition of the somatosensory inputs on sound detection behavior will be assessed. The experiments outlined above will further characterize the functional organization and behavioral relevance of the lateral cortex, which could have important implications for both normal and pathological hearing. Furthermore, these experiments may reveal generalizable principles regarding modular architectures, which could provide insights into other modular structures, such as the striatum.

PROJECT NARRATIVE In addition to their proposed roles in normal acoustico-motor behavior, it is possible that modular circuits are affected by pathologies involving phantom auditory percepts. The experiments outlined in this proposal will specifically investigate whether modular regions of the lateral cortex are involved in cross-modal gating of acoustic information, and whether manipulation of the somatosensory inputs to these zones can yield auditory percepts in the absence of an external acoustic stimulus. Therefore, the proposed experiments may identify a locus within the auditory system for the study and potential treatment of disorders involving phantom sounds, such as tinnitus and schizophrenia.