This is a competitive revision application for my NIH Pathway to Independence Award (4 R00DA023700) tilted """"""""Local Connections and In Vivo Physiology of Inhibitory Cortical Neurons"""""""", in response to the NIH funding notice (NOT-OD-09-058, NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications). Despite extensive knowledge of the basic blueprint of cortical circuits, detailed knowledge about local cortical circuits, the connectivity of specific cell types and how they function is still limited. The studies originally proposed investigate the laminar and fine-scale specificities of excitatory and inhibitory synaptic input to specific types of inhibitory neurons in the cerebral cortex, and examine in vivo physiology of distinct inhibitory cell types and their participation and regulation of cortical activities. We have accomplished the aims of examining the laminar specificity of functional input to distinct cell types by combining whole cell recordings with scanning laser photostimulation in brain slices. We also have progressed toward understanding in vivo physiology of specific inhibitory cell types. Recently, we have developed a technique enabling high-resolution and fast functional imaging in brain slices through a novel combination of voltage sensitive dye imaging and laser scanning photostimulation. This innovation will have broad impacts in the field of cortical circuitry studies, as it facilitates rapid mapping and precise evaluation of cortical organization and function. The innovation will enable the ability to map inhibition output from inhibitory cell types by examining their influence on neuronal population activities evoked by photostimulation and detected by voltage sensitive dye imaging. Given the exciting developments of my original projects, I would like to revise my original aims, and focus on further improving the new technique and extending such technology toward elucidating cortical circuitry. The newly revised Specific Aims are to (1) Refine and improve the high-resolution and fast functional imaging technique in brain slices;(2) Map inhibitory output of specific types of inhibitory neurons using the novel technique;(3) Characterize circuit alterations in dopamine receptor knockout (D2R-/-) mice with the novel technique. This revision requests support to purchase additional equipment and train one minority graduate student.
Studies of the detailed organization of cortical circuits involving specific inhibitory cell types are necessary toward understanding cortical function. These studies have important implications for human health, as these cell types and their activities are involved in many disease models and can mediate the cortical mechanisms related to drug addiction and abuse.
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