Comprehensively map the mesoscale thalamic circuits that route subcortical inputs to frontal cortex

Summary, Project 1 (Comprehensively map the mesoscale thalamic circuits that route subcortical inputs to frontal cortex) Frontal cortex displays rich patterns of neural activity underlying action planning, decision-making, and short- term memory. Across the brain, the cortex is strongly coupled to, and dependent upon, the thalamus, which represents the central hub of the forebrain. Here we map circuits involving the non-sensory ('higher-order') thalamus, which routes input from basal ganglia, midbrain, cerebellum, and hippocampus to the frontal cortex. Our overarching hypothesis is each subcortical input acts through the thalamus to control activity in frontal cortex and associated behavior. This idea is formalized in a modeling framework that links a dynamical systems view of neural computation with multi-regional neural circuits (Project 5). This model needs to be constrained by mesoscale (region-to-region) circuit diagrams linking subcortex to frontal cortex via thalamus. However, existing anatomical information is insufficiently detailed to guide either in vivo electrophysiology (Projects 3, 4) or develop computational models (Project 5). Therefore, a fine-scale mesoscale map of subcortex → thalamus → frontal cortex circuits is required to understand signaling through these regions. In this project, we combine existing pipelines for high-throughput imaging and informatics with cutting-edge, transcellular anterograde and retrograde viral tracing methods and new types of reporter mice. These rigorous and comprehensive experiments will create a fine-scale map between frontal cortex and non-sensory thalamus (AIM 1); discover the subcortical inputs to different populations of thalamocortical (TC) cells (AIM 2); and map subcortical inputs to thalamus, including divergence and convergence at the level of both thalamic regions and individual TC cells (AIM 3). Processed and raw image data will be registered to a standardized coordinate framework and made readily available in an accessible manner to the community.