The input-output connectional organization of the cortical-thalamic-basal ganglia network and its molecular underpinnings

Understanding the structure and organization of cortical-thalamic-basal ganglia (BG) network is essential for uncovering mechanisms underlying sensorimotor function, cognition, emotion, and disease. Here we generated a comprehensive cortical-thalamic-BG connectome in the mouse brain using viral tracers and explored the relationship between fine-grained connectivity patterns and spatially resolved transcriptomic cell types. As a major expansion of the Allen Mouse Brain Connectivity Atlas, we generated 851 standardized retrograde monosynaptic rabies virus tracing experiments targeting genetically defined cell populations in many areas in cortex, thalamus and basal ganglia. Combining this dataset with our previous anterograde adeno-associated virus (AAV) tracing dataset, we created an integrated brain-wide input-output connectome. We defined a reciprocal, modular and hierarchical organization throughout the cortico-thalamic-BG network, with integration at specific nodes at all levels. We systematically compared the retrograde input connectivity map with our spatial transcriptomic cell type map and identified potential cell type compositions of starter and presynaptic neurons in each node of the circuits, further confirming some by Retro-seq. Overall, this study provides a high-resolution quantitative whole-brain atlas of the cell type-specific input-output connectome across the cortical-thalamic-BG circuits and reveals its modular and integrative organizational logic as well as its molecular underpinnings.