Functional neuromics of the cerebral cortex. (360G-Wellcome-108726_Z_15_Z)

Cortical circuits comprise multiple classes of neurons and glia, whose interactions govern perception, behaviour, and thought. We propose to combine several new techniques to probe this circuitry with unprecedented precision by identifying, monitoring, and controlling the participating cells. We will: 1. Provide a definitive taxonomy of cortical cell classes. By applying single-cell RNA sequencing to tens of thousands of neocortical and hippocampal cells, we will identify cell classes and su bclasses, together with marker genes that in combination identify them. 2. Understand the anatomical organization of these classes. By applying in situ transcriptomics to cortical tissue, we will understand the position of each class in the circuit, and determine the molecular identity of selected projection classes. 3. Understand how these classes participate in sensory processing and behaviour. We will record the activity of neurons and glia in the neocortex and hippocampus of behaving mice, then classify the recorded cells by retrospective in situ transcriptomics. 4. Identify causal interactions among cell classes in vivo. We will reveal the causal influence of molecularly identified cells on the network by stimulating them using 2-photon optogenetics, while recording population activity. These data will constrain mechanistic models of the underlying circuit.