MESO_AG · Mesoscale dissection of neuronal populations underlying cognition

The brain is responsible for cognition, broadly defined as thinking, by combining mental processes such as sensory integration, perception, and working memory. One of neuroscience’s major challenges is understanding how the brain encodes cognition as a whole. The biggest obstacle to this goal is the complex nature of the brain, which contains billions of entangled neurons that form a dynamic, ever-changing network. We propose to use the mouse model to study cognitive processing streams across the brain. By applying a zoom-out/zoom-in approach, we first study cognition at the mesoscale level (i.e., the population level across many areas) and then zoom in and dissect a specific sub-population. Importantly, we focus on the dynamic brain-wide networks of different cognitive functions that are modulated within single trials and in each individual mouse. We hypothesize that cognitive functions are encoded at the mesoscale level in which information flexibly flows across many brain areas, but with certain motifs and rules. Each objective targets one processing stream and one cognitive function: streams within one cortical hemisphere during sensory integration, streams across cortical hemispheres transferring working memory, and streams between cortex and sub-cortex during perception. In each work package, we will train mice in cognitive behavioral paradigms, and perform a zoom-out/zoom-in protocol with the same mouse. First, we will implement a mesoscale approach (e.g., wide-field imaging and/or multi-fiber photometry) to outline the processing stream within the cognitive network. Second, we will zoom in to dissect a specific node or edge using multi-area two-photon microscopy, labeling techniques, and optogenetics. Importantly, these work packages are modulatory and with substantial overlaps, enabling us to obtain a brain-wide cognitive map that will aid in understanding cognition as a whole in both the healthy and the diseased brain.