Toward mechanistic cognitive neuroscience: cell types, connectivity, and patterned perturbations

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Summary The cognitive functions of the brain allow higher animals to interact with the world in complex and adaptive manners. For example, animals use past experiences to develop internal models of rules and contexts that shape subsequent decisions. These cognitive processes are disrupted in many devastating mental health disorders. Traditional experiments in cognitive neuroscience have identified correlations between cognitive processes and behavioral outputs or neural events. However, it has been challenging to uncover the causal mechanisms by which cognitive processes emerge from the basic building blocks of neurobiological computations: molecules, cells, synapses, and circuits. The reason is, in large part, because it has been difficult to combine emerging mechanistic approaches in neuroscience with paradigms to study cognitive processes. Here we aim to overcome these challenges by developing a research program to identify causal links between cognitive processes and the structure – cell types and connectivity – and function – spatiotemporal activity patterns in neural populations – of neural circuits. We recently devised a virtual reality system for mice and developed methods to train mice to perform complex, cognitive tasks as they navigate through virtual environments. Further, we developed neurophysiological and computational tools that have identified correlates of cognitive processes in the activity patterns in population of neurons. We will use this foundation to establish a research program for mechanistic cognitive neuroscience. First, we will develop an atlas of cell types in cognitive brain regions, use viral tools to label these cell types, and then study the functional roles of these cell types during flexible decision-making tasks. Second, we will establish methods based on single-neuron optogenetics to reveal connectivity between identified cells during cognitive behaviors. Third, we will use calcium imaging to ‘read’ patterns of neural activity during cognitive tasks and will then ‘write’ and ‘erase’ these patterns using patterned optogenetics to test sufficiency and necessity. We will study these structural and functional properties in local populations of neurons (microcircuits) and across brain areas (mesocircuits). This work will expand the emerging field of mechanistic cognitive neuroscience and develop a new research program toward the goal of defining cognition and mental health in terms of core biological components and mechanisms.