Large- and meso-scale cortical dynamics underlying evidence accumulation and decision-making Abstract The accumulation of sensory evidence is a crucial aspect of perceptual decision-making, and it involves complex neural computations requiring sensory processing, weighing of sensory evidence for or against a decision, as well as short-term memory of accrued evidence. Given this complexity, it is likely that many cortical areas are causally involved in evidence accumulation. However, little is known about which areas are necessary for evidence accumulation; moreover, we do not understand the neuronal circuit mechanisms underlying this important phenomenon. To answer these questions, we will use a novel virtual navigation-based visual accumulation task for head-fixed mice, and combine it with a suite of optical techniques to manipulate and record neural activity on meso- to large spatial scales, informed by detailed computational models of cognitive behavior. First, we propose to use optogenetic inactivation through the intact skull rendered optically transparent to systematically map cortical areas involved in accumulating visual evidence as the animal navigates the virtual maze. Taking advantage of this transparent skull preparation, we will also perform large-scale Ca2+ imaging from the entire dorsal portion of the cortex to map the large-scale spatiotemporal dynamics and flow of information during evidence accumulation and decision-making. Importantly, we will analyze the data using sophisticated quantitative models of evidence accumulation recently developed in the Brody laboratory, which will allow us to precisely quantify which aspect(s) of evidence accumulation depend on which cortical areas, and how dynamic patterns of neural activity map onto individual computations during decision-making. We thus aim use a unique combination of state-of-the-art techniques to provide a detailed and causal account of how cortical circuits underlie evidence accumulation for decision-making during spatial navigation. Beyond its importance for basic research, elucidating these processes will be crucial for understanding and treating the deficits in evidence accumulation and decision-making that are a hallmark of many psychiatric and neurological disorders such as obsessive-compulsive disorder, attention deficit hyperactivity disorder and drug abuse.