Lucas Pinto, M.D., Ph.D. Northwestern University, Chicago Campus
The ability to make decisions lies at the core of cognition, but much remains unknown about its underlying neural mechanisms. Progress has been hindered in part by the fact that decisions vary widely in terms of the underlying computations (e.g., stimulus processing, memory) and their timescales (split seconds, minutes). Until recently, another hurdle was our limited ability to record neural dynamics at large scales. Thus, most of what we know about decision-making has come from studies focusing on the role of single regions during single tasks. Yet it has become increasingly clear that decision-making is supported by distributed cortical dynamics. However, we still do not understand how the features of distributed dynamics vary as a function of the types and timescales of cognitive computations underlying particular decisions. We aim to fill this gap by recording and perturbing neural dynamics across the cortex with mesoscale or cellular resolution, over a parameterized task space of decision-making computations and the timescales thereof.
Our hypothesis is that a key task feature organizing large-scale cortical dynamics is the timescale over which its underlying computations occur. The cortex is known to be organized in a hierarchy of intrinsic timescales, whereby frontal areas have longer autocorrelation functions than posterior sensory areas. However, we do not know if this hierarchy can explain why and how cortical areas are recruited in a task-dependent fashion. Moreover, we do not understand which local circuit features are causal to area-level timescales, or how they are modulated by task demands. To answer these questions, we are developing a novel task for head-fixed mice making navigational decisions in virtual reality. This is a modified version of a delayed match-to-sample task, where the sample is noisy and must therefore be gradually accrued. We independently vary the timescales of accrual and sample memory, and accrual difficulty, to generate a three-dimensional task space of cognitive computations. We will use laser-scanning optogenetic inactivation and wide-field calcium imaging of genetically identified cell types and cortical layers to reveal how whole-cortical dynamics systematically varies as a function of this task space. Moreover, we will use simultaneous two-photon cellular-resolution calcium imaging and optogenetics from different cortical areas to understand how the known cellular diversity of intrinsic timescales within a region results in area-level organization. Specifically, we will causally test the hypothesis that the intrinsic timescales of different cortical areas arise from both the level of local excitatory recurrent connectivity and the ratio of inhibitory neuron subtypes. This in turn will determine whether a given area is involved in a task-specific computation.
I believe this work will greatly advance our understanding of the principles and mechanisms of cortical dynamics underlying cognitive behavior.