Project Summary/Abstract A central problem in neuroscience is to understand how activity arises from neural circuits to drive animal behaviors. Solving this problem requires integrating information from multiple experimental modalities and organization levels of the nervous system. While modern neurotechnologies are generating high-resolution maps of the brain-wide neural activity and anatomical connectivity, novel theoretical frameworks are urgently needed to realize the full potential of these datasets. Most state-of-the-art methods for analyzing high-dimensional data are based on detecting correlations in neural activity and do not provide links to the underlying anatomical connectivity and circuit mechanisms. As a result, conclusions derived with these methods rarely generalize across different behaviors and are hard to validate in perturbation experiments. In contrast, mechanistic theories, which combine connectivity, activity, and function, have been highly successful in understanding function of small neural circuits. Conditions under which insights from small circuits scale to large distributed circuits have not been explored. Mechanistic theories informed by multiple data modalities are critically missing to guide experiments probing global neural dynamics on the brain-wide scale. The main goal of this proposal is to develop computational frameworks for modeling global neural dynamics, which utilize anatomical connectivity and predict rich behavioral outputs on single trials. Our project will address two complementary aims. First, we will take advantage of recently available datasets of high-resolution brain- wide neural activity and anatomical connectivity to construct a multiscale model of functional dynamics across the mouse cortex. Integrating measurements across multiple scales, from mesoscopic to near-cellular resolution, we aim to reveal the effective degrees of freedom at each scale, which constrain global neural dynamics and drive rich patterns of behavior. Second, we will leverage techniques from dynamical systems theory and artificial recurrent neural networks to develop circuit reduction methods that infer interpretable low-dimensional circuit mechanisms of cognitive computations from high-dimensional neural activity data. Rather than merely detecting correlations, our method infers the structural connectivity of an equivalent low-dimensional circuit that fits projections of high-dimensional neural activity data and implements the behavioral task. We will apply this method to multi-area neural activity recordings from behaving animals to reveal distributed circuit mechanisms of context-dependent decision making. The computational frameworks developed in this proposal can be validated in perturbation experiments and extended to other nervous systems and behaviors.

Project Narrative Neural signals related to behavioral and cognitive functions are widespread across the distributed circuitry of the mammalian brain. We will take advantage of recently available high-resolution datasets of brain-wide neural activity and anatomical connectivity to develop mathematical models that integrate multiple data modalities to predict global neural dynamics and rich patterns of behavioral outputs. Our research will produce analytical tools capable to reveal distributed circuit mechanisms underlying behavioral and cognitive functions that are distorted in mental disorders.