Circuit Mechanisms Underlying Persistent Activity in a Neural Integrator

Abstract Short-term memory function is commonly supported through persistent activity, the sustained response of populations of neurons following the offset of a memorized stimulus. This form of activity underlies diverse tasks including navigation, motor control, and decision-making. Classic mechanistic theories have idealized such activity through models that assume strongly homogeneous populations of neurons that encode only a single variable and generate perfectly stable patterns of activity. This contrasts with recent work showing that neurons in real biological memory networks exhibit multiplexed encoding of multiple stimulus attributes, temporally varying responses across the population, and context dependence. Here we address the circuit mechanisms and role of this diversity in function through a combined experimental-theoretical approach. Experiments are conducted in a short-term memory circuit of the larval zebrafish gaze control system that contributes to stable vision by precisely maintaining the eyes on a visual target. Taking advantage of the quantitative precision and experimental tractability of this system, we combine whole-circuit, synapse-resolution anatomy with circuit-wide recordings and perturbations of activity at cellular resolution. In Aim 1, we combine these data into a model of the system in which neurons map in a one-to-one manner with experimentally recorded neurons. This enables us to infer the interactions within and between neurons of different anatomical, genotypic, and functional cell classes and form predictions for how these interactions govern circuit function. In Aim 2, we use 3D cellular resolution optical imaging and stimulating perturbations of neuronal activity to refine our model and test model predictions. In Aim 3, we expand our capacity to form precise characterizations of within and between cell-class interactions by developing and applying 3D suppression of neurons across the memory circuit. Altogether, this work promises to greatly expand our understanding of the circuit mechanisms and role of cell type diversity in persistent firing, short-term memory, and motor control.