Circuit Mechanisms Underlying Learned Changes in Persistent Neural Activity

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ABSTRACT Persistent neural activity, a sustained response following brief stimuli that is observed in many brain networks, needs to be appropriately tuned to meet the exacting demands of various motor and cognitive tasks. One task that has been particularly amenable to understanding persistent neural activity is the oculomotor control of gaze position. In the oculomotor system, where persistent activity maintains the appropriate gaze angle necessary for high-acuity vision, this tuning arises in large part through an interaction loop between the cerebellum and the oculomotor neural integrator, a brainstem structure that temporally integrates eye velocity commands to generate eye position encoding signals. Whereas we understand a fair bit about the coding properties and signal transformations within the cerebellum and especially the neural integrator proper, the interactions between these key brain centers is poorly understood. Here we aim to close this gap through an integrative approach using a combination of whole-network two-photon imaging, targeted optical perturbations, serial-section electron microscopy, in-vivo electrophysiology, and next-generation network modeling. In Aim 1, we will combine volumetric imaging of neuronal dynamics in the zebrafish with learning and targeted perturbations to examine the causal relationships between cerebellar and integrator populations. In Aim 2, we will perform high-resolution serial-section electron microscopy of a functionally imaged brain to gain insight into the global circuit's anatomical connectivity. In Aim 3, we will directly fit a network model to these dynamical and structural data to find the physiological interaction patterns in the circuit and predict the sites of plasticity. In Aim 4, we will probe predicted sites of plasticity using cell-targeted optical stimulations and whole-cell patch recordings. These tools and results will enable concrete predictions about the circuit mechanisms tuning persistent neural activity, guide understanding of the modular loops between the cerebellum and a wide range of other brain areas, and serve as a benchmark for efforts to understand the dynamics and plasticity of interactions across the brain.