State-space optimal feedback control of optogenetically driven neural activity

Objective.The rapid acceleration of tools for recording neuronal populations and targeted optogenetic manipulation has enabled real-time, feedback control of neuronal circuits in the brain. Continuously-graded control of measured neuronal activity poses a wide range of technical challenges, which we address through a combination of optogenetic stimulation and a state-space optimal control framework implemented in the thalamocortical circuit of the awake mouse.Approach.Closed-loop optogenetic control of neurons was performed in real-time via stimulation of channelrhodopsin-2 expressed in the somatosensory thalamus of the head-fixed mouse. A state-space linear dynamical system model structure was used to approximate the light-to-spiking input-output relationship in both single-neuron as well as multi-neuron scenarios when recording from multielectrode arrays. These models were utilized to design state feedback controller gains by way of linear quadratic optimal control and were also used online for estimation of state feedback, where a parameter-adaptive Kalman filter provided robustness to model-mismatch.Main results.This model-based control scheme proved effective for feedback control of single-neuron firing rate in the thalamus of awake animals. Notably, the graded optical actuation utilized here did not synchronize simultaneously recorded neurons, but heterogeneity across the neuronal population resulted in a varied response to stimulation. Simulated multi-output feedback control provided better control of a heterogeneous population and demonstrated how the approach generalizes beyond single-neuron applications.Significance.To our knowledge, this work represents the first experimental application of state space model-based feedback control for optogenetic stimulation. In combination with linear quadratic optimal control, the approaches laid out and tested here should generalize to future problems involving the control of highly complex neural circuits. More generally, feedback control of neuronal circuits opens the door to adaptively interacting with the dynamics underlying sensory, motor, and cognitive signaling, enabling a deeper understanding of circuit function and ultimately the control of function in the face of injury or disease.