Multisite optical neuromodulation : invention and application to emotion circuits

Abstract

A single neural circuit, such as the network of neural populations involved in learning, expressing, and regulating fear, may spread across many brain regions and show functional heterogeneity among spatially overlapping cell types within each region. These populations, represented as discrete circuit elements in models of circuit function, may also show different patterns of activity and connectivity within the circuit over time. More effective therapies for fear related diseases such as anxiety disorders and post-traumatic stress disorder could be achieved if the populations responsible for the pathology were known and could be precisely controlled to restore healthy behavior. The algae- and bacteria-derived light-activated ion channels Channelrhodopsin-2 (ChR2) and Halorhodopsin (Halo) could be used to treat circuit pathologies because they enable bidirectional control of transfected neurons with high temporal and spatial resolution. Virally delivered to mammalian neurons and expressed under cell-class specific promoters, they can be used to address neural populations which share similar morphology, connectivity, electrophysiology, and, likely, function. Furthermore, the fear circuit may be reverse-engineered by perturbing neural populations, both individually and combinatorially, over many points in the timecourse of fear behavior, to see their effect on both behavior and the electrophysiological function of other neural populations. This requires a tool for multisite optical activation in the freely-moving rodent behaviors used to study fear, which is impossible to achieve with current laser-based optical systems. We developed LED-Coupled Optical Fiber Arrays whose high power output (>200mW/mm2 at fiber tip), high packing density (>1 fiber/mm 2), low cost (~$2/fiber), low weight (1-2gms), and modular design enable highly scalable, rapid customization for networks with many circuit elements and large structures requiring many points of optical delivery for full coverage. We found that optical activation of pyramidal cells in the medial prefrontal cortex can facilitate fear extinction in mice who have learned tone-shock association, a resulted strongly suggested but unproved by electrical stimulation experiments which could not differentiate between cell classes. We also demonstrate that the Fiber Arrays are compatible with simultaneous neural recording by properly shielding electrodes and neural amplifiers from the large (-Amp) nearby LED-driving currents. Fiber Arrays constitute a flexible platform for simultaneous neural modulation and observation with exceptional temporal, spatial, and functional resolution.