Limitations in technology have prevented the full capture of millisecond-scale neural circuit dynamics in intact tissue from psychiatric disease models. Now, intact circuit function can be mapped and quantified with high temporal- and spatial-resolution optical tools. This approach complements optogenetic technologies used for fast optical control of specific cell types within intact neural circuits.
To match the millisecond precision of optogenetics, readout technology that is equally fast is needed. Voltage-sensitive dye imaging (VSDI) captures and quantifies millisecond-scale dynamics of electrically or optically evoked activity propagation while maintaining a full-circuit perspective, thereby allowing circuit-dynamics hypotheses to be tested in animal models of brain disorders. Using high-speed VSDI in living circuits from animals with known behavioral phenotypes, a single measure of activity propagation through specific hippocampal subfields was found to substantially predict both depressed-like behavior and antidepressant treatment response, despite fundamentally different cellular mechanisms. Specifically, in the chronic mild stress (CMS) rodent model of depression, VSDI of slices prepared from the ventral hippocampus revealed a consistent decrease in the relative percolation of evoked electrical activity in the dentate gyrus (DG) versus CA1 subfields, while the opposite effect was seen with antidepressant treatment (panels A, B).
This circuit-dynamics approach can be integrated currently with fast optical control of defined cell types. The voltage sensitive dye RH-155 has an absorbance band spectrally separated from the excitation peaks of the optical control tools ChR2, NpHR, and VChR1, which therefore permits smooth integration of fast optical control and recording (panel C). For example, using living brain slices from ChR2 expressing mice, optically evoked hippocampal activity arising from defined cell types can be imaged and quantified on the millisecond time scale (panel C). These fast optical control tools can be used to quantitatively and dynamically determine the causal roles that different cell types play in modulating neural circuit activity in the normal and diseased brain.