Cell-Type-Specific Optical Recording of Membrane Voltage Dynamics in Freely Moving Mice

Electrophysiological field potential dynamics are of fundamental interest in basic and clinical neuroscience, but how specific cell types shape these dynamics in the live brain is poorly understood. To empower mechanistic studies, we created an optical technique, TEMPO, that records the aggregate trans-membrane voltage dynamics of genetically specified neurons in freely behaving mice. TEMPO has >10-fold greater sensitivity than prior fiber-optic techniques and attains the noise minimum set by quantum mechanical photon shot noise. After validating TEMPO’s capacity to track established oscillations in the delta, theta, and gamma frequency bands, we compared the D1- and D2-dopamine-receptor-expressing striatal medium spiny neurons (MSNs), which are interspersed and electrically indistinguishable. Unexpectedly, MSN population dynamics exhibited two distinct coherent states that were commonly indiscernible in electrical recordings and involved synchronized hyperpolarizations across both MSN subtypes. Overall, TEMPO allows the deconstruction of normal and pathologic neurophysiological states into trans-membrane voltage activity patterns of specific cell types. [Display omitted] •TEMPO, an optical tool to track trans-membrane voltage in freely behaving mice•Recordings at the physical sensitivity limit set by photon shot noise•Monitoring of cortical and hippocampal delta, theta, and gamma oscillations•Striatal medium spiny cells have two forms of synchronized hyperpolarization A fiber-optic recording technique allows the voltage activity of specific cell types to be monitored deep in the brains of freely moving animals, moving beyond the temporal and sensitivity limitations of current approaches.