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

Abstract

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.

Interhemispheric gamma synchrony between parvalbumin interneurons supports behavioral adaptation

“…To examine whether this PV activity, which occurs at critical behavioral timepoints, was associated with long-range gamma synchrony, we used TEMPO (Trans-membrane Electrical Measurements Performed Optically). TEMPO utilizes bulk measurements of fluorescence from the voltage indicator Ace2N-4AA-mNeon (mNeon), to quantify rhythmic activity in specific cell types 28 . We injected AAV into mPFC bilaterally to drive Cre-dependent mNeon expression in PV-Cre, Ai14 mice, and implanted multimode optical fibers to measure mNeon and tdTomato fluorescence from PV interneurons in the left and right mPFC ( Fig.…”

“…Fluorescent signals from genetically encoded voltage indicators such as mNeon are contaminated by hemodynamic signals, making their effective signal-to-noise relatively low 28,29 . What this means is that conventional spectral analyses of these signals, e.g., measuring their power or coherence at different frequencies, will be dominated by non-neuronal artifacts.…”

Locomotion-Related Population Cortical Ca2+ Transients in Freely Behaving Mice

“…By locally injecting a small amount of Ca 2+ dyes, we could achieve a recording of activity in a highly restricted area approximately 300–500 μm in diameter. In many other studies (Lütcke et al, 2010; Marshall et al, 2016), the use of genetically encoded Ca 2+ or voltage sensors allowed the activity of cell type-specific neural populations to be recorded during free behavior. Using this simple but efficient approach, we studied locomotion-related population signals of neurons in deep layers of both the M1 and V1.…”

The yin and yang of KV channels in cerebral small vessel pathologies

“…These findings highlight the importance of conducted hyperpolarization along PAs and hold the promise of resolving controversies regarding SVD‐induced neurovascular dysfunction, potentially providing a paradigm‐shifting concept. The recent development of cell type specific, genetically encoded fluorescent voltage sensors brings the possibility of in vivo and ex vivo optical electrophysiology within reach . In the context of electrical signaling between capillaries and arterioles, this may allow us to image how changes in K V channels alter the regenerative hyperpolarization of the endothelium during NVC.…”