Population imaging of neural activity in awake behaving mice in multiple brain regions

Abstract

A longstanding goal in neuroscience has been to image membrane voltage, with high temporal precision and sensitivity, in awake behaving mammals. Here, we report a genetically encoded voltage indicator, SomArchon, which exhibits millisecond response times and compatibility with optogenetic control, and which increases the sensitivity, signal-to-noise ratio, and number of neurons observable, by manyfold over previous reagents. SomArchon only requires conventional one-photon microscopy to achieve these high performance characteristics. These improvements enable population analysis of neural activity, both at the subthreshold and spiking levels, in multiple brain regions -cortex, hippocampus, and striatum -of awake behaving mice. Using SomArchon, we detect both positive and negative responses of striatal neurons during movement, highlighting the power of voltage imaging to reveal bidirectional modulation. We also examine how the intracellular subthreshold theta oscillations of hippocampal neurons govern spike output, finding that nearby cells can exhibit highly correlated subthreshold activities, even as they generate highly divergent spiking patterns.

All-optical electrophysiology reveals excitation, inhibition, and neuromodulation in cortical layer 1

“…1I, L). Spontaneous spikes rode atop a baseline depolarization that both preceded and followed the spike, whereas whisker-evoked spikes arose abruptly and were followed by a period 20 of hyperpolarization ( Fig. 1I, L).…”

“…Due to their multimodal, temporally precise inputs (16) and temporally precise outputs, 15 one would like to measure the sub-threshold dynamics and spike timing of L1 neurons with high precision in voltage and time. Recent advances in genetically encoded voltage indicators (GEVIs) enabled voltage imaging with single-neuron, single-spike resolution in hippocampus (17)(18)(19)(20) and in superficial cortex (18,19) in vivo, opening the possibility for optical explorations of L1 circuit function in vivo. 20 Voltage alone does not distinguish the relative contributions of E and I synaptic inputs, yet this distinction is critical for understanding circuit mechanisms.…”

“…Recent advances in genetically encoded voltage indicators (GEVIs) enabled voltage imaging with single-neuron, single-spike resolution in hippocampus (17)(18)(19)(20) and in superficial cortex (18,19) in vivo, opening the possibility for optical explorations of L1 circuit function in vivo. 20 Voltage alone does not distinguish the relative contributions of E and I synaptic inputs, yet this distinction is critical for understanding circuit mechanisms. A commonly used patch clamp technique is to inject current to achieve different levels of baseline depolarization and thereby to shift the relative driving force of E vs.…”

“…Archon1 is an Arch-derived GEVI with improved trafficking and brightness (24). A soma-localized variant, SomArchon, enabled voltage imaging in vivo with good signal-to-noise ratio (20). We made a Cre-dependent bicistronic construct for co-expression of SomArchon and a blue light-activated soma-localized channelrhodopsin, CheRiff (25).…”

“…We characterized the performance of the system by imaging SomArchon-expressing neurons in vivo in the cortex. Under wide-field red illumination, the cells were not visible due to 20 high background from scattered light ( Fig. 1B).…”