Research · Area of focus
Optical brain machine interfacing
We build optical brain–machine interfaces that read and write neural activity with cellular resolution and millisecond precision across large volumes of the brain, engineering new opsins, holographic photostimulation, and all-optical read–write systems that can place arbitrary activity patterns into cortical circuits.
Selected papers
Five papers that define our work on optical brain machine interfacing.
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Probing inter-areal computations with a cellular resolution two-photon holographic mesoscope
Brain computation depends on intricately connected yet highly distributed networks, and causally testing hypotheses about inter-areal processing had remained largely out of reach for lack of the necessary technology. This work developed a two-photon holographic mesoscope that simultaneously reads and writes neural activity patterns with near-single-cell resolution across large regions of the mouse cortex. Spatial and temporal sequences of neurons were precisely photoactivated in one or multiple cortical areas while the downstream effects were read out in several other regions, establishing mesoscale holographic optogenetics as a platform for mapping functional connectivity and causal interactions across distributed cortical areas.
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High-performance microbial opsins for spatially and temporally precise perturbations of large neuronal networks
The biophysical properties of existing optogenetic tools constrain the scale, speed, and fidelity of precise optogenetic control, so structure-guided mutagenesis was used to engineer opsins with very high potency that retain fast kinetics. The new opsins were extensively benchmarked against existing tools, with a detailed biophysical characterization of a diverse opsin family under two-photon illumination that serves as a resource for matching an opsin to an experiment's goals and constraints. Combined with optimized holographic photostimulation, they allowed several hundred spatially defined neurons to be co-activated with a single hologram, and nearly twice that number by temporally interleaving holograms at fast rates.
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All-optical recreation of naturalistic neural activity with a multifunctional transgenic reporter mouse
Determining which features of the neural code drive behavior requires simultaneously reading out and writing in activity patterns with high precision across many neurons, but existing all-optical systems could not both read and write cell-specific firing rates. This work introduced a genetic line of mice for Cre-dependent co-expression of a calcium indicator and a potent soma-targeted microbial opsin. Using that line, it developed a method for reading out and writing in precise population vectors of neural activity by calibrating the photostimulation to each individual cell.
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Precise multimodal optical control of neural ensemble activity
A multiphoton holographic approach was developed to activate or suppress the activity of ensembles of cortical neurons with cellular resolution and sub-millisecond precision. Because existing opsins were inadequate, the work engineered new soma-targeted optogenetic tools, ST-ChroME and IRES-ST-eGtACR1, optimized for multiphoton activation and suppression. Using a three-dimensional all-optical read–write interface, up to 50 neurons distributed in three dimensions across a 550 × 550 × 100 µm³ volume of brain tissue were photostimulated simultaneously, allowing complex neural activity patterns to be synthesized and edited.
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Three-dimensional scanless holographic optogenetics with temporal focusing (3D-SHOT)
Manipulating neural activity with cellular resolution and millisecond precision in three dimensions requires optical methods that existing approaches for targeting individual neurons could not deliver. 3D-SHOT is a multiphoton photo-excitation method that precisely and simultaneously photo-activates arbitrary sets of neurons anywhere within the addressable volume of a microscope, using point-cloud holography to place multiple copies of a temporally focused disc matched to the dimensions of a neuron's cell body. Experiments in cultured cells, brain slices, and living mice demonstrated single-neuron spatial resolution even when targeting randomly distributed groups of neurons in three dimensions.