Bayesian target optimisation for high-precision holographic optogenetics

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Abstract

Two-photon optogenetics has transformed our ability to probe the structure and function of neural circuits. However, achieving precise optogenetic control of neural ensemble activity has remained fundamentally constrained by the problem of off-target stimulation (OTS): the inadvertent activation of nearby non-target neurons due to imperfect confinement of light onto target neurons. Here we propose a novel computational approach to this problem called Bayesian target optimisation. Our approach uses nonparametric Bayesian inference to model neural responses to optogenetic stimulation, and then optimises the laser powers and optical target locations needed to achieve a desired activity pattern with minimal OTS. We validate our approach in simulations and using data from in vitro experiments, showing that Bayesian target optimisation considerably reduces OTS across all conditions we test. Together, these results establish our ability to overcome OTS, enabling optogenetic stimulation with substantially improved precision.

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Most cited references 51

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Cortical layer–specific critical dynamics triggering perception

James H Marshel, Yoon Seok Kim, Timothy A. Machado … (2019)

Perceptual experiences may arise from neuronal activity patterns in mammalian neocortex. We probed mouse neocortex during visual discrimination using a red-shifted channelrhodopsin (ChRmine, discovered through structure-guided genome mining) alongside multiplexed multiphoton-holography (MultiSLM), achieving control of individually-specified neurons spanning large cortical volumes with millisecond precision. Stimulating a critical number of stimulus-orientation-selective neurons drove widespread recruitment of functionally-related neurons, a process enhanced by (but not requiring) orientation-discrimination task learning. Optogenetic targeting of orientation-selective ensembles elicited correct behavioral discrimination. Cortical layer specific-dynamics were apparent, as emergent neuronal activity asymmetrically propagated from layer-2/3 to layer-5, and smaller layer-5 ensembles were as effective as larger layer-2/3 ensembles in eliciting orientation discrimination behavior. Population dynamics emerging after optogenetic stimulation both correctly predicted behavior and resembled natural neural representations of visual stimuli.

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Simultaneous all-optical manipulation and recording of neural circuit activity with cellular resolution in vivo

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We describe an all-optical strategy for simultaneously manipulating and recording the activity of multiple neurons with cellular resolution in vivo. Concurrent two-photon optogenetic activation and calcium imaging is enabled by coexpression of a red-shifted opsin and a genetically encoded calcium indicator. A spatial light modulator allows tens of user-selected neurons to be targeted for spatiotemporally precise optogenetic activation, while simultaneous fast calcium imaging provides high-resolution network-wide readout of the manipulation with negligible optical crosstalk. Proof-of-principle experiments in mouse barrel cortex demonstrate interrogation of the same neuronal population during different behavioral states, and targeting of neuronal ensembles based on their functional signature. This approach extends the optogenetic toolkit beyond the specificity obtained with genetic or viral approaches, enabling high-throughput, flexible and long-term optical interrogation of functionally defined neural circuits with single-cell and single-spike resolution in the mammalian brain in vivo.

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All-Optical Interrogation of Neural Circuits.

V. Emiliani, A COHEN, K Deisseroth … (2015)

There have been two recent revolutionary advances in neuroscience: First, genetically encoded activity sensors have brought the goal of optical detection of single action potentials in vivo within reach. Second, optogenetic actuators now allow the activity of neurons to be controlled with millisecond precision. These revolutions have now been combined, together with advanced microscopies, to allow "all-optical" readout and manipulation of activity in neural circuits with single-spike and single-neuron precision. This is a transformational advance that will open new frontiers in neuroscience research. Harnessing the power of light in the all-optical approach requires coexpression of genetically encoded activity sensors and optogenetic probes in the same neurons, as well as the ability to simultaneously target and record the light from the selected neurons. It has recently become possible to combine sensors and optical strategies that are sufficiently sensitive and cross talk free to enable single-action-potential sensitivity and precision for both readout and manipulation in the intact brain. The combination of simultaneous readout and manipulation from the same genetically defined cells will enable a wide range of new experiments as well as inspire new technologies for interacting with the brain. The advances described in this review herald a future where the traditional tools used for generations by physiologists to study and interact with the brain-stimulation and recording electrodes-can largely be replaced by light. We outline potential future developments in this field and discuss how the all-optical strategy can be applied to solve fundamental problems in neuroscience.

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Author and article information

Journal

Journal ID (nlm-ta): bioRxiv

Journal ID (publisher-id): BIORXIV

Title: bioRxiv

Publisher: Cold Spring Harbor Laboratory

Publication date (Electronic): 26 October 2023

Electronic Location Identifier: 2023.05.25.542307

Affiliations

[1 ]Department of Statistics, Columbia University

[2 ]Zuckerman Mind Brain Behavior Institute, Columbia University

[3 ]Department of Molecular and Cell Biology, UC Berkeley

Author notes

[† ] marcus.triplett@ 123456columbia.edu

Article

DOI: 10.1101/2023.05.25.542307

PMC ID: 10246014

PubMed ID: 37292661

SO-VID: cd17bb9d-33b5-471d-904f-9111ec7bece5

License:

This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.