High-density multi-fiber photometry for studying large-scale brain circuit dynamics

Animal behavior originates from neuronal activity distributed across brain-wide networks. However, techniques available to assess large-scale neural dynamics in behaving animals remain limited. Here we present compact, chronically implantable, high-density arrays of optical fibers that enable multi-fiber photometry and optogenetic perturbations across many regions in the mammalian brain. In mice engaged in a texture discrimination task, we achieved simultaneous photometric calcium recordings from networks of 12–48 brain regions, including striatal, thalamic, hippocampal and cortical areas. Furthermore, we optically perturbed subsets of regions in VGAT-ChR2 mice by targeting specific fiber channels with a spatial light modulator. Perturbation of ventral thalamic nuclei caused distributed network modulation and behavioral deficits. Finally, we demonstrate multi-fiber photometry in freely moving animals, including simultaneous recordings from two mice during social interaction. High-density multi-fiber arrays are versatile tools for the investigation of large-scale brain dynamics during behavior.High-density arrays of optical fibers enable monitoring and manipulation of neural activity at large scale across many brain regions. The multi-fiber arrays can be used in head-fixed tasks, in freely behaving animals and during social interactions.

[1]  Edward M. Callaway,et al.  Genetic Dissection of Neural Circuits: A Decade of Progress. , 2018, Neuron.

[2]  Bernardo L. Sabatini,et al.  Silk Fibroin Films Facilitate Single-Step Targeted Expression of Optogenetic Proteins , 2018, Cell reports.

[3]  Benjamin F. Grewe,et al.  Visualizing mammalian brain area interactions by dual-axis two-photon calcium imaging , 2015, 2015 Conference on Lasers and Electro-Optics (CLEO).

[4]  Karl Deisseroth,et al.  Optetrode: a multichannel readout for optogenetic control in freely moving mice , 2011, Nature Neuroscience.

[5]  Dongmin Lee,et al.  A calcium- and light-gated switch to induce gene expression in activated neurons , 2017, Nature Biotechnology.

[6]  Jessica A. Cardin,et al.  Optical neural interfaces. , 2014, Annual review of biomedical engineering.

[7]  M. Fink,et al.  Functional ultrasound imaging of the brain , 2011, Nature Methods.

[8]  Misha B. Ahrens,et al.  Visualizing Whole-Brain Activity and Development at the Single-Cell Level Using Light-Sheet Microscopy , 2015, Neuron.

[9]  Ranulfo Romo,et al.  Local domains of motor cortical activity revealed by fiber-optic calcium recordings in behaving nonhuman primates , 2013, Proceedings of the National Academy of Sciences.

[10]  F. Helmchen,et al.  Simultaneous BOLD fMRI and fiber-optic calcium recording in rat neocortex , 2012, Nature Methods.

[11]  Stefan R. Pulver,et al.  Ultra-sensitive fluorescent proteins for imaging neuronal activity , 2013, Nature.

[12]  Stefano Panzeri,et al.  Open Source Tools for the Information Theoretic Analysis of Neural Data , 2009, Frontiers in neuroscience.

[13]  Misha B. Ahrens,et al.  Labeling of active neural circuits in vivo with designed calcium integrators , 2015, Science.

[14]  Allan R. Jones,et al.  A mesoscale connectome of the mouse brain , 2014, Nature.

[15]  Nicholas A. Steinmetz,et al.  Diverse coupling of neurons to populations in sensory cortex , 2015, Nature.

[16]  Mohamed S. Emara,et al.  Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber , 2017, Nature Neuroscience.

[17]  G. Feng,et al.  Cell type–specific channelrhodopsin-2 transgenic mice for optogenetic dissection of neural circuitry function , 2011, Nature Methods.

[18]  Jeffrey N. Stirman,et al.  Wide field-of-view, multi-region two-photon imaging of neuronal activity in the mammalian brain , 2016, Nature Biotechnology.

[19]  Pierre J Magistretti,et al.  In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons. , 2016, Cell metabolism.

[20]  A. Nimmerjahn,et al.  Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors , 2018, Science.

[21]  Jessica A. Cardin,et al.  Noninvasive optical inhibition with a red-shifted microbial rhodopsin , 2014, Nature Neuroscience.

[22]  Michael Z. Lin,et al.  Cell-Type-Specific Optical Recording of Membrane Voltage Dynamics in Freely Moving Mice , 2016, Cell.

[23]  Shaoqun Zeng,et al.  Multi-channel fiber photometry for population neuronal activity recording. , 2015, Biomedical optics express.

[24]  O. Garaschuk,et al.  Cortical calcium waves in resting newborn mice , 2005, Nature Neuroscience.

[25]  F. Helmchen,et al.  Behaviour-dependent recruitment of long-range projection neurons in somatosensory cortex , 2013, Nature.

[26]  Mikhail Drobizhev,et al.  Deciphering the molecular mechanism responsible for GCaMP6m's Ca2+-dependent change in fluorescence , 2017, PloS one.

[27]  G. Feng,et al.  Cell-type Specific Optogenetic Mice for Dissecting Neural Circuitry Function , 2011, Nature methods.

[28]  Aileen Schroeter,et al.  Fiber-optic implant for simultaneous fluorescence-based calcium recordings and BOLD fMRI in mice , 2018, Nature Protocols.

[29]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[30]  T. Murphy,et al.  In vivo Large-Scale Cortical Mapping Using Channelrhodopsin-2 Stimulation in Transgenic Mice Reveals Asymmetric and Reciprocal Relationships between Cortical Areas , 2012, Front. Neural Circuits.

[31]  A. Seth,et al.  Granger Causality Analysis in Neuroscience and Neuroimaging , 2015, The Journal of Neuroscience.

[32]  Robert Langer,et al.  Subcellular probes for neurochemical recording from multiple brain sites. , 2017, Lab on a chip.

[33]  Talia N. Lerner,et al.  Simultaneous fast measurement of circuit dynamics at multiple sites across the mammalian brain , 2016, Nature Methods.

[34]  Mitra Javadzadeh,et al.  Long-range population dynamics of anatomically defined neocortical networks , 2016, eLife.

[35]  Edward M. Reingold,et al.  Graph drawing by force‐directed placement , 1991, Softw. Pract. Exp..

[36]  Max A. Viergever,et al.  elastix: A Toolbox for Intensity-Based Medical Image Registration , 2010, IEEE Transactions on Medical Imaging.

[37]  Tsai-Wen Chen,et al.  A Map of Anticipatory Activity in Mouse Motor Cortex , 2017, Neuron.

[38]  Markus Siegel,et al.  Cortical information flow during flexible sensorimotor decisions , 2015, Science.

[39]  G. Buzsáki,et al.  Monolithically Integrated μLEDs on Silicon Neural Probes for High-Resolution Optogenetic Studies in Behaving Animals , 2015, Neuron.

[40]  Andrew C. N. Chen,et al.  Mapping cortical mesoscopic networks of single spiking cortical or sub-cortical neurons , 2017, eLife.

[41]  Kevin J Mann,et al.  Whole-Brain Calcium Imaging Reveals an Intrinsic Functional Network in Drosophila , 2017, Current Biology.

[42]  Scott T. Grafton,et al.  Dynamic reconfiguration of human brain networks during learning , 2010, Proceedings of the National Academy of Sciences.

[43]  William E. Allen,et al.  Global Representations of Goal-Directed Behavior in Distinct Cell Types of Mouse Neocortex , 2017, Neuron.

[44]  F. Helmchen,et al.  Behavioral Strategy Determines Frontal or Posterior Location of Short-Term Memory in Neocortex , 2018, Neuron.

[45]  Srinivas C. Turaga,et al.  Mapping social behavior-induced brain activation at cellular resolution in the mouse. , 2014, Cell reports.

[46]  M. Larkum,et al.  Frontiers in Neural Circuits Neural Circuits Methods Article , 2022 .

[47]  K. Svoboda,et al.  A large field of view two-photon mesoscope with subcellular resolution for in vivo imaging , 2016, bioRxiv.

[48]  Paul G Anastasiades,et al.  Reciprocal Circuits Linking the Prefrontal Cortex with Dorsal and Ventral Thalamic Nuclei , 2018, Neuron.

[49]  Sergey L. Gratiy,et al.  Fully integrated silicon probes for high-density recording of neural activity , 2017, Nature.

[50]  John A Rogers,et al.  Wireless optoelectronic photometers for monitoring neuronal dynamics in the deep brain , 2018, Proceedings of the National Academy of Sciences.

[51]  Raag D. Airan,et al.  Natural Neural Projection Dynamics Underlying Social Behavior , 2014, Cell.

[52]  Steven S. Vogel,et al.  Concurrent Activation of Striatal Direct and Indirect Pathways During Action Initiation , 2013, Nature.

[53]  E. Boyden,et al.  Simultaneous whole-animal 3D-imaging of neuronal activity using light-field microscopy , 2014, Nature Methods.

[54]  D. Joel,et al.  The organization of the basal ganglia-thalamocortical circuits: Open interconnected rather than closed segregated , 1994, Neuroscience.

[55]  Colin Studholme,et al.  An overlap invariant entropy measure of 3D medical image alignment , 1999, Pattern Recognit..

[56]  A. Gamal,et al.  Miniaturized integration of a fluorescence microscope , 2011, Nature Methods.

[57]  Valentina Emiliani,et al.  Towards circuit optogenetics , 2018, Current Opinion in Neurobiology.

[58]  Dae-Shik Kim,et al.  Global and local fMRI signals driven by neurons defined optogenetically by type and wiring , 2010, Nature.

[59]  Paul H. E. Tiesinga,et al.  The Scalable Brain Atlas: Instant Web-Based Access to Public Brain Atlases and Related Content , 2013, Neuroinformatics.

[60]  Nathan C. Klapoetke,et al.  Transgenic Mice for Intersectional Targeting of Neural Sensors and Effectors with High Specificity and Performance , 2015, Neuron.

[61]  Fritjof Helmchen,et al.  Functional Imaging of Dentate Granule Cells in the Adult Mouse Hippocampus , 2016, The Journal of Neuroscience.