Simultaneous mesoscopic and two-photon imaging of neuronal activity in cortical circuits

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Abstract

Spontaneous and sensory-evoked activity propagates across varying spatial scales in the mammalian cortex, but technical challenges have limited conceptual links between the function of local neuronal circuits and brain-wide network dynamics. We present a method for simultaneous cellular-resolution two-photon calcium imaging of a local microcircuit and mesoscopic widefield calcium imaging of the entire cortical mantle in awake mice. Our multi-scale approach employs an orthogonal axis design where the mesoscopic objective is oriented above the brain and the two-photon objective is oriented horizontally, with imaging performed through a microprism. We also introduce a viral method for robust and widespread gene delivery in the mouse brain. These approaches allow us to identify the behavioral state-dependent functional connectivity of pyramidal neurons and vasoactive intestinal peptide (VIP)-expressing interneurons with long-range cortical networks. Our novel imaging system provides a powerful strategy for investigating cortical architecture across a wide range of spatial scales.

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Further information on research design is available in the Life Sciences Reporting Summary linked to this article.

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Most cited references 52

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A mesoscale connectome of the mouse brain.

Seung Wook Oh, Julie Harris, Lydia Ng … (2014)

Comprehensive knowledge of the brain's wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.

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A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex.

Hiroki Taniguchi, Miao He, Priscilla Wu … (2011)

A key obstacle to understanding neural circuits in the cerebral cortex is that of unraveling the diversity of GABAergic interneurons. This diversity poses general questions for neural circuit analysis: how are these interneuron cell types generated and assembled into stereotyped local circuits and how do they differentially contribute to circuit operations that underlie cortical functions ranging from perception to cognition? Using genetic engineering in mice, we have generated and characterized approximately 20 Cre and inducible CreER knockin driver lines that reliably target major classes and lineages of GABAergic neurons. More select populations are captured by intersection of Cre and Flp drivers. Genetic targeting allows reliable identification, monitoring, and manipulation of cortical GABAergic neurons, thereby enabling a systematic and comprehensive analysis from cell fate specification, migration, and connectivity, to their functions in network dynamics and behavior. As such, this approach will accelerate the study of GABAergic circuits throughout the mammalian brain. Copyright © 2011 Elsevier Inc. All rights reserved.

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Fully integrated silicon probes for high-density recording of neural activity

Matteo Carandini, James Jun, Nicholas Steinmetz … (2017)

Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures. Existing extracellular probes record neural activity with excellent spatial and temporal (sub-millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca2+ imaging offers more coverage but lacks the temporal resolution needed to distinguish individual spikes reliably and does not measure local field potentials. Until now, no technology compatible with use in unrestrained animals has combined high spatiotemporal resolution with large volume coverage. Here we design, fabricate and test a new silicon probe known as Neuropixels to meet this need. Each probe has 384 recording channels that can programmably address 960 complementary metal–oxide–semiconductor (CMOS) processing-compatible low-impedance TiN sites that tile a single 10-mm long, 70 × 20-μm cross-section shank. The 6 × 9-mm probe base is fabricated with the shank on a single chip. Voltage signals are filtered, amplified, multiplexed and digitized on the base, allowing the direct transmission of noise-free digital data from the probe. The combination of dense recording sites and high channel count yielded well-isolated spiking activity from hundreds of neurons per probe implanted in mice and rats. Using two probes, more than 700 well-isolated single neurons were recorded simultaneously from five brain structures in an awake mouse. The fully integrated functionality and small size of Neuropixels probes allowed large populations of neurons from several brain structures to be recorded in freely moving animals. This combination of high-performance electrode technology and scalable chip fabrication methods opens a path towards recording of brain-wide neural activity during behaviour.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101215604

Journal ID (pubmed-jr-id): 32338

Journal ID (nlm-ta): Nat Methods

Journal ID (iso-abbrev): Nat. Methods

Title: Nature methods

ISSN (Print): 1548-7091

ISSN (Electronic): 1548-7105

Publication date Nihms-submitted: 7 October 2019

Publication date (Electronic): 04 November 2019

Publication date (Print): January 2020

Publication date PMC-release: 04 May 2020

Volume: 17

Issue: 1

Pages: 107-113

Affiliations

[1 ]Department of Neuroscience, Yale School of Medicine

[2 ]Interdepartmental Neuroscience Program, Yale School of Medicine

[3 ]MD/PhD Program, Yale School of Medicine

[4 ]Department of Radiology and Biomedical Imaging, Yale School of Medicine

[5 ]Present address: Department of Neurobiology and Behavior, University of California, Irvine

[6 ]Department of Neurosurgery, Yale School of Medicine

[7 ]Kavli Institute for Neuroscience, Yale School of Medicine

[8 ]Department of Ophthalmology and Visual Science, Yale School of Medicine

[9 ]Program in Cellular Neuroscience, Neurodegeneration and Repair

Author notes

[*]

These authors contributed equally

[^]

Co-corresponding authors.

Author Contributions

All authors contributed to overall study design. DB, ASH, JAC collected the data. DB, ASH, XS, JAC analyzed the data. DB, ASH, MCC, and MJH wrote the manuscript. RTC, JAC, MCC, and MJH supervised the project.

To whom correspondence should be addressed: Michael J. Higley, m.higley@ 123456yale.edu , Michael C. Crair, michael.crair@ 123456yale.edu

Article

Manuscript ID: NIHMS1540817

DOI: 10.1038/s41592-019-0625-2

PMC ID: 6946863

PubMed ID: 31686040

SO-VID: 13095701-3c68-47b6-aee0-5ca496c22c5f

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Simultaneous mesoscopic and two-photon imaging of neuronal activity in cortical circuits

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Most cited references 52

A mesoscale connectome of the mouse brain.

A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex.

Fully integrated silicon probes for high-density recording of neural activity

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