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130 Publications

Showing 11-20 of 130 results
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    Svoboda Lab
    04/06/21 | High-fidelity estimates of spikes and subthreshold waveforms from 1-photon voltage imaging in vivo.
    Xie ME, Adam Y, Fan LZ, Böhm UL, Kinsella I, Zhou D, Rozsa M, Singh A, Svoboda K, Paninski L, Cohen AE
    Cell Reports. 2021 Apr 06;35(1):108954. doi: 10.1016/j.celrep.2021.108954

    The ability to probe the membrane potential of multiple genetically defined neurons simultaneously would have a profound impact on neuroscience research. Genetically encoded voltage indicators are a promising tool for this purpose, and recent developments have achieved a high signal-to-noise ratio in vivo with 1-photon fluorescence imaging. However, these recordings exhibit several sources of noise and signal extraction remains a challenge. We present an improved signal extraction pipeline, spike-guided penalized matrix decomposition-nonnegative matrix factorization (SGPMD-NMF), which resolves supra- and subthreshold voltages in vivo. The method incorporates biophysical and optical constraints. We validate the pipeline with simultaneous patch-clamp and optical recordings from mouse layer 1 in vivo and with simulated and composite datasets with realistic noise. We demonstrate applications to mouse hippocampus expressing paQuasAr3-s or SomArchon1, mouse cortex expressing SomArchon1 or Voltron, and zebrafish spines expressing zArchon1.

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    03/08/21 | Expansion-Assisted Iterative-FISH defines lateral hypothalamus spatio-molecular organization
    Yuhan Wang , Mark Eddison , Greg Fleishman , Martin Weigert , Shengjin Xu , Frederick E. Henry , Tim Wang , Andrew L. Lemire , Uwe Schmidt , Hui Yang , Konrad Rokicki , Cristian Goina , Karel Svoboda , Eugene W. Myers , Stephan Saalfeld , Wyatt Korff , Scott M. Sternson , Paul W. Tillberg
    bioRxiv. 2021 Mar 8:. doi: 10.1101/2021.03.08.434304

    Determining the spatial organization and morphological characteristics of molecularly defined cell types is a major bottleneck for characterizing the architecture underpinning brain function. We developed Expansion-Assisted Iterative Fluorescence In Situ Hybridization (EASI-FISH) to survey gene expression in brain tissue, as well as a turnkey computational pipeline to rapidly process large EASI-FISH image datasets. EASI-FISH was optimized for thick brain sections (300 µm) to facilitate reconstruction of spatio-molecular domains that generalize across brains. Using the EASI-FISH pipeline, we investigated the spatial distribution of dozens of molecularly defined cell types in the lateral hypothalamic area (LHA), a brain region with poorly defined anatomical organization. Mapping cell types in the LHA revealed nine novel spatially and molecularly defined subregions. EASI-FISH also facilitates iterative re-analysis of scRNA-Seq datasets to determine marker-genes that further dissociated spatial and morphological heterogeneity. The EASI-FISH pipeline democratizes mapping molecularly defined cell types, enabling discoveries about brain organization.

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    Svoboda Lab
    01/25/21 | Targeted photostimulation uncovers circuit motifs supporting short-term memory.
    Daie K, Svoboda K, Druckmann S
    Nature Neuroscience. 2021 Jan 25;24(2):259-265. doi: 10.1038/s41593-020-00776-3

    Short-term memory is associated with persistent neural activity that is maintained by positive feedback between neurons. To explore the neural circuit motifs that produce memory-related persistent activity, we measured coupling between functionally characterized motor cortex neurons in mice performing a memory-guided response task. Targeted two-photon photostimulation of small (<10) groups of neurons produced sparse calcium responses in coupled neurons over approximately 100 μm. Neurons with similar task-related selectivity were preferentially coupled. Photostimulation of different groups of neurons modulated activity in different subpopulations of coupled neurons. Responses of stimulated and coupled neurons persisted for seconds, far outlasting the duration of the photostimuli. Photostimuli produced behavioral biases that were predictable based on the selectivity of the perturbed neuronal population, even though photostimulation preceded the behavioral response by seconds. Our results suggest that memory-related neural circuits contain intercalated, recurrently connected modules, which can independently maintain selective persistent activity.

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    Svoboda Lab
    12/01/20 | High throughput instrument to screen fluorescent proteins under two-photon excitation.
    Molina RS, King J, Franklin J, Clack N, McRaven C, Goncharov V, Flickinger D, Svoboda K, Drobizhev M, Hughes TE
    Biomedical Optics Express. 2020 Dec 01;11(12):7192-7203. doi: 10.1364/BOE.409353

    Two-photon microscopy together with fluorescent proteins and fluorescent protein-based biosensors are commonly used tools in neuroscience. To enhance their experimental scope, it is important to optimize fluorescent proteins for two-photon excitation. Directed evolution of fluorescent proteins under one-photon excitation is common, but many one-photon properties do not correlate with two-photon properties. A simple system for expressing fluorescent protein mutants is colonies on an agar plate. The small focal volume of two-photon excitation makes creating a high throughput screen in this system a challenge for a conventional point-scanning approach. We present an instrument and accompanying software that solves this challenge by selectively scanning each colony based on a colony map captured under one-photon excitation. This instrument, called the GIZMO, can measure the two-photon excited fluorescence of 10,000 colonies in 7 hours. We show that the GIZMO can be used to evolve a fluorescent protein under two-photon excitation.

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    Rubin LabSvoboda Lab
    09/17/20 | The mind of a mouse.
    Abbott LF, Bock DD, Callaway EM, Denk W, Dulac C, Fairhall AL, Fiete I, Harris KM, Helmstaedter M, Jain V, Kasthuri N, LeCun Y, Lichtman JW, Littlewood PB, Luo L, Maunsell JH, Reid RC, Rosen BR, Rubin GM, Sejnowski TJ, Seung HS, Svoboda K, Tank DW, Tsao D, Van Essen DC
    Cell. 2020 Sep 17;182(6):1372-1376. doi: 10.1016/j.cell.2020.08.010

    Large scientific projects in genomics and astronomy are influential not because they answer any single question but because they enable investigation of continuously arising new questions from the same data-rich sources. Advances in automated mapping of the brain's synaptic connections (connectomics) suggest that the complicated circuits underlying brain function are ripe for analysis. We discuss benefits of mapping a mouse brain at the level of synapses.

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    Svoboda LabGENIE
    09/15/20 | A comparison of neuronal population dynamics measured with calcium imaging and electrophysiology.
    Wei Z, Lin B, Chen T, Daie K, Svoboda K, Druckmann S
    PLoS Computational Biology. 2020 Sep 15;16(9):e1008198. doi: 10.1371/journal.pcbi.1008198

    Calcium imaging with fluorescent protein sensors is widely used to record activity in neuronal populations. The transform between neural activity and calcium-related fluorescence involves nonlinearities and low-pass filtering, but the effects of the transformation on analyses of neural populations are not well understood. We compared neuronal spikes and fluorescence in matched neural populations in behaving mice. We report multiple discrepancies between analyses performed on the two types of data, including changes in single-neuron selectivity and population decoding. These were only partially resolved by spike inference algorithms applied to fluorescence. To model the relation between spiking and fluorescence we simultaneously recorded spikes and fluorescence from individual neurons. Using these recordings we developed a model transforming spike trains to synthetic-imaging data. The model recapitulated the differences in analyses. Our analysis highlights challenges in relating electrophysiology and imaging data, and suggests forward modeling as an effective way to understand differences between these data.

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    03/04/20 | Recurrent interactions in local cortical circuits.
    Peron S, Pancholi R, Voelcker B, Wittenbach JD, Ólafsdóttir HF, Freeman J, Svoboda K
    Nature. 2020 Mar 04;579(7798):256-59. doi: 10.1038/s41586-020-2062-x

    Most cortical synapses are local and excitatory. Local recurrent circuits could implement amplification, allowing pattern completion and other computations. Cortical circuits contain subnetworks that consist of neurons with similar receptive fields and increased connectivity relative to the network average. Cortical neurons that encode different types of information are spatially intermingled and distributed over large brain volumes, and this complexity has hindered attempts to probe the function of these subnetworks by perturbing them individually. Here we use computational modelling, optical recordings and manipulations to probe the function of recurrent coupling in layer 2/3 of the mouse vibrissal somatosensory cortex during active tactile discrimination. A neural circuit model of layer 2/3 revealed that recurrent excitation enhances sensory signals by amplification, but only for subnetworks with increased connectivity. Model networks with high amplification were sensitive to damage: loss of a few members of the subnetwork degraded stimulus encoding. We tested this prediction by mapping neuronal selectivity and photoablating neurons with specific selectivity. Ablation of a small proportion of layer 2/3 neurons (10-20, less than 5% of the total) representing touch markedly reduced responses in the spared touch representation, but not in other representations. Ablations most strongly affected neurons with stimulus responses that were similar to those of the ablated population, which is also consistent with network models. Recurrence among cortical neurons with similar selectivity therefore drives input-specific amplification during behaviour.

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    03/02/20 | Rapid mesoscale volumetric imaging of neural activity with synaptic resolution.
    Lu R, Liang Y, Meng G, Zhou P, Svoboda K, Paninski L, Ji N
    Nature Methods. 2020 Mar 02;17(3):291-4. doi: 10.1038/s41592-020-0760-9

    Imaging neurons and neural circuits over large volumes at high speed and subcellular resolution is a difficult task. Incorporating a Bessel focus module into a two-photon fluorescence mesoscope, we achieved rapid volumetric imaging of neural activity over the mesoscale with synaptic resolution. We applied the technology to calcium imaging of entire dendritic spans of neurons as well as neural ensembles within multiple cortical regions over two hemispheres of the awake mouse brain.

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    Spruston LabSvoboda Lab
    10/30/19 | Functional clustering of dendritic activity during decision-making.
    Kerlin A, Boaz M, Flickinger D, MacLennan BJ, Dean MB, Davis C, Spruston N, Svoboda K
    Elife. 2019 Oct 30;8:. doi: 10.7554/eLife.46966

    The active properties of dendrites can support local nonlinear operations, but previous imaging and electrophysiological measurements have produced conflicting views regarding the prevalence and selectivity of local nonlinearities in vivo. We imaged calcium signals in pyramidal cell dendrites in the motor cortex of mice performing a tactile decision task. A custom microscope allowed us to image the soma and up to 300 μm of contiguous dendrite at 15 Hz, while resolving individual spines. New analysis methods were used to estimate the frequency and spatial scales of activity in dendritic branches and spines. The majority of dendritic calcium transients were coincident with global events. However, task-associated calcium signals in dendrites and spines were compartmentalized by dendritic branching and clustered within branches over approximately 10 μm. Diverse behavior-related signals were intermingled and distributed throughout the dendritic arbor, potentially supporting a large learning capacity in individual neurons.

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    Svoboda Lab
    10/23/19 | Recruitment of GABAergic interneurons in the barrel cortex during active tactile behavior.
    Yu J, Hu H, Agmon A, Svoboda K
    Neuron. 2019 Oct 23;104(2):412-27. doi: 10.1016/j.neuron.2019.07.027

    Neural computation involves diverse types of GABAergic inhibitory interneurons that are integrated with excitatory (E) neurons into precisely structured circuits. To understand how each neuron type shapes sensory representations, we measured firing patterns of defined types of neurons in the barrel cortex while mice performed an active, whisker-dependent object localization task. Touch excited fast-spiking (FS) interneurons at short latency, followed by activation of E neurons and somatostatin-expressing (SST) interneurons. Touch only weakly modulated vasoactive intestinal polypeptide-expressing (VIP) interneurons. Voluntary whisker movement activated FS neurons in the ventral posteromedial nucleus (VPM) target layers, a subset of SST neurons and a majority of VIP neurons. Together, FS neurons track thalamic input, mediating feedforward inhibition. SST neurons monitor local excitation, providing feedback inhibition. VIP neurons are activated by non-sensory inputs, disinhibiting E and FS neurons. Our data reveal rules of recruitment for interneuron types during behavior, providing foundations for understanding computation in cortical microcircuits.

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