Karel Svoboda

Karel Svoboda
Howard Hughes Medical Institute | HHMI · Janelia Farm Research Campus

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237
Publications
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Publications

Publications (237)
Preprint
Cortical neurons exhibit temporally irregular spiking patterns and heterogeneous firing rates. These features arise in model circuits operating in a 'fluctuation-driven regime', in which fluctuations in membrane potentials emerge from the network dynamics. However, it is still unclear whether the cortex operates in this regime. We evaluated the flu...
Article
The brain plans and executes volitional movements. The underlying patterns of neural population activity have been explored in the context of movements of the eyes, limbs, tongue, and head in nonhuman primates and rodents. How do networks of neurons produce the slow neural dynamics that prepare specific movements and the fast dynamics that ultimate...
Preprint
Task-related neural activity is widespread across populations of neurons during goal-directed behaviors. However, little is known about the synaptic reorganization and circuit mechanisms that lead to broad activity changes. Here we trained a limited subset of neurons in a spiking network with strong synaptic interactions to reproduce the activity o...
Article
Motor behaviors are often planned long before execution but only released after specific sensory events. Planning and execution are each associated with distinct patterns of motor cortex activity. Key questions are how these dynamic activity patterns are generated and how they relate to behavior. Here, we investigate the multi-regional neural circu...
Article
Full-text available
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 compu...
Preprint
Full-text available
The ability to optically image cellular transmembrane voltage at millisecond-timescale resolution can offer unprecedented insight into the function of living brains in behaving animals. The chemigenetic voltage indicator Voltron is bright and photostable, making it a favorable choice for long in vivo imaging of neuronal populations at cellular reso...
Preprint
Calcium imaging with protein-based indicators is widely used to follow neural activity in intact nervous systems. The popular GCaMP indicators are based on the calcium-binding protein calmodulin and the RS20 peptide. These sensors report neural activity at timescales much slower than electrical signaling, limited by their biophysical properties and...
Preprint
Full-text available
Calcium imaging with protein-based indicators is widely used to follow neural activity in intact nervous systems. The popular GCaMP indicators are based on the calcium-binding protein calmodulin and the RS20 peptide. These sensors report neural activity at timescales much slower than electrical signaling, limited by their biophysical properties and...
Article
Full-text available
Recently developed probes for extracellular electrophysiological recordings have large numbers of electrodes on long linear shanks. Linear electrode arrays, such as Neuropixels probes, have hundreds of recording electrodes distributed over linear shanks that span several millimeters. Because of the length of the probes, linear probe recordings in r...
Article
Full-text available
Decisions are held in memory until enacted, which makes them potentially vulnerable to distracting sensory input. Gating of information flow from sensory to motor areas could protect memory from interference during decision-making, but the underlying network mechanisms are not understood. Here, we trained mice to detect optogenetic stimulation of t...
Article
Recording many neurons for a long time The ultimate aim of chronic recordings is to sample from the same neuron over days and weeks. However, this goal has been difficult to achieve for large populations of neurons. Steinmetz et al. describe the development and testing of Neuropixels 2.0. This new electrophysiological recording tool is a miniaturiz...
Article
Full-text available
Measuring the dynamics of neural processing across time scales requires following the spiking of thousands of individual neurons over milliseconds and months. To address this need, we introduce the Neuropixels 2.0 probe together with newly designed analysis algorithms. The probe has more than 5000 sites and is miniaturized to facilitate chronic imp...
Article
Full-text available
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...
Preprint
Full-text available
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 E xpansion- As sisted Iterative F luorescence In S itu H ybridization (EASI-FISH) to survey gene expression in brain tissue, as well as a turnkey...
Article
Full-text available
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-pho...
Preprint
Head Post and Cranial Window Outline Janelia Research Campus Svoboda Lab Developed by Karel Svoboda for Trachtenberg et al 2002 Improved by Anthony Holtmaat for Holtmaat et al 2006 and Holtmaat et al 2009 Improved by Daniel Huber for Huber et al 2012 Compiled by Bryan Maclennan (2013), Abridged version by Courtney Davis (2015) Compiled to protocols...
Article
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-pho...
Preprint
Full-text available
To study the dynamics of neural processing across timescales, we require the ability to follow the spiking of thousands of individually separable neurons over weeks and months, during unrestrained behavior. To address this need, we introduce the Neuropixels 2.0 probe together with novel analysis algorithms. The new probe has over 5,000 sites and is...
Article
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...
Article
Full-text available
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 spike...
Preprint
Full-text available
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-pho...
Article
Full-text available
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...
Article
Full-text available
Most cortical synapses are local and excitatory. Local recurrent circuits could implement amplification, allowing pattern completion and other computations1–4. Cortical circuits contain subnetworks that consist of neurons with similar receptive fields and increased connectivity relative to the network average5,6. Cortical neurons that encode differ...
Preprint
Full-text available
Recently developed silicon probes have large numbers of recording electrodes on long linear shanks. Specifically, Neuropixels probes have 960 recording electrodes distributed over 9.6 mm shanks. Because of their length, Neuropixels probe recordings in rodents naturally span multiple brain areas. Typical studies collate recordings across several rec...
Preprint
Decisions about future actions are held in memory until enacted, making them vulnerable to distractors. The neural mechanisms controlling decision robustness to distractors remain unknown. We trained mice to report optogenetic stimulation of somatosensory cortex, with a delay separating sensation and action. Distracting stimuli influenced behavior...
Preprint
Full-text available
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 a low-pass filter, but the effects of the transformation on analyses of neural populations are not well understood. We compared neuronal spikes...
Preprint
Recording well and craniotomy for acute extracellular electrophysiological recordings in head-restrained mice
Article
Full-text available
Optogenetics allows manipulations of genetically and spatially defined neuronal populations with excellent temporal control. However, neurons are coupled with other neurons over multiple length scales, and the effects of localized manipulations thus spread beyond the targeted neurons. We benchmarked several optogenetic methods to inactivate small r...
Article
Full-text available
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 decisio...
Article
Full-text available
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 decisio...
Preprint
Full-text available
The majority of cortical synapses are local and excitatory. Local recurrent circuits could implement amplification, allowing for pattern completion and other computations1. Cortical circuits contain subnetworks, consisting of neurons with similar receptive fields and elevated connectivity relative to the network average2,3. Understanding the comput...
Article
Full-text available
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 decisio...
Preprint
Step-by-step instructions for electrophysiological recordings using multiple Neuropixels probes in head-fixed mice
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Neuronal cell types are the nodes of neural circuits that determine the flow of information within the brain. Neuronal morphology, especially the shape of the axonal arbor, provides an essential descriptor of cell type and reveals how individual neurons route their output across the brain. Despite the importance of morphology, few projection neuron...
Article
In a recent Editorial, De Schutter commented on our recent study on the roles of a cortico-cerebellar loop in motor planning in mice (De Schutter 2019, Neuroinformatics, 17, 181–183, Gao et al. 2018, Nature, 563, 113–116). Two issues were raised. First, De Schutter questions the involvement of the fastigial nucleus in motor planning, rather than th...
Article
Full-text available
Point-scanning two-photon microscopy enables high-resolution imaging within scattering specimens such as the mammalian brain, but sequential acquisition of voxels fundamentally limits its speed. We developed a two-photon imaging technique that scans lines of excitation across a focal plane at multiple angles and computationally recovers high-resolu...
Article
Imaging changes in membrane potential using genetically encoded fluorescent voltage indicators (GEVIs) has great potential for monitoring neuronal activity with high spatial and temporal resolution. Brightness and photostability of fluorescent proteins and rhodopsins have limited the utility of existing GEVIs. We engineered a novel GEVI, “Voltron”,...
Article
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-dep...
Article
Full-text available
Calcium imaging with genetically encoded calcium indicators (GECIs) is routinely used to measure neural activity in intact nervous systems. GECIs are frequently used in one of two different modes: to track activity in large populations of neuronal cell bodies, or to follow dynamics in subcellular compartments such as axons, dendrites and individual...
Preprint
Neuronal inactivation is commonly used to assess the involvement of groups of neurons in specific brain functions. Optogenetic tools allow manipulations of genetically and spatially defined neuronal populations with excellent temporal resolution. However, the targeted neurons are coupled with other neural populations over multiple length scales. As...
Preprint
Short-term memory is associated with persistent neural activity without sustained input, arising from the interactions between neurons with short time constants. A variety of neural circuit motifs could account for measured neural activity. A mechanistic understanding of the neural circuits supporting short-term memory requires probing network conn...
Preprint
Full-text available
Information processing in the neocortex is performed by GABAergic interneurons that are integrated with excitatory neurons into precisely structured circuits. To reveal how each neuron type shapes sensory representations, we measured spikes and membrane potential of specific types of neurons in the barrel cortex while mice performed an active, whis...
Preprint
Full-text available
Neuronal cell types are the nodes of neural circuits that determine the flow of information within the brain. Neuronal morphology, especially the shape of the axonal arbor, provides an essential descriptor of cell type and reveals how individual neurons route their output across the brain. Despite the importance of morphology, few projection neuron...
Article
Full-text available
Short-term memories link events separated in time, such as past sensation and future actions. Short-term memories are correlated with slow neural dynamics, including selective persistent activity, which can be maintained over seconds. In a delayed response task that requires short-term memory, neurons in the mouse anterior lateral motor cortex (ALM...
Article
Full-text available
Animals are not simple input-output machines. Their responses to even very similar stimuli are variable. A key, long-standing question in neuroscience is to understand the neural correlates of such behavioral variability. To reveal these correlates, behavior and neural population activity must be related to one another on single trials. Such analys...
Article
Full-text available
Persistent and ramping neural activity in the frontal cortex anticipates specific movements1–6. Preparatory activity is distributed across several brain regions7,8, but it is unclear which brain areas are involved and how this activity is mediated by multi-regional interactions. The cerebellum is thought to be primarily involved in the short-timesc...
Article
Full-text available
Activity in the motor cortex predicts movements, seconds before they are initiated. This preparatory activity has been observed across cortical layers, including in descending pyramidal tract neurons in layer 5. A key question is how preparatory activity is maintained without causing movement, and is ultimately converted to a motor command to trigg...
Article
Full-text available
The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here we analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. We define 133...
Article
Full-text available
Calcium imaging is commonly used to measure the neural activity of large groups of neurons in mice. Genetically encoded calcium indicators (GECIs) can be delivered for this purpose using non-invasive genetic methods. Compared to viral gene transfer, transgenic targeting of GECIs provides stable long-term expression and obviates the need for invasiv...
Data
Comparison of AAV and Thy1-transgenic labeling patterns. Typical labeling patterns of AAV-mediated expression (left) and Thy1-transgenic expression (GP8.20, right) are shown. AAV-mediated expression is localized around the injection site and exhibits large variability in fluorescence protein expression level. The Thy1-transgenic expression is gener...
Data
Comparison of orientation selectivity index (OSI). OSI indicates the tuning level of a cell to a specific orientation of a drifting grating stimulus. The similar distribution of OSI values for Thy1-jRGECO1a and AAV-jRGECO1a, showed in panel a, and summarized in panel b, indicates that the tuning of the measured cells was not disturbed (Thy1-jRGECO1...
Data
Similar labeling pattern across different mice from the same line. Confocal images of coronal sections from four different GP8.58 mice, taken from the first and second generations of this line (F1 and F2 respectively), show similar labeling patterns. (TIF)
Preprint
Full-text available
The active properties of dendrites support local nonlinear operations, but previous imaging and electrophysiological measurements have produced conflicting views regarding the prevalence 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 mic...
Preprint
Full-text available
Imaging changes in membrane potential using genetically encoded fluorescent voltage indicators (GEVIs) has great potential for monitoring neuronal activity with high spatial and temporal resolution. Brightness and photostability of fluorescent proteins and rhodopsins have limited the utility of existing GEVIs. We engineered a novel GEVI, Voltron, t...
Preprint
Full-text available
Calcium imaging with genetically encoded calcium indicators (GECIs) is routinely used to measure neural activity in intact nervous systems. GECIs are frequently used in one of two different modes: to track activity in large populations of neuronal cell bodies, or to follow dynamics in subcellular compartments such as axons, dendrites and individual...
Article
The anterolateral motor cortex (ALM) and ventromedial (VM) thalamus are functionally linked to support persistent activity during motor planning. We analyzed the underlying synaptic interconnections using optogenetics and electrophysiology in mice (♀/♂). In cortex, thalamocortical (TC) axons from VM excited VM-projecting pyramidal-tract (PT) neuron...