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135 Publications

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    Svoboda Lab
    10/17/18 | A cortico-cerebellar loop for motor planning.
    Gao Z, Davis C, Thomas AM, Economo MN, Abrego AM, Svoboda K, De Zeeuw CI, Li N
    Nature. 2018 Oct 17;563:113-6. doi: 10.1038/s41586-018-0633-x

    Persistent and ramping neural activity in the frontal cortex anticipates specific movements. Preparatory activity is distributed across several brain regions, 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-timescale control of movement; however, roles for this structure in cognitive processes have also been proposed. In humans, cerebellar damage can cause defects in planning and working memory. Here we show that persistent representation of information in the frontal cortex during motor planning is dependent on the cerebellum. Mice performed a sensory discrimination task in which they used short-term memory to plan a future directional movement. A transient perturbation in the medial deep cerebellar nucleus (fastigial nucleus) disrupted subsequent correct responses without hampering movement execution. Preparatory activity was observed in both the frontal cortex and the cerebellar nuclei, seconds before the onset of movement. The silencing of frontal cortex activity abolished preparatory activity in the cerebellar nuclei, and fastigial activity was necessary to maintain cortical preparatory activity. Fastigial output selectively targeted the behaviourally relevant part of the frontal cortex through the thalamus, thus closing a cortico-cerebellar loop. Our results support the view that persistent neural dynamics during motor planning is maintained by neural circuits that span multiple brain regions, and that cerebellar computations extend beyond online motor control.

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    10/11/18 | Thy1 transgenic mice expressing the red fluorescent calcium indicator jRGECO1a for neuronal population imaging in vivo.
    Dana H, Novak O, Guardado-Montesino M, Fransen JW, Hu A, Borghuis BG, Guo C, Kim DS, Svoboda K
    PloS One. 2018;13(10):e0205444. doi: 10.1371/journal.pone.0205444

    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 invasive viral injections. Transgenic mice expressing the green GECI GCaMP6 are already widely used. Here we present the generation and characterization of transgenic mice expressing the sensitive red GECI jRGECO1a, driven by the Thy1 promoter. Four transgenic lines with different expression patterns showed sufficiently high expression for cellular in vivo imaging. We used two-photon microscopy to characterize visual responses of individual neurons in the visual cortex in vivo. The signal-to-noise ratio in transgenic mice was comparable to, or better than, mice transduced with adeno-associated virus. In addition, we show that Thy1-jRGECO1a transgenic mice are useful for transcranial population imaging and functional mapping using widefield fluorescence microscopy. We also demonstrate imaging of visual responses in retinal ganglion cells in vitro. Thy1-jRGECO1a transgenic mice are therefore a useful addition to the toolbox for imaging activity in intact neural networks.

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    10/03/18 | High-performance GFP-based calcium indicators for imaging activity in neuronal populations and microcompartments.
    Dana H, Sun Y, Mohar B, Hulse B, Hasseman JP, Tsegaye G, Tsang A, Wong A, Patel R, Macklin JJ, Chen Y, Konnerth A, Jayaraman V, Looger LL, Schreiter ER, Svoboda K, Kim DS
    bioRxiv. 2018 Oct 3:. doi: 10.1101/434589

    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 synaptic compartments. Despite major advances, calcium imaging is still limited by the biophysical properties of existing GECIs, including affinity, signal-to-noise ratio, rise and decay kinetics, and dynamic range. Using structure-guided mutagenesis and neuron-based screening, we optimized the green fluorescent protein-based GECI GCaMP6 for different modes of in vivo imaging. The jGCaMP7 sensors provide improved detection of individual spikes (jGCaMP7s,f), imaging in neurites and neuropil (jGCaMP7b), and tracking large populations of neurons using 2-photon (jGCaMP7s,f) or wide-field (jGCaMP7c) imaging.

     

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    Svoboda Lab
    08/24/18 | Anterolateral motor cortex connects with a medial subdivision of ventromedial thalamus through cell-type-specific circuits, forming an excitatory thalamo-cortico-thalamic loop via layer 1 apical tuft dendrites of layer 5B pyramidal tract type neurons.
    Guo K, Yamawaki N, Svoboda K, Shepherd GM
    The Journal of Neuroscience : the official journal of the Society for Neuroscience. 2018 Aug 24;38(41):8787-97. doi: 10.1523/JNEUROSCI.1333-18.2018

    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) neurons in layer 5B of ALM. These axons also strongly excited layer 2/3 neurons (which strongly excite PT neurons, as previously shown) but not VM-projecting corticothalamic (CT) neurons in layer 6. The strongest connections in the VM→PT circuit were localized to apical-tuft dendrites of PT neurons, in layer 1. These tuft inputs were selectively augmented after blocking hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. In thalamus, axons from ALM PT neurons excited ALM-projecting VM neurons, located medially in VM. These axons provided weak input to neurons in mediodorsal nucleus, and little or no input either to neurons in the GABAergic reticular thalamic nucleus or to neurons in VM projecting to primary motor cortex (M1). Conversely, M1 PT axons excited M1- but not ALM-projecting VM neurons. Our findings indicate, first, a set of cell-type-specific connections forming an excitatory thalamo-cortico-thalamic (T-C-T) loop for ALM↔VM communication and a circuit-level substrate for supporting reverberant activity in this system. Second, a key feature of this loop is the prominent involvement of layer 1 synapses onto apical dendrites, a subcellular compartment with distinct signaling properties, including HCN-mediated gain control. Third, the segregation of the ALM↔VM loop from M1-related circuits of VM adds cellular-level support for the concept of parallel pathway organization in the motor system.Anterolateral motor cortex (ALM), a higher-order motor area in the mouse, and ventromedial thalamus (VM) are anatomically and functionally linked, but their synaptic interconnections at the cellular level are unknown. Our results show that ALM pyramidal tract neurons monosynaptically excite ALM-projecting thalamocortical neurons in a medial subdivision of VM, and vice versa. The thalamo-cortico-thalamic loop formed by these recurrent connections constitutes a circuit-level substrate for supporting reverberant activity in this system.

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    Svoboda Lab
    06/04/18 | Motor control: three-dimensional metric of head movements in the mouse brain.
    Finkelstein A
    Current Biology : CB. 2018 Jun 04;28(11):R660-R662. doi: 10.1016/j.cub.2018.04.079

    Many forms of human and animal behavior involve head movements. A new study reveals the neural code for three-dimensional head movements in the midbrain of freely moving mice.

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    Svoboda Lab
    04/18/18 | Genetic dissection of neural circuits: a decade of progress
    Luo L, Callaway EM, Svoboda K
    Neuron. 2018 Apr 18;98(2):256-81. doi: 10.1016/j.neuron.2018.03.040

    Tremendous progress has been made since Neuron published our Primer on genetic dissection of neural circuits 10 years ago. Since then, cell-type-specific anatomical, neurophysiological, and perturbation studies have been carried out in a multitude of invertebrate and vertebrate organisms, linking neurons and circuits to behavioral functions. New methods allow systematic classification of cell types and provide genetic access to diverse neuronal types for studies of connectivity and neural coding during behavior. Here we evaluate key advances over the past decade and discuss future directions.

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    Romani LabSvoboda LabDruckmann Lab
    04/25/18 | Low-dimensional and monotonic preparatory activity in mouse anterior lateral motor cortex.
    Inagaki HK, Inagaki M, Romani S, Svoboda K
    The Journal of Neuroscience : the official journal of the Society for Neuroscience. 2018 Apr 25;38(17):4163-85. doi: 10.1523/JNEUROSCI.3152-17.2018

    Neurons in multiple brain regions fire trains of action potentials anticipating specific movements, but this 'preparatory activity' has not been systematically compared across behavioral tasks. We compared preparatory activity in auditory and tactile delayed-response tasks in male mice. Skilled, directional licking was the motor output. The anterior lateral motor cortex (ALM) is necessary for motor planning in both tasks. Multiple features of ALM preparatory activity during the delay epoch were similar across tasks. First, majority of neurons showed direction-selective activity and spatially intermingled neurons were selective for either movement direction. Second, many cells showed mixed coding of sensory stimulus and licking direction, with a bias toward licking direction. Third, delay activity was monotonic and low-dimensional. Fourth, pairs of neurons with similar direction selectivity showed high spike-count correlations. Our study forms the foundation to analyze the neural circuit mechanisms underlying preparatory activity in a genetically tractable model organism.Short-term memories link events separated in time. Neurons in frontal cortex fire trains of action potentials anticipating specific movements, often seconds before the movement. This 'preparatory activity' has been observed in multiple brain regions, but has rarely been compared systematically across behavioral tasks in the same brain region. To identify common features of preparatory activity, we developed and compared preparatory activity in auditory and tactile delayed-response tasks in mice. The same cortical area is necessary for both tasks. Multiple features of preparatory activity, measured with high-density silicon probes, were similar across tasks. We find that preparatory activity is low-dimensional and monotonic. Our study forms the foundation to analyze the circuit mechanisms underlying preparatory activity in a genetically tractable model organism.

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    Svoboda Lab
    03/27/18 | Dynamic cues for whisker-based object localization: An analytical solution to vibration during active whisker touch.
    Vaxenburg R, Wyche I, Svoboda K, Efros AL, Hires SA
    PLoS Computational Biology. 2018 Mar 27;14(3):e1006032. doi: 10.1371/journal.pcbi.1006032

    Vibrations are important cues for tactile perception across species. Whisker-based sensation in mice is a powerful model system for investigating mechanisms of tactile perception. However, the role vibration plays in whisker-based sensation remains unsettled, in part due to difficulties in modeling the vibration of whiskers. Here, we develop an analytical approach to calculate the vibrations of whiskers striking objects. We use this approach to quantify vibration forces during active whisker touch at a range of locations along the whisker. The frequency and amplitude of vibrations evoked by contact are strongly dependent on the position of contact along the whisker. The magnitude of vibrational shear force and bending moment is comparable to quasi-static forces. The fundamental vibration frequencies are in a detectable range for mechanoreceptor properties and below the maximum spike rates of primary sensory afferents. These results suggest two dynamic cues exist that rodents can use for object localization: vibration frequency and comparison of vibrational to quasi-static force magnitude. These complement the use of quasi-static force angle as a distance cue, particularly for touches close to the follicle, where whiskers are stiff and force angles hardly change during touch. Our approach also provides a general solution to calculation of whisker vibrations in other sensing tasks.

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    Svoboda Lab
    11/20/17 | Neural mechanisms of movement planning: motor cortex and beyond.
    Svoboda K, Li N
    Current Opinion in Neurobiology. 2017 Nov 20;49:33-41. doi: 10.1016/j.conb.2017.10.023

    Neurons in motor cortex and connected brain regions fire in anticipation of specific movements, long before movement occurs. This neural activity reflects internal processes by which the brain plans and executes volitional movements. The study of motor planning offers an opportunity to understand how the structure and dynamics of neural circuits support persistent internal states and how these states influence behavior. Recent advances in large-scale neural recordings are beginning to decipher the relationship of the dynamics of populations of neurons during motor planning and movements. New behavioral tasks in rodents, together with quantified perturbations, link dynamics in specific nodes of neural circuits to behavior. These studies reveal a neural network distributed across multiple brain regions that collectively supports motor planning. We review recent advances and highlight areas where further work is needed to achieve a deeper understanding of the mechanisms underlying motor planning and related cognitive processes.

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    11/08/17 | Fully integrated silicon probes for high-density recording of neural activity.
    Jun JJ, Steinmetz NA, Siegle JH, Denman DJ, Bauza M, Barbarits B, Lee AK, Anastassiou CA, Andrei A, Aydın Ç, Barbic M, Blanche TJ, Bonin V, Couto J, Dutta B, Gratiy SL, Gutnisky DA, Häusser M, Karsh B, Ledochowitsch P, Lopez CM, Mitelut C, Musa S, Okun M, Pachitariu M, Putzeys J, Rich PD, Rossant C, Sun W, Svoboda K, Carandini M, Harris KD, Koch C, O'Keefe J, Harris TD
    Nature. 2017 Nov 08;551(7679):232-236. doi: 10.1038/nature24636

    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 Ca(2+) 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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