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130 Publications

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    Svoboda Lab
    10/15/09 | Reverse engineering the mouse brain.
    O’Connor DH, Huber D, Svoboda K
    Nature. 2009 Oct 15;461:923-9. doi: 10.1038/nature08539

    Behaviour is governed by activity in highly structured neural circuits. Genetically targeted sensors and switches facilitate measurement and manipulation of activity in vivo, linking activity in defined nodes of neural circuits to behaviour. Because of access to specific cell types, these molecular tools will have the largest impact in genetic model systems such as the mouse. Emerging assays of mouse behaviour are beginning to rival those of behaving monkeys in terms of stimulus and behavioural control. We predict that the confluence of new behavioural and molecular tools in the mouse will reveal the logic of complex mammalian circuits.

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    Svoboda Lab
    09/01/09 | Experience-dependent structural synaptic plasticity in the mammalian brain.
    Holtmaat A, Svoboda K
    Nature Reviews Neuroscience. 2009 Sep;10(9):647-58. doi: 10.1038/nrn2699

    Synaptic plasticity in adult neural circuits may involve the strengthening or weakening of existing synapses as well as structural plasticity, including synapse formation and elimination. Indeed, long-term in vivo imaging studies are beginning to reveal the structural dynamics of neocortical neurons in the normal and injured adult brain. Although the overall cell-specific morphology of axons and dendrites, as well as of a subpopulation of small synaptic structures, are remarkably stable, there is increasing evidence that experience-dependent plasticity of specific circuits in the somatosensory and visual cortex involves cell type-specific structural plasticity: some boutons and dendritic spines appear and disappear, accompanied by synapse formation and elimination, respectively. This Review focuses on recent evidence for such structural forms of synaptic plasticity in the mammalian cortex and outlines open questions.

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    Svoboda LabPastalkova Lab
    05/30/09 | Enemy avoidance task: a novel behavioral paradigm for assessing spatial avoidance of a moving subject.
    Telensky P, Svoboda J, Pastalkova E, Blahna K, Bures J, Stuchlik A
    Journal of Neuroscience Methods. 2009 May 30;180(1):29-33. doi: 10.1523/JNEUROSCI.3773-10.2011

    Navigation with respect to moving goals represents a useful ability in the everyday life of animals. We have developed a novel behavioral paradigm, "enemy avoidance task", in which a laboratory rat (subject) was trained to avoid another rat (enemy), while searching for small pasta pellets dispensed onto an experimental arena. Whenever the distance between the two animals was smaller than 25 cm, the subject was given a mild electric footshock. The results have shown that rats are capable of avoiding another rat while exploring an environment. Therefore, the enemy avoidance task can be used in electrophysiological, lesion or neuropharmacological studies exploring neuronal substrate coding for egocentric and allocentric positions of an observed animal.

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    Svoboda Lab
    05/14/09 | Subcellular dynamics of type II PKA in neurons.
    Zhong H, Sia G, Sato TR, Gray NW, Mao T, Khuchua Z, Huganir RL, Svoboda K
    Neuron. 2009 May 14;62:363-74. doi: 10.1016/j.neuron.2009.03.013

    Protein kinase A (PKA) plays multiple roles in neurons. The localization and specificity of PKA are largely controlled by A-kinase anchoring proteins (AKAPs). However, the dynamics of PKA in neurons and the roles of specific AKAPs are poorly understood. We imaged the distribution of type II PKA in hippocampal and cortical layer 2/3 pyramidal neurons in vitro and in vivo. PKA was concentrated in dendritic shafts compared to the soma, axons, and dendritic spines. This spatial distribution was imposed by the microtubule-binding protein MAP2, indicating that MAP2 is the dominant AKAP in neurons. Following cAMP elevation, catalytic subunits dissociated from the MAP2-tethered regulatory subunits and rapidly became enriched in nearby spines. The spatial gradient of type II PKA between dendritic shafts and spines was critical for the regulation of synaptic strength and long-term potentiation. Therefore, the localization and activity-dependent translocation of type II PKA are important determinants of PKA function.

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    Svoboda Lab
    05/01/09 | Myosin-dependent targeting of transmembrane proteins to neuronal dendrites.
    Lewis TL, Mao T, Svoboda K, Arnold DB
    Nature Neuroscience. 2009 May;12(5):568-76. doi: 10.1038/nn.2318

    The distinct electrical properties of axonal and dendritic membranes are largely a result of specific transport of vesicle-bound membrane proteins to each compartment. How this specificity arises is unclear because kinesin motors that transport vesicles cannot autonomously distinguish dendritically projecting microtubules from those projecting axonally. We hypothesized that interaction with a second motor might enable vesicles containing dendritic proteins to preferentially associate with dendritically projecting microtubules and avoid those that project to the axon. Here we show that in rat cortical neurons, localization of several distinct transmembrane proteins to dendrites is dependent on specific myosin motors and an intact actin network. Moreover, fusion with a myosin-binding domain from Melanophilin targeted Channelrhodopsin-2 specifically to the somatodendritic compartment of neurons in mice in vivo. Together, our results suggest that dendritic transmembrane proteins direct the vesicles in which they are transported to avoid the axonal compartment through interaction with myosin motors.

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    Svoboda Lab
    03/01/09 | A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale.
    Bohland JW, Wu C, Barbas H, Bokil H, Bota M, Breiter HC, Cline HT, Doyle JC, Freed PJ, Greenspan RJ, Haber SN, Hawrylycz M, Herrera DG, Hilgetag CC, Huang ZJ, Jones A, Jones EG, Karten HJ, Kleinfeld D, Kötter R, Lester HA, Lin JM, Mensh BD, Mikula S, Panksepp J, Price JL, Safdieh J, Saper CB, Schiff ND, Schmahmann JD, Stillman BW, Svoboda K, Swanson LW, Toga AW, Van Essen DC, Watson JD, Mitra PP
    PLoS Computational Biology. 2009 Mar;5(3):e1000334. doi: 10.1371/journal.pcbi.1000334

    In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.

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    Sternson LabSvoboda Lab
    02/26/09 | The subcellular organization of neocortical excitatory connections.
    Petreanu L, Mao T, Sternson SM, Svoboda K
    Nature. 2009 Feb 26;457:1142-5. doi: 10.1038/nature07709

    Understanding cortical circuits will require mapping the connections between specific populations of neurons, as well as determining the dendritic locations where the synapses occur. The dendrites of individual cortical neurons overlap with numerous types of local and long-range excitatory axons, but axodendritic overlap is not always a good predictor of actual connection strength. Here we developed an efficient channelrhodopsin-2 (ChR2)-assisted method to map the spatial distribution of synaptic inputs, defined by presynaptic ChR2 expression, within the dendritic arborizations of recorded neurons. We expressed ChR2 in two thalamic nuclei, the whisker motor cortex and local excitatory neurons and mapped their synapses with pyramidal neurons in layers 3, 5A and 5B (L3, L5A and L5B) in the mouse barrel cortex. Within the dendritic arborizations of L3 cells, individual inputs impinged onto distinct single domains. These domains were arrayed in an orderly, monotonic pattern along the apical axis: axons from more central origins targeted progressively higher regions of the apical dendrites. In L5 arborizations, different inputs targeted separate basal and apical domains. Input to L3 and L5 dendrites in L1 was related to whisker movement and position, suggesting that these signals have a role in controlling the gain of their target neurons. Our experiments reveal high specificity in the subcellular organization of excitatory circuits.

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    Svoboda Lab
    01/29/09 | Rapid functional maturation of nascent dendritic spines.
    Zito K, Scheuss V, Knott G, Hill T, Svoboda K
    Neuron. 2009 Jan 29;61(2):247-58. doi: 10.1016/j.neuron.2008.10.054

    Spine growth and retraction with synapse formation and elimination plays an important role in shaping brain circuits during development and in the adult brain, yet the temporal relationship between spine morphogenesis and the formation of functional synapses remains poorly defined. We imaged hippocampal pyramidal neurons to identify spines of different ages. We then used two-photon glutamate uncaging, whole-cell recording, and Ca(2+) imaging to analyze the properties of nascent spines and their older neighbors. New spines expressed glutamate-sensitive currents that were indistinguishable from mature spines of comparable volumes. Some spines exhibited negligible AMPA receptor-mediated responses, but the occurrence of these "silent" spines was uncorrelated with spine age. In contrast, NMDA receptor-mediated Ca(2+) accumulations were significantly lower in new spines. New spines reconstructed using electron microscopy made synapses. Our data support a model in which outgrowth and enlargement of nascent spines is tightly coupled to formation and maturation of glutamatergic synapses.

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    Svoboda Lab
    12/09/08 | A genetically encoded fluorescent sensor of ERK activity.
    Harvey CD, Ehrhardt AG, Cellurale C, Zhong H, Yasuda R, Davis RJ, Svoboda K
    Proceedings of the National Academy of Sciences of the United States of America. 2008 Dec 9;105(49):19264-9. doi: 10.1073/pnas.0804598105

    The activity of the ERK has complex spatial and temporal dynamics that are important for the specificity of downstream effects. However, current biochemical techniques do not allow for the measurement of ERK signaling with fine spatiotemporal resolution. We developed a genetically encoded, FRET-based sensor of ERK activity (the extracellular signal-regulated kinase activity reporter, EKAR), optimized for signal-to-noise ratio and fluorescence lifetime imaging. EKAR selectively and reversibly reported ERK activation in HEK293 cells after epidermal growth factor stimulation. EKAR signals were correlated with ERK phosphorylation, required ERK activity, and did not report the activities of JNK or p38. EKAR reported ERK activation in the dendrites and nucleus of hippocampal pyramidal neurons in brain slices after theta-burst stimuli or trains of back-propagating action potentials. EKAR therefore permits the measurement of spatiotemporal ERK signaling dynamics in living cells, including in neuronal compartments in intact tissues.

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    Looger LabSvoboda Lab
    08/06/08 | Reporting neural activity with genetically encoded calcium indicators.
    Hires SA, Tian L, Looger LL
    Brain Cell Biology. 2008 Aug 6;36(1-4):69-86. doi: 10.1007/s11068-008-9029-4

    Genetically encoded calcium indicators (GECIs), based on recombinant fluorescent proteins, have been engineered to observe calcium transients in living cells and organisms. Through observation of calcium, these indicators also report neural activity. We review progress in GECI construction and application, particularly toward in vivo monitoring of sparse action potentials (APs). We summarize the extrinsic and intrinsic factors that influence GECI performance. A simple model of GECI response to AP firing demonstrates the relative significance of these factors. We recommend a standardized protocol for evaluating GECIs in a physiologically relevant context. A potential method of simultaneous optical control and recording of neuronal circuits is presented.

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