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22 Janelia Publications

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    The prefrontal cortex (PFC)'s functions are thought to include working memory, as its activity can reflect information that must be temporarily maintained to realize the current goal. We designed a flexible spatial working memory task that required rats to navigate - after distractions and a delay - to multiple possible goal locations from different starting points and via multiple routes. This made the current goal location the key variable to remember, instead of a particular direction or route to the goal. However, across a broad population of PFC neurons, we found no evidence of current-goal-specific memory in any previously reported form - that is differences in the rate, sequence, phase, or covariance of firing. This suggests that such patterns do not hold working memory in the PFC when information must be employed flexibly. Instead, the PFC grouped locations representing behaviorally equivalent task features together, consistent with a role in encoding long-term knowledge of task structure.

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    12/07/20 | The claustrum.
    Smith JB, Lee AK, Jackson J
    Current Biology. 2020 Dec 07;30(23):R1401-R1406. doi: 10.1016/j.cub.2020.09.069

    The claustrum is a brain region that has been investigated for over 200 years, yet its precise function remains unknown. In the final posthumously released article of Francis Crick, written with Christof Koch, the claustrum was suggested to be critically linked to consciousness. Though the claustrum remained relatively obscure throughout the last half century, it has enjoyed a renewed interest in the last 15 years since Crick and Koch's article. During this time, the claustrum, like many other brain regions, has been studied with the myriad of modern systems neuroscience tools that have been made available by the intersection of genetic and viral technologies. This has uncovered new information about its anatomical connectivity and physiological properties and begun to reveal aspects of its function. From these studies, one clear consensus has emerged which supports Crick and Koch's primary interest in the claustrum: the claustrum has widespread extensive connectivity with the entire cerebral cortex, suggesting a prominent role in 'higher order processes'.

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    10/29/20 | The Statistical Structure of the Hippocampal Code for Space as a Function of Time, Context, and Value.
    Lee JS, Briguglio JJ, Cohen JD, Romani S, Lee AK
    Cell. 2020 Oct 29;183(3):620-35. doi: 10.1016/j.cell.2020.09.024

    Hippocampal activity represents many behaviorally important variables, including context, an animal's location within a given environmental context, time, and reward. Using longitudinal calcium imaging in mice, multiple large virtual environments, and differing reward contingencies, we derived a unified probabilistic model of CA1 representations centered on a single feature-the field propensity. Each cell's propensity governs how many place fields it has per unit space, predicts its reward-related activity, and is preserved across distinct environments and over months. Propensity is broadly distributed-with many low, and some very high, propensity cells-and thus strongly shapes hippocampal representations. This results in a range of spatial codes, from sparse to dense. Propensity varied ∼10-fold between adjacent cells in salt-and-pepper fashion, indicating substantial functional differences within a presumed cell type. Intracellular recordings linked propensity to cell excitability. The stability of each cell's propensity across conditions suggests this fundamental property has anatomical, transcriptional, and/or developmental origins.

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    10/16/20 | Robotic Multi-Probe-Single-Actuator Inchworm Neural Microdrive
    Smith R, Kolb I, Tanaka S, Lee A, Harris T, Barbic M
    bioRxiv. 2020 Oct 16:

    Electrophysiology is one of the major experimental techniques used in neuroscience. The favorable spatial and temporal resolution as well as the increasingly larger site counts of brain recording electrodes contribute to the popularity and importance of electrophysiology in neuroscience. Such electrodes are typically mechanically placed in the brain to perform acute or chronic freely moving animal measurements. The micro positioners currently used for such tasks employ a single translator per independent probe being placed into the targeted brain region, leading to significant size and weight restrictions. To overcome this limitation, we have developed a miniature robotic multi-probe neural microdrive that utilizes novel phase-change-material-filled resistive heater micro-grippers. The microscopic dimensions, gentle gripping action, independent electronic actuation control, and high packing density of the grippers allow for micrometer-precision independent positioning of multiple arbitrarily shaped parallel neural electrodes with only a single piezo actuator in an inchworm motor configuration. This multi-probe-single-actuator design allows for significant size and weight reduction, as well as remote control and potential automation of the microdrive. We demonstrate accurate placement of multiple independent recording electrodes into the CA1 region of the rat hippocampus in vivo in acute and chronic settings. Thus, our robotic neural microdrive technology is applicable towards basic neuroscience and clinical studies, as well as other multi-probe or multi-sensor micro-positioning applications.

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    07/01/20 | The anatomy and physiology of claustrum-cortex interactions.
    Jackson J, Smith JB, Lee AK
    Annual Review of Neuroscience. 2020 Jul 1;43:231-47. doi: 10.1146/annurev-neuro-092519-101637

    The claustrum is one of the most widely connected regions of the forebrain, yet its function has remained obscure, largely due to the experimentally challenging nature of targeting this small, thin, and elongated brain area. However, recent advances in molecular techniques have enabled the anatomy and physiology of the claustrum to be studied with the spatiotemporal and cell type-specific precision required to eventually converge on what this area does. Here we review early anatomical and electrophysiological results from cats and primates, as well as recent work in the rodent, identifying the connectivity, cell types, and physiological circuit mechanisms underlying the communication between the claustrum and the cortex. The emerging picture is one in which the rodent claustrum is closely tied to frontal/limbic regions and plays a role in processes, such as attention, that are associated with these areas. Expected final online publication date for the , Volume 43 is July 8, 2020. Please see for revised estimates.

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    04/01/19 | Multimodal in vivo brain electrophysiology with integrated glass microelectrodes.
    Hunt DL, Lai C, Smith RD, Lee AK, Harris TD, Barbic M
    Nature Biomedical Engineering. 2019 Apr 01;3(9):741-53. doi: 10.1038/s41551-019-0373-8

    Electrophysiology is the most used approach for the collection of functional data in basic and translational neuroscience, but it is typically limited to either intracellular or extracellular recordings. The integration of multiple physiological modalities for the routine acquisition of multimodal data with microelectrodes could be useful for biomedical applications, yet this has been challenging owing to incompatibilities of fabrication methods. Here, we present a suite of glass pipettes with integrated microelectrodes for the simultaneous acquisition of multimodal intracellular and extracellular information in vivo, electrochemistry assessments, and optogenetic perturbations of neural activity. We used the integrated devices to acquire multimodal signals from the CA1 region of the hippocampus in mice and rats, and show that these data can serve as ground-truth validation for the performance of spike-sorting algorithms. The microdevices are applicable for basic and translational neurobiology, and for the development of next-generation brain-machine interfaces.

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    08/07/18 | Inhibitory control of prefrontal cortex by the claustrum.
    Jackson J, Karnani MM, Zemelman BV, Burdakov D, Lee AK
    Neuron. 2018 Aug 07;99(5):1029-39. doi: 10.1016/j.neuron.2018.07.031

    The claustrum is a small subcortical nucleus that has extensive excitatory connections with many cortical areas. While the anatomical connectivity from the claustrum to the cortex has been studied intensively, the physiological effect and underlying circuit mechanisms of claustrocortical communication remain elusive. Here we show that the claustrum provides strong, widespread, and long-lasting feedforward inhibition of the prefrontal cortex (PFC) sufficient to silence ongoing neural activity. This claustrocortical feedforward inhibition was predominantly mediated by interneurons containing neuropeptide Y, and to a lesser extent those containing parvalbumin. Therefore, in contrast to other long-range excitatory inputs to the PFC, the claustrocortical pathway is designed to provide overall inhibition of cortical activity. This unique circuit organization allows the claustrum to rapidly and powerfully suppress cortical networks and suggests a distinct role for the claustrum in regulating cognitive processes in prefrontal circuits.

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    04/20/18 | Elucidating neuronal mechanisms using intracellular recordings during behavior.
    Lee AK, Brecht M
    Trends in Neurosciences. 2018 Apr 20;41(6):385-403. doi: 10.1016/j.tins.2018.03.014

    Intracellular recording allows measurement and perturbation of the membrane potential of identified neurons with sub-millisecond and sub-millivolt precision. This gives intracellular recordings a unique capacity to provide rich information about individual cells (e.g., high-resolution characterization of inputs, outputs, excitability, and structure). Hence, such recordings can elucidate the mechanisms that underlie fundamental phenomena, such as brain state, sparse coding, gating, gain modulation, and learning. Technical developments have increased the range of behaviors during which intracellular recording methods can be employed, such as in freely moving animals and head-fixed animals actively performing tasks, including in virtual environments. Such advances, and the combination of intracellular recordings with genetic and imaging techniques, have enabled investigation of the mechanisms that underlie neural computations during natural and trained behaviors.

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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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    07/25/17 | Experience-dependent shaping of hippocampal CA1 intracellular activity in novel and familiar environments.
    Cohen JD, Bolstad M, Lee AK
    eLife. 2017 Jul 25;6:. doi: 10.7554/eLife.23040

    The hippocampus is critical for producing stable representations of familiar spaces. How these representations arise is poorly understood, largely because changes to hippocampal inputs have not been measured during spatial learning. Here, using intracellular recording, we monitored inputs and plasticity-inducing complex spikes (CSs) in CA1 neurons while mice explored novel and familiar virtual environments. Inputs driving place field spiking increased in amplitude - often suddenly - during novel environment exploration. However, these increases were not sustained in familiar environments. Rather, the spatial tuning of inputs became increasingly similar across repeated traversals of the environment with experience - both within fields and throughout the whole environment. In novel environments, CSs were not necessary for place field formation. Our findings support a model in which initial inhomogeneities in inputs are amplified to produce robust place field activity, then plasticity refines this representation into one with less strongly modulated, but more stable, inputs for long-term storage.

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