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2685 Publications

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    07/10/25 | Activity-dependent synapse elimination requires caspase-3 activation
    Yu Z, Gutu A, Kim N, O’Shea EK
    eLife. 2025 Jul 10:. doi: 10.7554/eLife.101779.2

    During brain development, synapses are initially formed in excess and are later eliminated in an activity-dependent manner, with weak synapses being preferentially removed. Previous studies identified glia as mediators of synapse removal, but it is unclear how glia specifically target weak synapses. Here we show that, in the developing mouse visual pathway, inhibiting synaptic transmission induces postsynaptic activation of caspase-3. Caspase-3 is essential for synapse elimination driven by both spontaneous and experience-dependent neural activity. Synapse weakening-induced caspase-3 activation determines the specificity of synapse elimination mediated by microglia but not astrocytes. Furthermore, in a mouse model of Alzheimer’s disease, caspase-3 deficiency protects against synapse loss induced by amyloid-β deposition. Our results reveal caspase-3 activation as a key step in activity-dependent synapse elimination during development and synapse loss in neurodegeneration.

    bioRxiv preprint: https://doi.org/10.1101/2024.08.02.606316

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    06/25/25 | De novo designed bright, hyperstable rhodamine binders for fluorescence microscopy
    Chen Y, Yserentant K, Hong K, Kuang Y, Bhowmick A, Charles-Orszag A, Lord SJ, Lu L, Hou K, Mann SI, Grimm JB, Lavis LD, Mullins RD, DeGrado WF, Huang B
    bioRxiv. 2025 Jun 25:. doi: 10.1101/2025.06.24.661379

    De novo protein design has emerged as a powerful strategy with the promise to create new tools. The practical performance of designed fluorophore binders, however, has remained far from meeting fluorescence microscopy demands. Here, we design de novo Rhodamine Binder (Rhobin) tags that combine ideal properties including size, brightness, and now adding hyperstability. Rhobin allows live and fixed cell imaging of a wide range of subcellular targets in mammalian cells. Its reversible fluorophore binding further enables live super-resolution STED microscopy with low photobleaching, as well as PAINT-type single-molecule localization microscopy. We showcase Rhobin in the extremophile Sulfolobus acidocaldarius living at 75 degrees Celsius, an application previously inaccessible by existing tags. Rhobin will serve as the basis for a new class of live cell fluorescent tags and biosensors.

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    06/25/25 | SLAy-ing oversplitting errors in high-density electrophysiology spike sorting
    Koukuntla S, DeWeese T, Cheng A, Mildren R, Lawrence A, Graves AR, Colonell J, Harris TD, Charles AS
    bioRxiv. 2025 Jun 25:. doi: 10.1101/2025.06.20.660590

    The growing channel count of silicon probes has substantially increased the number of neurons recorded in electrophysiology (ephys) experiments, rendering traditional manual spike sorting impractical. Instead, modern ephys recordings are processed with automated methods that use waveform template matching to isolate putative single neurons. While scalable, automated methods are subject to assumptions that often fail to account for biophysical changes in action potential waveforms, leading to systematic errors. Consequently, manual curation of these errors, which is both time-consuming and lacks reproducibility, remains necessary. To improve efficiency and reproducibility in the spike-sorting pipeline, we introduce here the Spike-sorting Lapse Amelioration System (SLAy), an algorithm that automatically merges oversplit spike clusters. SLAy employs two novel metrics: (1) a waveform similarity metric that uses a neural network to obtain spatially informed, time-shift invariant low-dimensional waveform representations, and (2) a cross-correlogram significance metric based on the earth-movers distance between the observed and null cross-correlograms. We demonstrate that SLAy achieves 85% agreement with human curators across a diverse set of animal models, brain regions, and probe geometries. To illustrate the impact of spike sorting errors on downstream analyses, we develop a new burst-detection algorithm and show that SLAy fixes spike sorting errors that preclude the accurate detection of bursts in neural data. SLAy leverages GPU parallelization and multithreading for computational efficiency, and is compatible with Phy and NeuroData Without Borders, making it a practical and flexible solution for large-scale ephys data analysis.

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    06/23/25 | Large-scale high-density brain-wide neural recording in nonhuman primates.
    Trautmann EM, Hesse JK, Stine GM, Xia R, Zhu S, O'Shea DJ, Karsh B, Colonell J, Lanfranchi FF, Vyas S, Zimnik A, Amematsro E, Steinemann NA, Wagenaar DA, Pachitariu M, Andrei A, Lopez CM, O'Callaghan J, Putzeys J, Raducanu BC, Welkenhuysen M, Churchland M, Moore T, Shadlen M, Shenoy K, Tsao D, Dutta B, Harris T
    Nat Neurosci. 2025 Jun 23:. doi: 10.1038/s41593-025-01976-5

    High-density silicon probes have transformed neuroscience by enabling large-scale neural recordings at single-cell resolution. However, existing technologies have provided limited functionality in nonhuman primates (NHPs) such as macaques. In the present report, we describe the design, fabrication and performance of Neuropixels 1.0 NHP, a high-channel electrode array designed to enable large-scale acute recording throughout large animal brains. The probe features 4,416 recording sites distributed along a 45-mm shank. Experimenters can programmably select 384 recording channels, enabling simultaneous multi-area recording from thousands of neurons with single or multiple probes. This technology substantially increases scalability and recording access relative to existing technologies and enables new classes of experiments that involve electrophysiological mapping of brain areas at single-neuron and single-spike resolution, measurement of spike-spike correlations between cells and simultaneous brain-wide recordings at scale.

     

    Preprint: https://doi.org/10.1101/2023.02.01.526664 

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    06/25/25 | A genetic driver of epileptic encephalopathy impairs gating of synaptic glycolysis
    Koshenov Z, Kokotos AC, Benedetti L, Schwartz JL, Ryan TA
    bioRxiv. 2025 Jun 19:. doi: 10.1101/2025.06.17.660213

    The brain is a disproportionately large consumer of fuel, estimated to expend \~20% of the whole-body energy budget, and therefore it is critical to adequately control brain fuel expenditures while satisfying its on-demand needs for continued function. The brain is also metabolically vulnerable as the inability to adequately fuel cellular processes that support information transfer between cells leads to rapid neurological impairment. We show here that a genetic driver of early onset epileptic encephalopathy (EOEE), SLC13A5, a Na+/citrate cotransporter (NaCT), is critical for gating the activation of local presynaptic glycolysis. We show that SLC13A5 is in part localized to a presynaptic pool of membrane-bound organelles and acts to transiently clear axonal citrate during electrical activity, in turn activating phosphofructokinase 1. We show that loss of SLC13A5 or mistargeting to the plasma membrane results in suppressed glycolytic gating, activity dependent presynaptic bioenergetic deficits and synapse dysfunction.

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    06/19/25 | Sleep need-dependent plasticity of a thalamic circuit promotes homeostatic recovery sleep.
    Lee SS, Liu Q, Cheng AH, Kim DW, Boudreau DM, Mehta A, Keles MF, Fejfer R, Palmer I, Park KH, Münzberg H, Harris TD, Graves AR, Blackshaw S, Wu MN
    Science. 2025 Jun 19;388(6753):eadm8203. doi: 10.1126/science.adm8203

    Prolonged wakefulness leads to persistent, deep recovery sleep (RS). However, the neuronal circuits that mediate this process remain elusive. From a circuit screen in mice, we identified a group of thalamic nucleus reuniens (RE) neurons activated during sleep deprivation (SD) and required for sleep homeostasis. Optogenetic activation of RE neurons leads to an unusual phenotype: presleep behaviors (grooming and nest organizing) followed by prolonged, intense sleep that resembles RS. Inhibiting RE activity during SD impairs subsequent RS, which suggests that these neurons signal sleep need. RE neurons act upstream of sleep-promoting zona incerta cells, and SD triggers plasticity of this circuit to strengthen their connectivity. These findings reveal a circuit mechanism by which sleep need transforms the functional coupling of a sleep circuit to promote persistent, deep sleep.

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    Integrative Imaging
    06/16/25 | Bioimaging Brasil: democratizing in vivo optical microscopy to drive scientific progress across a vast nation.
    Antunes MM, Oliveira AG, de Paula CM, Chew T, Paula-Neto HA, Menezes GB
    Nat Methods. 2025 Jun 16:. doi: 10.1038/s41592-025-02686-3
    06/18/25 | Unsupervised pretraining in biological neural networks
    Lin Zhong , Scott Baptista , Rachel Gattoni , Jon Arnold , Daniel Flickinger , Carsen Stringer , Marius Pachitariu
    Nature. 2025 Jun 18:. doi: 10.1038/s41586-025-09180-y

    Representation learning in neural networks may be implemented with supervised or unsupervised algorithms, distinguished by the availability of instruction. In the sensory cortex, perceptual learning drives neural plasticity1-13, but it is not known whether this is due to supervised or unsupervised learning. Here we recorded populations of up to 90,000 neurons simultaneously from the primary visual cortex (V1) and higher visual areas (HVAs) while mice learned multiple tasks, as well as during unrewarded exposure to the same stimuli. Similar to previous studies, we found that neural changes in task mice were correlated with their behavioural learning. However, the neural changes were mostly replicated in mice with unrewarded exposure, suggesting that the changes were in fact due to unsupervised learning. The neural plasticity was highest in the medial HVAs and obeyed visual, rather than spatial, learning rules. In task mice only, we found a ramping reward-prediction signal in anterior HVAs, potentially involved in supervised learning. Our neural results predict that unsupervised learning may accelerate subsequent task learning, a prediction that we validated with behavioural experiments.

     

    Preprint: https://www.biorxiv.org/content/early/2024/02/27/2024.02.25.581990

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    06/17/25 | Skin health and biological aging.
    Furman D, Auwerx J, Bulteau A, Church G, Couturaud V, Crabbe L, Davies KJ, Decottignies A, Gladyshev VN, Kennedy BK, Neretti N, Nizard C, Pays K, Robinton D, Sebastiano V, Watson RE, Wang MC, Woltjen K
    Nat Aging. 2025 Jun 17:. doi: 10.1038/s43587-025-00901-6

    Accumulating evidence indicates that biological aging can be accelerated by environmental exposures, collectively called the 'exposome'. The skin, as the largest and most exposed organ, can be viewed as a 'window' for the deep exploration of the exposome and its effects on systemic aging. The complex interplay across hallmarks of aging in the skin and systemic biological aging suggests that physiological processes associated with skin aging influence, and are influenced by, systemic hallmarks of aging. This bidirectional relationship provides potential avenues for the prevention of accelerated biological aging and the identification of therapeutic targets. We provide a review of the interactions between skin exposure, aging hallmarks in the skin and associated systemic changes, and their implications in treatment and disease. We also discuss key questions that need to be addressed to maintain skin and overall health, highlighting the need for the development of precise biomarkers and advanced skin models.

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    06/16/25 | A Multimodal Adaptive Optical Microscope For In Vivo Imaging from Molecules to Organisms
    Fu T, Liu G, Milkie DE, Ruan X, Görlitz F, Shi Y, Ferro V, Divekar NS, Wang W, York HM, Kilic V, Mueller M, Liang Y, Daugird TA, Gacha-Garay MJ, Larkin KA, Adikes RC, Harrison N, Shirazinejad C, Williams S, Nourse JL, Sheu S, Gao L, Li T, Mondal C, Achour K, Hercule W, Stabley D, Emmerich K, Dong P, Drubin D, Liu ZJ, Clapham D, Mumm JS, Koyama M, Killilea A, Bravo-Cordero JJ, Keene CD, Luo L, Kirchhausen T, Pathak MM, Arumugam S, Nunez JK, Gao R, Matus DQ, Martin BL, Swinburne IA, Betzig E, Legant WR, Upadhyayula S
    bioRxiv. 2025 Jun 16:. doi: 10.1101/2025.06.02.657494

    Understanding biological systems requires observing features and processes across vast spatial and temporal scales, spanning nanometers to centimeters and milliseconds to days, often using multiple imaging modalities within complex native microenvironments. Yet, achieving this comprehensive view is challenging because microscopes optimized for specific tasks typically lack versatility due to inherent optical and sample handling trade-offs, and frequently suffer performance degradation from sample-induced optical aberrations in multicellular contexts. Here, we present MOSAIC, a reconfigurable microscope that integrates multiple advanced imaging techniques including light-sheet, label-free, super-resolution, and multi-photon, all equipped with adaptive optics. MOSAIC enables non-invasive imaging of subcellular dynamics in both cultured cells and live multicellular organisms, nanoscale mapping of molecular architectures across millimeter-scale expanded tissues, and structural/functional neural imaging within live mice. MOSAIC facilitates correlative studies across biological scales within the same specimen, providing an integrated platform for broad biological investigation.

    Preprint: https://www.biorxiv.org/content/early/2025/06/13/2025.06.02.657494

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