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54 Publications

Showing 1-10 of 54 results
05/10/24 | Imaging the extracellular matrix in live tissues and organisms with a glycan-binding fluorophore
Fiore A, Yu G, Northey JJ, Patel R, Ravenscroft TA, Ikegami R, Kolkman W, Kumar P, Grimm JB, Dilan TL, Ruetten VM, Ahrens MB, Shroff H, Lavis LD, Wang S, Weaver VM, Pedram K
bioRxiv. 2024 May 10:. doi: 10.1101/2024.05.09.593460

All multicellular systems produce and dynamically regulate extracellular matrices (ECM) that play important roles in both biochemical and mechanical signaling. Though the spatial arrangement of these extracellular assemblies is critical to their biological functions, visualization of ECM structure is challenging, in part because the biomolecules that compose the ECM are difficult to fluorescently label individually and collectively. Here, we present a cell-impermeable small molecule fluorophore, termed Rhobo6, that turns on and red shifts upon reversible binding to glycans. Given that most ECM components are densely glycosylated, the dye enables wash-free visualization of ECM, in systems ranging from in vitro substrates to in vivo mouse mammary tumors. Relative to existing techniques, Rhobo6 provides a broad substrate profile, superior tissue penetration, nonperturbative labeling, and negligible photobleaching. This work establishes a straightforward method for imaging the distribution of ECM in live tissues and organisms, lowering barriers for investigation of extracellular biology.

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05/07/24 | Fast, Accurate, and Versatile Data Analysis Platform for the Quantification of Molecular Spatiotemporal Signals
Xuelong Mi , Alex Bo-Yuan Chen , Daniela Duarte , Erin Carey , Charlotte R. Taylor , Philipp N. Braaker , Mark Bright , Rafael G. Almeida , Jing-Xuan Lim , Virginia M. Rutten , Wei Zheng , Mengfan Wang , Michael E. Reitman , Yizhi Wang , Kira E. Poskanzer , David A. Lyons , Axel Nimmerjahn , Misha B. Ahrens , Guoqiang Yu
bioRxiv. 2024 May 07:. doi: 10.1101/2024.05.02.592259

Optical recording of intricate molecular dynamics is becoming an indispensable technique for biological studies, accelerated by the development of new or improved biosensors and microscopy technology. This creates major computational challenges to extract and quantify biologically meaningful patterns embedded within complex and rich data sources. Here, we introduce Activity Quantification and Analysis (AQuA2), a fast, accurate and versatile data analysis platform built upon advanced machine learning techniques. It decomposes complex live imaging-based datasets into elementary signaling events, allowing accurate and unbiased quantification of molecular activities and identification of consensus functional units. We demonstrate applications across a range of biosensors (calcium, norepinephrine, ATP, acetylcholine, dopamine), cell types (astrocytes, oligodendrocytes, microglia, neurons), organs (brains and spinal cords), animal models (zebrafish and mouse), and imaging modalities (confocal, two-photon, light sheet). As exemplar findings, we show how AQuA2 identified drug-dependent interactions between neurons and astroglia, and distinct sensorimotor signal propagation patterns in the mouse spinal cord.

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03/20/24 | Motor neurons generate pose-targeted movements via proprioceptive sculpting.
Gorko B, Siwanowicz I, Close K, Christoforou C, Hibbard KL, Kabra M, Lee A, Park J, Li SY, Chen AB, Namiki S, Chen C, Tuthill JC, Bock DD, Rouault H, Branson K, Ihrke G, Huston SJ
Nature. 2024 Mar 20:. doi: 10.1038/s41586-024-07222-5

Motor neurons are the final common pathway through which the brain controls movement of the body, forming the basic elements from which all movement is composed. Yet how a single motor neuron contributes to control during natural movement remains unclear. Here we anatomically and functionally characterize the individual roles of the motor neurons that control head movement in the fly, Drosophila melanogaster. Counterintuitively, we find that activity in a single motor neuron rotates the head in different directions, depending on the starting posture of the head, such that the head converges towards a pose determined by the identity of the stimulated motor neuron. A feedback model predicts that this convergent behaviour results from motor neuron drive interacting with proprioceptive feedback. We identify and genetically suppress a single class of proprioceptive neuron that changes the motor neuron-induced convergence as predicted by the feedback model. These data suggest a framework for how the brain controls movements: instead of directly generating movement in a given direction by activating a fixed set of motor neurons, the brain controls movements by adding bias to a continuing proprioceptive-motor loop.

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12/29/23 | Ketamine modulates a norepinephrine-astroglial circuit to persistently suppress futility-induced passivity.
Marc Duque , Alex B. Chen , Eric Hsu , Sujatha Narayan , Altyn Rymbek , Shahinoor Begum , Gesine Saher , Adam E. Cohen , David E. Olson , David A. Prober , Dwight E. Bergles , Mark C. Fishman , Florian Engert , Misha B. Ahrens
bioRxiv. 2023 Dec 29:. doi: 10.1101/2022.12.29.522099

Mood-altering compounds hold promise for the treatment of many psychiatric disorders, such as depression, but connecting their molecular, circuit, and behavioral effects has been challenging. Here we find that, analogous to effects in rodent learned helplessness models, ketamine pre-exposure persistently suppresses futility-induced passivity in larval zebrafish. While antidepressants are thought to primarily act on neurons, brain-wide imaging in behaving zebrafish showed that ketamine elevates intracellular calcium in astroglia for many minutes, followed by persistent calcium downregulation post-washout. Calcium elevation depends on astroglial α1-adrenergic receptors and is required for suppression of passivity. Chemo-/optogenetic perturbations of noradrenergic neurons and astroglia demonstrate that the aftereffects of glial calcium elevation are sufficient to suppress passivity by inhibiting neuronal-astroglial integration of behavioral futility. Imaging in mouse cortex reveals that ketamine elevates astroglial calcium through conserved pathways, suggesting that ketamine exerts its behavioral effects by persistently modulating evolutionarily ancient neuromodulatory systems spanning neurons and astroglia.

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03/24/23 | Time-resolved correlation of distributed brain activity tracks E-I balance and accounts for diverse scale-free phenomena.
Nanda A, Johnson GW, Mu Y, Ahrens MB, Chang C, Englot DJ, Breakspear M, Rubinov M
Cell Reports. 2023 Mar 24;42(4):112254. doi: 10.1016/j.celrep.2023.112254

Much of systems neuroscience posits the functional importance of brain activity patterns that lack natural scales of sizes, durations, or frequencies. The field has developed prominent, and sometimes competing, explanations for the nature of this scale-free activity. Here, we reconcile these explanations across species and modalities. First, we link estimates of excitation-inhibition (E-I) balance with time-resolved correlation of distributed brain activity. Second, we develop an unbiased method for sampling time series constrained by this time-resolved correlation. Third, we use this method to show that estimates of E-I balance account for diverse scale-free phenomena without need to attribute additional function or importance to these phenomena. Collectively, our results simplify existing explanations of scale-free brain activity and provide stringent tests on future theories that seek to transcend these explanations.

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03/15/23 | Fast and sensitive GCaMP calcium indicators for imaging neural populations.
Zhang Y, Rozsa M, Liang Y, Bushey D, Wei Z, Zheng J, Reep D, Broussard GJ, Tsang A, Tsegaye G, Narayan S, Obara CJ, Lim J, Patel R, Zhang R, Ahrens MB, Turner GC, Wang SS, Korff WL, Schreiter ER, Svoboda K, Hasseman JP, Kolb I, Looger LL
Nature. 2023 Mar 15:. doi: 10.1038/s41586-023-05828-9

Calcium imaging with protein-based indicators is widely used to follow neural activity in intact nervous systems, but current protein sensors report neural activity at timescales much slower than electrical signalling and are limited by trade-offs between sensitivity and kinetics. Here we used large-scale screening and structure-guided mutagenesis to develop and optimize several fast and sensitive GCaMP-type indicators. The resulting 'jGCaMP8' sensors, based on the calcium-binding protein calmodulin and a fragment of endothelial nitric oxide synthase, have ultra-fast kinetics (half-rise times of 2 ms) and the highest sensitivity for neural activity reported for a protein-based calcium sensor. jGCaMP8 sensors will allow tracking of large populations of neurons on timescales relevant to neural computation.

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01/01/23 | Dimensionality reduction of calcium-imaged neuronal population activity
Tze Hui Koh , William E. Bishop , Takashi Kawashima , Brian B. Jeon , Ranjani Srinivasan , Sandra J. Kuhlman , Misha B. Ahrens , Steven M. Chase , Byron M. Yu
Nature Computational Science. 2023 Jan 01:. doi: 10.1038/s43588-022-00390-2

Calcium imaging has been widely adopted for its ability to record from large neuronal populations. To summarize the time course of neural activity, dimensionality reduction methods, which have been applied extensively to population spiking activity, may be particularly useful. However, it is unclear if the dimensionality reduction methods applied to spiking activity are appropriate for calcium imaging. We thus carried out a systematic study of design choices based on standard dimensionality reduction methods. We also developed a novel method to perform deconvolution and dimensionality reduction simultaneously (termed CILDS). CILDS most accurately recovered the single-trial, low-dimensional time courses from calcium imaging that would have been recovered from spiking activity. CILDS also outperformed the other methods on calcium imaging recordings from larval zebrafish and mice. More broadly, this study represents a foundation for summarizing calcium imaging recordings of large neuronal populations using dimensionality reduction in diverse experimental settings.

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12/22/22 | A brainstem integrator for self-localization and positional homeostasis
Yang E, Zwart MF, Rubinov M, James B, Wei Z, Narayan S, Vladimirov N, Mensh BD, Fitzgerald JE, Ahrens MB
Cell. 2022 Dec 22;185(26):5011-5027.e20. doi: 10.1101/2021.11.26.468907

To accurately track self-location, animals need to integrate their movements through space. In amniotes, representations of self-location have been found in regions such as the hippocampus. It is unknown whether more ancient brain regions contain such representations and by which pathways they may drive locomotion. Fish displaced by water currents must prevent uncontrolled drift to potentially dangerous areas. We found that larval zebrafish track such movements and can later swim back to their earlier location. Whole-brain functional imaging revealed the circuit enabling this process of positional homeostasis. Position-encoding brainstem neurons integrate optic flow, then bias future swimming to correct for past displacements by modulating inferior olive and cerebellar activity. Manipulation of position-encoding or olivary neurons abolished positional homeostasis or evoked behavior as if animals had experienced positional shifts. These results reveal a multiregional hindbrain circuit in vertebrates for optic flow integration, memory of self-location, and its neural pathway to behavior.Competing Interest StatementThe authors have declared no competing interest.

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10/31/22 | FourierNets enable the design of highly non-local optical encoders for computational imaging
Diptodip Deb , Zhenfei Jiao , Ruth R Sims , Alex Bo-Yuan Chen , Michael Broxton , Misha Ahrens , Kaspar Podgorski , Srinivas C Turaga , Alice H. Oh , Alekh Agarwal , Danielle Belgrave , Kyunghyun Cho
Advances in Neural Information Processing Systems. 10/2022:. doi:

Differentiable simulations of optical systems can be combined with deep learning-based reconstruction networks to enable high performance computational imaging via end-to-end (E2E) optimization of both the optical encoder and the deep decoder. This has enabled imaging applications such as 3D localization microscopy, depth estimation, and lensless photography via the optimization of local optical encoders. More challenging computational imaging applications, such as 3D snapshot microscopy which compresses 3D volumes into single 2D images, require a highly non-local optical encoder. We show that existing deep network decoders have a locality bias which prevents the optimization of such highly non-local optical encoders. We address this with a decoder based on a shallow neural network architecture using global kernel Fourier convolutional neural networks (FourierNets). We show that FourierNets surpass existing deep network based decoders at reconstructing photographs captured by the highly non-local DiffuserCam optical encoder. Further, we show that FourierNets enable E2E optimization of highly non-local optical encoders for 3D snapshot microscopy. By combining FourierNets with a large-scale multi-GPU differentiable optical simulation, we are able to optimize non-local optical encoders 170× to 7372× larger than prior state of the art, and demonstrate the potential for ROI-type specific optical encoding with a programmable microscope.

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04/06/22 | Voltage imaging identifies spinal circuits that modulate locomotor adaptation in zebrafish.
Böhm UL, Kimura Y, Kawashima T, Ahrens MB, Higashijima S, Engert F, Cohen AE
Neuron. 2022 Apr 06;110(7):1211-1222.e4. doi: 10.1016/j.neuron.2022.01.001

Motor systems must continuously adapt their output to maintain a desired trajectory. While the spinal circuits underlying rhythmic locomotion are well described, little is known about how the network modulates its output strength. A major challenge has been the difficulty of recording from spinal neurons during behavior. Here, we use voltage imaging to map the membrane potential of large populations of glutamatergic neurons throughout the spinal cord of the larval zebrafish during fictive swimming in a virtual environment. We characterized a previously undescribed subpopulation of tonic-spiking ventral V3 neurons whose spike rate correlated with swimming strength and bout length. Optogenetic activation of V3 neurons led to stronger swimming and longer bouts but did not affect tail beat frequency. Genetic ablation of V3 neurons led to reduced locomotor adaptation. The power of voltage imaging allowed us to identify V3 neurons as a critical driver of locomotor adaptation in zebrafish.

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