Person: Lichtman, Jeff
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Lichtman
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Lichtman, Jeff
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Publication Connectomes across development reveal principles of brain maturation(Cold Spring Harbor Laboratory, 2020-04-30) Witvliet, Daniel; Mulcahy, Ben; Mitchell, James; Meirovitch, Yaron; Berger, Daniel; Wu, Yuelong; Liu, Yufang; Koh, Wan Xian; Parvathala, Rajeev; Holmyard, Douglas; Schalek, Richard; Shavit, Nir; Chisholm, Andrew; Lichtman, Jeff; Samuel, Aravi; Zhen, MeiFrom birth to adulthood, an animal’s nervous system changes as its body grows and its behaviours mature. The form and extent of circuit remodelling across the connectome is unknown. We used serial-section electron microscopy to reconstruct the full brain of eight isogenic C. elegans individuals across postnatal stages to learn how it changes with age. The overall geometry of the nervous system is preserved from birth to adulthood. Upon this constant scaffold, substantial changes in chemical synaptic connectivity emerge. Comparing connectomes among individuals reveals substantial connectivity differences that make each brain partly unique. Comparing connectomes across maturation reveals consistent wiring changes between different neurons. These changes alter the strength of existing connections and create new connections. Collective changes in the network alter information processing. Over development, the central decision-making circuitry is maintained whereas sensory and motor pathways substantially remodel. With age, the brain progressively becomes more feedforward and discernibly modular. Developmental connectomics reveals principles that underlie brain maturation.Publication Efficiency of Cathodoluminescence Emission by Nitrogen-Vacancy Color Centers in Nanodiamonds(Wiley, 2017-04-18) Zhang, Huiliang; Glenn, David; Schalek, Richard; Lichtman, Jeff; Walsworth, RonaldCorrelated electron microscopy and cathodoluminescence (CL) imaging using functionalized nanoparticles is a promising nanoscale probe of biological structure and function. Nanodiamonds (NDs) that contain CL‐emitting color centers are particularly well suited for such applications. The intensity of CL emission from NDs is determined by a combination of factors, including particle size, density of color centers, efficiency of energy deposition by electrons passing through the particle, and conversion efficiency from deposited energy to CL emission. This paper reports experiments and numerical simulations that investigate the relative importance of each of these factors in determining CL emission intensity from NDs containing nitrogen‐vacancy (NV) color centers. In particular, it is found that CL can be detected from NV‐doped NDs with dimensions as small as ≈40 nm, although CL emission decreases significantly for smaller NDs.Publication Ultrastructurally-smooth thick partitioning and volume stitching for larger-scale connectomics(2015) Hayworth, Kenneth J.; Xu, C. Shan; Lu, Zhiyuan; Knott, Graham W.; Fetter, Richard D.; Tapia, Juan Carlos; Lichtman, Jeff; Hess, Harald F.FIB-SEM has become an essential tool for studying neural tissue at resolutions below 10×10×10 nm, producing datasets superior for automatic connectome tracing. We present a technical advance, ultrathick sectioning, which reliably subdivides embedded tissue samples into chunks (20 µm thick) optimally sized and mounted for efficient, parallel FIB-SEM imaging. These chunks are imaged separately and then ‘volume stitched’ back together, producing a final 3D dataset suitable for connectome tracing.Publication Reconstruction of genetically identified neurons imaged by serial-section electron microscopy(eLife Sciences Publications, Ltd, 2016) Joesch, Maximilian; Mankus, David; Yamagata, Masahito; Shahbazi, Ali; Schalek, Richard; Suissa-Peleg, Adi; Meister, Markus; Lichtman, Jeff; Scheirer, Walter J; Sanes, JoshuaResolving patterns of synaptic connectivity in neural circuits currently requires serial section electron microscopy. However, complete circuit reconstruction is prohibitively slow and may not be necessary for many purposes such as comparing neuronal structure and connectivity among multiple animals. Here, we present an alternative strategy, targeted reconstruction of specific neuronal types. We used viral vectors to deliver peroxidase derivatives, which catalyze production of an electron-dense tracer, to genetically identify neurons, and developed a protocol that enhances the electron-density of the labeled cells while retaining the quality of the ultrastructure. The high contrast of the marked neurons enabled two innovations that speed data acquisition: targeted high-resolution reimaging of regions selected from rapidly-acquired lower resolution reconstruction, and an unsupervised segmentation algorithm. This pipeline reduces imaging and reconstruction times by two orders of magnitude, facilitating directed inquiry of circuit motifs. DOI: http://dx.doi.org/10.7554/eLife.15015.001Publication Similar synapse elimination motifs at successive relays in the same efferent pathway during development in mice(eLife Sciences Publications, Ltd, 2017) Sheu, Shu-Hsien; Tapia, Juan Carlos; Tsuriel, Shlomo; Lichtman, JeffIn many parts of the nervous system, signals pass across multiple synaptic relays on their way to a destination, but little is known about how these relays form and the function they serve. To get some insight into this question we ask how the connectivity patterns are organized at two successive synaptic relays in a simple, cholinergic efferent pathway. We found that the organization at successive relays in the parasympathetic nervous system strongly resemble each other despite the different embryological origin and physiological properties of the pre- and postsynaptic cells. Additionally, we found a similar developmental synaptic pruning and elaboration strategy is used at both sites to generate their adult organizations. The striking parallels in adult innervation and developmental mechanisms at the relays argue that a general strategy is in operation. We discuss why from a functional standpoint this structural organization may amplify central signals while at the same time maintaining positional targeting. DOI: http://dx.doi.org/10.7554/eLife.23193.001Publication Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors(Proceedings of the National Academy of Sciences, 2009) Borselli, C.; Storrie, H.; Benesch-Lee, F.; Shvartsman, Dmitry; Cezar, Christine Anne; Lichtman, Jeff; Vandenburgh, H. H.; Mooney, DavidRegenerative efforts typically focus on the delivery of single factors, but it is likely that multiple factors regulating distinct aspects of the regenerative process (e.g., vascularization and stem cell activation) can be used in parallel to affect regeneration of functional tissues. This possibility was addressed in the context of ischemic muscle injury, which typically leads to necrosis and loss of tissue and function. The role of sustained delivery, via injectable gel, of a combination of VEGF to promote angiogenesis and insulin-like growth factor-1 (IGF1) to directly promote muscle regeneration and the return of muscle function in ischemic rodent hindlimbs was investigated. Sustained VEGF delivery alone led to neoangiogenesis in ischemic limbs, with complete return of tissue perfusion to normal levels by 3 weeks, as well as protection from hypoxia and tissue necrosis, leading to an improvement in muscle contractility. Sustained IGF1 delivery alone was found to enhance muscle fiber regeneration and protected cells from apoptosis. However, the combined delivery of VEGF and IGF1 led to parallel angiogenesis, reinnervation, and myogenesis; as satellite cell activation and proliferation was stimulated, cells were protected from apoptosis, the inflammatory response was muted, and highly functional muscle tissue was formed. In contrast, bolus delivery of factors did not have any benefit in terms of neoangiogenesis and perfusion and had minimal effect on muscle regeneration. These results support the utility of simultaneously targeting distinct aspects of the regenerative process.Publication Lamellar projections in the endolymphatic sac act as a relief valve to regulate inner ear pressure(eLife Sciences Publications, Ltd, 2018) Swinburne, Ian; Mosaliganti, Kishore R; Upadhyayula, Srigokul; Liu, Tsung-Li; Hildebrand, David; Tsai, Tony Y -C; Chen, Anzhi; Al-Obeidi, Ebaa; Fass, Anna K; Malhotra, Samir; Engert, Florian; Lichtman, Jeff; Kirchausen, Tomas; Betzig, Eric; Megason, SeanThe inner ear is a fluid-filled closed-epithelial structure whose function requires maintenance of an internal hydrostatic pressure and fluid composition. The endolymphatic sac (ES) is a dead-end epithelial tube connected to the inner ear whose function is unclear. ES defects can cause distended ear tissue, a pathology often seen in hearing and balance disorders. Using live imaging of zebrafish larvae, we reveal that the ES undergoes cycles of slow pressure-driven inflation followed by rapid deflation. Absence of these cycles in lmx1bb mutants leads to distended ear tissue. Using serial-section electron microscopy and adaptive optics lattice light-sheet microscopy, we find a pressure relief valve in the ES comprised of partially separated apical junctions and dynamic overlapping basal lamellae that separate under pressure to release fluid. We propose that this lmx1-dependent pressure relief valve is required to maintain fluid homeostasis in the inner ear and other fluid-filled cavities.Publication NEW TOOLS FOR THE BRAINBOW TOOLBOX(2013) Cai, Dawen; Cohen, Kimberly B.; Luo, Tuanlian; Lichtman, Jeff; Sanes, JoshuaIn a recently introduced transgenic multicolor labeling strategy called “Brainbow,” Cre-lox recombination is used to create a stochastic choice of expression among fluorescent proteins (XFPs), resulting in the indelible marking of mouse neurons with multiple, distinct colors. This method has been adapted to non-neuronal cells in mice and to neurons in fish and flies, but has yet to realize its full potential in the mouse brain. Here, we present several new lines of mice that overcome limitations of the initial lines and an adaptation of the method for use in adeno-associated viral (AAV) vectors. We also provide technical advice about how best to image Brainbow transgenes.Publication Exploring the Connectome: Petascale Volume Visualization of Microscopy Data Streams(Institute of Electrical & Electronics Engineers (IEEE), 2013) Beyer, Johanna; Hadwiger, Markus; Al-Awami, Ali; Jeong, Won-Ki; Kasthuri, Narayanan; Lichtman, Jeff; Pfister, HanspeterRecent advances in high-resolution microscopy let neuroscientists acquire neural-tissue volume data of extremely large sizes. However, the tremendous resolution and the high complexity of neural structures present big challenges to storage, processing, and visualization at interactive rates. A proposed system provides interactive exploration of petascale (petavoxel) volumes resulting from high-throughput electron microscopy data streams. The system can concurrently handle multiple volumes and can support the simultaneous visualization of high-resolution voxel segmentation data. Its visualization-driven design restricts most computations to a small subset of the data. It employs a multiresolution virtual-memory architecture for better scalability than previous approaches and for handling incomplete data. Researchers have employed it for a 1-teravoxel mouse cortex volume, of which several hundred axons and dendrites as well as synapses have been segmented and labeled.Publication Developmental Bias in Cleavage-Stage Mouse Blastomeres(Elsevier BV, 2013) Tabansky, Inna; Lenarcic, Alan; Draft, Ryan; Loulier, Karine; Keskin, Derin Benerci; Rosains, Jacqueline; Rivera-Feliciano, Jose; Lichtman, Jeff; Livet, Jean; Stern, Joel N H; Sanes, Joshua; Eggan, KevinBACKGROUND: The cleavage-stage mouse embryo is composed of superficially equivalent blastomeres that will generate both the embryonic inner cell mass (ICM) and the supportive trophectoderm (TE). However, it remains unsettled whether the contribution of each blastomere to these two lineages can be accounted for by chance. Addressing the question of blastomere cell fate may be of practical importance, because preimplantation genetic diagnosis requires removal of blastomeres from the early human embryo. To determine whether blastomere allocation to the two earliest lineages is random, we developed and utilized a recombination-mediated, noninvasive combinatorial fluorescent labeling method for embryonic lineage tracing. RESULTS: When we induced recombination at cleavage stages, we observed a statistically significant bias in the contribution of the resulting labeled clones to the trophectoderm or the inner cell mass in a subset of embryos. Surprisingly, we did not find a correlation between localization of clones in the embryonic and abembryonic hemispheres of the late blastocyst and their allocation to the TE and ICM, suggesting that TE-ICM bias arises separately from embryonic-abembryonic bias. Rainbow lineage tracing also allowed us to demonstrate that the bias observed in the blastocyst persists into postimplantation stages and therefore has relevance for subsequent development. CONCLUSIONS: The Rainbow transgenic mice that we describe here have allowed us to detect lineage-dependent bias in early development. They should also enable assessment of the developmental equivalence of mammalian progenitor cells in a variety of tissues.