2011 Ph.D. Neurobiology, Harvard University
1997 A.B. Biology, Brown University
Multiterabyte electron microscopy image volumes containing the neuronal circuits of interest are generated using high-throughput electron microscopy of serial thin sections. The arbors of selected neurons and the synaptic connections between them are then mapped, and the resulting 'wiring diagram' is analyzed in the context of circuit function.
Connectivity between neurons is established by tracing the axons, dendrites, and synapses through the imaged volume, and patterns of connectivity are compared with the functional properties of the neurons in the circuit. In this way, the relationship between how neuronal circuits process information and how their constituent neurons are connected to one another can be explored.
We currently use large-scale, high-throughput transmission electron microscopy (EM) of serial thin (<50 nm) sections of brain tissue, followed by reconstruction of the neurons within the EM-imaged volume, to map the anatomical connectivity of a set of neurons.
The advantage of EM is that it can resolve both the "wires" between neurons—their axons, dendrites, and dendritic spines—and the connections between the wires, which are composed of chemical synapses and gap junctions. The method used to prepare neural tissue for EM labels cellular membrane in a complete and unbiased fashion. This means that, in principle, we can start at a given "seed" neuron in an EM-imaged volume and trace out its complete dendritic and axonal arbors and, in the process, note all sites of input and output to the cell (chemical and electrical synapses).
The tracing process can be continued iteratively. The pre- or postsynaptic partners of the seed neuron can be reconstructed, and then their partners, and so on, until the connectivity underlying a given circuit has been mapped out. (This mapping strategy is similar to how Web crawlers deployed by search engine companies chart the connectivity of the World Wide Web, by traversing from one Web page to the next.) A key output of the tracing effort is a graph, in the mathematical sense, with neurons represented by vertices and connections represented as edges. Pairwise and higher order connectivity patterns can be extracted from the graph and related to cell type, neural geometry, and most importantly, function: the physiological properties of the neurons in the graph, and information processing at the level of the circuit.
The method for obtaining functional information about the neurons in a given circuit depends on the species and the specific physiological parameters of interest. My past work in Clay Reid's lab at Harvard Medical School (now at the Allen Brain Institute), in collaboration with other members of the lab and researchers in the Center for Brain Science at Harvard and the Pittsburgh Supercomputing Center, provides an early proof-of-principle of combined network anatomy and function in mouse primary visual cortex. We used in vivo two-photon calcium imaging to characterize the preferred stimulus orientations of a group of neurons in layer 2/3 of visual cortex. We then prepared the tissue for EM and cut serial thin sections through the cluster of physiologically characterized cells.
We imaged the thin sections using a custom high-throughput transmission electron microscope camera array (TEMCA1). This resulted in a 10-terabyte EM-imaged volume, with each section represented by a 120,000 × 80,000 pixel composite image (4 nm/pixel), encompassing about 450 × 350 × 50 micrometers of brain tissue. This volume was sufficiently large that we could construct the proximal portions of the axonal and dendritic arbors of the physiologically characterized neurons. We then traced all the dendrites postsynaptic to the physiologically characterized cells' axons, and examined the patterns of convergence by similarly and differently tuned cells onto their post-synaptic targets. In this way we were able to explore whether a relationship existed between the structure of this partial connectivity graph of visual cortex and the orientation tunings of the cells within it. Our prototype effort revealed a number of technical limitations.
Foremost was the size of the EM-imaged volume. Although it was unusually large by historical standards, it was just barely big enough to contain some interesting cortical circuitry. Currently, the lab has three dedicated FEI T12 electron microscopes. Two host next-generation camera arrays, which acquire data at ~6x the rate of TEMCA1; the third hosts a prototype 'autoloader' allowing for 24-7 unattended fast imaging and sample exchange. The goal of this infrastructure development is to allow significantly larger volumes of neural tissue (large enough, for example, to span all the cortical laminae, or the complete brain of the fruit fly or zebrafish), to be imaged in a few months' time. We also continue to collaborate for the development of tools for efficient manual and semi-automated tracing of subsets of neural circuitry contained in our multi-terabyte EM image volumes.
Overall, our goal is to explore the extent to which anatomical connectivity can be related to the functional properties of a circuit. Although it is unlikely that an anatomical correlate can be found to all of a circuit's physiological properties, knowing the structure of a circuit's connectivity will likely constrain hypotheses about how the circuit processes information, generate new hypotheses, and help guide new experimental work.
- 1993 Brown University. Undergraduate Teaching and Research Award (UTRA); for summer
- research in marsh ecology.
- 1997 Santa Fe Institute. Research Experience for Undergraduates (REU) Fellowship; for summer
- research in cellular automata and evolutionary computation.
- 2004-2005 Harvard NeuroDiscovery Center (formerly Harvard Center for Neurodegeneration and Repair) Fellow.
- 2007 Harvard Department of Neurobiology. First place, departmental poster competition.2011 Cajal Club. Krieg Cortical Scholar.
- 2017 Marine Biological Laboratory, Woods Hole. Whitman Center Early Career Investigator
- Award, for summertime lab space and housing at the MBL.
11/06/19 | A neural circuit arbitrates between persistence and withdrawal in hungry drosophila. Sayin S, De Backer J, Siju KP, Wosniack ME, Lewis LP, Frisch L, Gansen B, Schlegel P, Edmondson-Stait A, Sharifi N, Fisher CB, Calle-Schuler SA, Lauritzen JS, Bock DD, Costa M, Jefferis GS, Gjorgjieva J, Grunwald Kadow IC
Neuron. 2019 Nov 6;104(3):544-58. doi: 10.1016/j.neuron.2019.07.028
05/21/19 | Functional and anatomical specificity in a higher olfactory centre. Frechter S, Bates AS, Tootoonian S, Dolan M, Manton JD, Jamasb AR, Kohl J, Bock D, Jefferis GS
Elife. 2019 May 21;8:. doi: 10.7554/eLife.44590
05/21/19 | Neurogenetic dissection of the lateral horn reveals major outputs, diverse behavioural functions, and interactions with the mushroom body. Dolan M, Frechter S, Bates AS, Dan C, Huoviala P, Roberts RJ, Schlegel P, Dhawan S, Tabano R, Dionne H, Christoforou C, Close K, Sutcliffe B, Giuliani B, Li F, Costa M, Ihrke G, Meissner GW, Bock DD, Aso Y, Rubin GM, Jefferis GS
Elife. 2019 May 21;8:. doi: 10.7554/eLife.43079
02/28/19 | Neural basis for looming size and velocity encoding in the Drosophila giant fiber escape pathway. Ache JM, Polsky J, Alghailani S, Parekh R, Breads P, Peek MY, Bock DD, von Reyn CR, Card GM
Current Biology : CB. 2019 Feb 28;29(6):1073. doi: 10.1016/j.cub.2019.01.079
01/16/19 | Regulation of modulatory cell activity across olfactory structures in Drosophila melanogaster. Zhang X, Coates K, Dacks A, Gunay C, Lauritzen JS, Li F, Calle-Schuler SA, Bock DD, Gaudry Q
bioRxiv. 2019 Jan 16:. doi: 10.1101/522177
09/19/18 | Communication from learned to innate olfactory processing centers is required for memory retrieval in Drosophila. Dolan M, Belliart-Guérin G, Bates AS, Frechter S, Lampin-Saint-Amaux A, Aso Y, Roberts RJ, Schlegel P, Wong A, Hammad A, Bock D, Rubin GM, Preat T, Placais P, Jefferis GS
Neuron. 2018 Sep 19;100(3):651-68. doi: 10.1016/j.neuron.2018.08.037
09/06/18 | Integration of parallel opposing memories underlies memory extinction. Felsenberg J, Jacob PF, Walker T, Barnstedt O, Edmondson-Stait AJ, Pleijzier MW, Otto N, Schlegel P, Sharifi N, Perisse E, Smith CS, Lauritzen JS, Costa M, Jefferis GS, Bock DD, Waddell S
Cell. 2018 Sep 06;175(3):709-22. doi: 10.1016/j.cell.2018.08.021
07/12/18 | A complete electron microscopy volume of the brain of adult Drosophila melanogaster. Zheng Z, Lauritzen JS, Perlman E, Robinson CG, Nichols M, Milkie DE, Torrens O, Price J, Fisher CB, Sharifi N, Calle-Schuler SA, Kmecova L, Ali IJ, Karsh B, Trautman ET, Bogovic JA, Hanslovsky P, Jefferis GS, Kazhdan M, Khairy K
Cell. 2018 Jul 12;174(3):730-43. doi: 10.1016/j.cell.2018.06.019
01/31/17 | Multicut brings automated neurite segmentation closer to human performance. Beier T, Pape C, Rahaman N, Prange T, Berg S, Bock DD, Cardona A, Knott GW, Plaza SM, Scheffer LK, Koethe U, Kreshuk A, Hamprecht FA
Nature Methods. 2017 Jan 31;14(2):101-102. doi: 10.1038/nmeth.4151
07/06/16 | A large fraction of neocortical myelin ensheathes axons of local inhibitory neurons. Micheva KD, Wolman D, Mensh BD, Pax E, Buchanan J, Smith SJ, Bock DD
eLife. 2016 Jul 6:. doi: 10.7554/eLife.15784
10/01/13 | Optimizing the quantity/quality trade-off in connectome inference. Priebe CE, Vogelstein J, Bock D
Communications in Statistics-Theory and Methods. 2013 Oct;42:3455-62. doi: 10.1080/03610926.2011.630768
06/18/13 | The Open Connectome Project Data Cluster: Scalable analysis and vision for high-throughput neuroscience. Burns R, Roncal WG, Kleissas D, Lillaney K, Manavalan P, Perlman E, Berger DR, Bock DD, Chung K, Grosenick L, Kasthuri N, Weiler NC, Deisseroth K, Kazhdan M, Lichtman J, Reid RC, Smith SJ, Szalay AS, Vogelstein JT, Vogelstein RJ
Scientific and Statistical Database Management: International Conference, SSDBM ... : Proceedings. International Conference on Scientific and Statistical Database Management. 2013 Jun 18:. doi: 10.1145/2484838.2484870
02/01/12 | Volume electron microscopy for neuronal circuit reconstruction.
Briggman KL, Bock DD
Current Opinion in Neurobiology. 2012 Feb;22(1):154-61. doi: 10.1016/j.conb.2011.10.022
11/09/11 | Large-scale automated histology in the pursuit of connectomes.
Kleinfeld D, Bharioke A, Blinder P, Bock DD, Briggman KL, Chklovskii DB, Denk W, Helmstaedter M, Kaufhold JP, Lee WA, Meyer HS, Micheva KD, Oberlaender M, Prohaska S, Reid RC, Smith SJ, Takemura S, Tsai PS, Sakmann B
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2011 Nov 9;31(45):16125-38. doi: 10.1523/JNEUROSCI.4077-11.2011
03/10/11 | Network anatomy and in vivo physiology of visual cortical neurons.
Bock DD, Lee WA, Kerlin AM, Andermann ML, Hood G, Wetzel AW, Yurgenson S, Soucy ER, Kim HS, Reid RC
Nature. 2011 Mar 10;471(7337):177-82. doi: 10.1038/nature09802
01/01/09 | Accelerating feature based registration using the Johnson-Lindenstrauss Lemma.
Akselrod-Ballin A, Bock D, Reid RC, Warfield SK
Medical Image Computing and Computer-Assisted Intervention: MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention. 2009;12:632-9
01/01/07 | Alignment of large image series using cubic B-splines tessellation: application to transmission electron microscopy data.
Dauguet J, Bock D, Reid RC, Warfield SK
Medical Image Computing and Computer-Assisted Intervention: MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention. 2007;10:710-7