Jeff Lichtman

Jeff Lichtman, MD, PhD
Jeremy R. Knowles Professor of Molecular and Cellular Biology
Santiago Ramón y Cajal Professor of Arts and Sciences
Email: jeff@mcb.harvard.edu
Lab website: http://lichtmanlab.fas.harvard.edu/

We are interested in understanding how information is physically encoded in the nervous system. One of our major goals is to generate, in collaboration with others, a complete map of the neural connections in the brain—known as the “connectome.” Like the Human Genome Project, we believe that connectome work is necessary from both a basic science and clinical standpoint. From the basic science perspective, studying how the connectome changes as our brains mature will address fundamental questions of brain development, learning and memory, and comparing the connectomes of different individuals will reveal to what degree the pattern of neural connections in each human brain is unique. From a clinical perspective, connectomics will allow us to thoroughly examine the hypothesis that many brain disorders are “connectopathies”—in other words, the idea that the pathology lies in miswiring of neural circuits.

The cerebral cortex of the human brain contains more than 160 trillion synaptic connections. Each neuron receives synaptic connections from hundreds or even thousands of different neurons, and each sends outputs to a similar number of target neurons, spread out over a large distance. Thus, establishing the complete wiring diagram of even one type of neuron in the cortex poses enormous challenges. In the past several years we have been developing novel imaging methods to overcome these challenges. One new method is the “Brainbow” mouse, in which combinations of distinct fluorescent proteins are stochastically expressed in neurons, resulting in labeling with over a hundred unique hues that allow neighboring neuronal processes to be clearly distinguished from one another. Another technique we have optimized is serial electron microscopy reconstruction. For this we have developed a new device that makes possible automated ultrathin sectioning of large volumes of brain tissue (several cubic millimeters), called an Automatic Tape-Collecting Lathe Ultramicrotome (ATLUM).

As part of the Conte Center, we will now apply these technologies, as well as viral tracing, to deciphering the connectome of a specific population of inhibitory interneurons in the mouse prefrontal cortex—a population believed to be particularly vulnerable in mental illness. Examining various time points in relation to critical periods of cortical development and comparing healthy mice to mouse models of early life stress, autism, or schizophrenia, we hope to gain broad insights into the developmental circuit basis of mental illness.

About Professor Lichtman
Jeff Lichtman is Jeremy R. Knowles Professor of Molecular and Cellular Biology at Harvard. He received an AB from Bowdoin (1973), and an M.D. and Ph.D. from Washington University (1980) where he worked for 30 years before moving to Cambridge in 2004. He is a member of the newly established Center for Brain Science. Lichtman’s research interest revolves around the question of how mammalian brain circuits are physically altered by experiences, especially in early life.  He has focused on the dramatic re-wiring of neural connections that takes place in early postnatal development when animals are doing most of their learning. This work has required development of techniques such as “Brainbow” transgenic mice to visualize neural connections and monitor how they are altered over time.  Recently his efforts have focused on developing new electron microscopy methods to map the entire wiring diagram of the developing and adult brain.  This "connectomics" approach has as one of its aims uncovering the ways information is stored in neural networks.

Recent Publications
Saturated Reconstruction of a Volume of Neocortex.
Kasthuri N, Hayworth KJ, Berger DR, Schalek RL, Conchello JA, Knowles-Barley S, Lee D, Vázquez-Reina A, Kaynig V, Jones TR, Roberts M, Morgan JL, Tapia JC, Seung HS, Roncal WG, Vogelstein JT, Burns R, Sussman DL, Priebe CE, Pfister H, Lichtman JW.
Cell. 2015 Jul 30;162(3):648-61. doi: 10.1016/j.cell.2015.06.054.
PMID: 26232230

Multispectral labeling technique to map many neighboring axonal projections in the same tissue.
Tsuriel S, Gudes S, Draft RW, Binshtok AM, Lichtman JW.
Nat Methods. 2015 Apr 27. doi: 10.1038/nmeth.3367. [Epub ahead of print]
PMID: 25915122

Ultrastructurally smooth thick partitioning and volume stitching for large-scale connectomics.
Hayworth KJ, Xu CS, Lu Z, Knott GW, Fetter RD, Tapia JC, Lichtman JW, Hess HF.
Nat Methods. 2015 Apr;12(4):319-22. doi: 10.1038/nmeth.3292. Epub 2015 Feb 16.
PMID: 25686390

High-resolution, high-throughput imaging with a multibeam scanning electron microscope.
Eberle AL, Mikula S, Schalek R, Lichtman JW, Tate ML, Zeidler D.
J Microsc. 2015 Jan 27. doi: 10.1111/jmi.12224. [Epub ahead of print]
PMID: 25627873

The big data challenges of connectomics.
Lichtman JW, Pfister H, Shavit N.
Nat Neurosci. 2014 Nov;17(11):1448-54. doi: 10.1038/nn.3837. Epub 2014 Oct 28. Review.
PMID: 25349911 

Imaging ATUM ultrathin section libraries with WaferMapper: a multi-scale approach to EM reconstruction of neural circuits.
Hayworth KJ, Morgan JL, Schalek R, Berger DR, Hildebrand DG, Lichtman JW.
Front Neural Circuits. 2014 Jun 27;8:68. doi: 10.3389/fncir.2014.00068. eCollection 2014.
PMID: 25018701

Exploring the connectome: petascale volume visualization of microscopy data streams.
Beyer J, Hadwiger M, Al-Awami A, Jeong WK, Kasthuri N, Lichtman JW, Pfister H.
IEEE Comput Graph Appl. 2013 Jul-Aug;33(4):50-61. doi: 10.1109/MCG.2013.55.
PMID: 24808059

Distinct profiles of myelin distribution along single axons of pyramidal neurons in the neocortex.
Tomassy GS, Berger DR, Chen HH, Kasthuri N, Hayworth KJ, Vercelli A, Seung HS, Lichtman JW, Arlotta P.
Science. 2014 Apr 18;344(6181):319-24. doi: 10.1126/science.1249766.
PMID: 24744380

ConnectomeExplorer: query-guided visual analysis of large volumetric neuroscience data.
Beyer J, Al-Awami A, Kasthuri N, Lichtman JW, Pfister H, Hadwiger M.
IEEE Trans Vis Comput Graph. 2013 Dec;19(12):2868-77. doi: 10.1109/TVCG.2013.142.
PMID: 24051854 

Improved tools for the Brainbow toolbox.
Cai D, Cohen KB, Luo T, Lichtman JW, Sanes JR.
Nat Methods. 2013 Jun;10(6):540-7.
PMID: 23866336 

Why not connectomics?
Morgan JL, Lichtman JW.
Nat Methods. 2013 Jun;10(6):494-500.
PMID: 23722208 

Reversing the outcome of synapse elimination at developing neuromuscular junctions in vivo: evidence for synaptic competition and its mechanism.
Turney SG, Lichtman JW.
PLoS Biol. 2012;10(6):e1001352.
PMID: 22745601  

Pervasive synaptic branch removal in the mammalian neuromuscular system at birth. 
Tapia JC, Wylie JD, Kasthuri N, Hayworth KJ, Schalek R, Berger DR, Guatimosim C, Seung HS, Lichtman JW.
Neuron. 2012 Jun 7;74(5):816-29.

High-contrast en bloc staining of neuronal tissue for field emission scanning electron microscopy.
Tapia JC, Kasthuri N, Hayworth KJ, Schalek R, Lichtman JW, Smith SJ, Buchanan J. Nat Protoc. 2012. 7(2):193-206.

The big and the small: challenges of imaging the brain's circuits. 
Lichtman JW, Denk W.
Science. 2011. 334(6056):618-23.

In the News

Rainbow of dyes maps neurons' tangled paths in brain
2015 Simons Foundation Autism Research Initiative News

The Neuroscientist Who Wants To Upload Humanity To A Computer
2014 Popular Science article

Turning Science on Its Head
2014 Harvard Gazette

Secrets of the Brain: New technologies are shedding light on biology's greatest unsolved mystery: how the brain really works. 
2014 National Geographic article

A Voyage Into the Brain (video)
2014 National Geographic video

What Makes Us Human (video)
2013 BBC Horizon's Television Show

The growing brain
2012 Harvard Gazette story

A Beautiful Mind
2011 Proto magazine story

Brain navigation: Research team turns terabytes of image data into model of neural circuits
2011 Harvard Gazette story

In Pursuit of a Mind Map, Slice by Slice
2010 NY Times story

‘The art of seeing things invisible’
2010 Harvard Gazette story

Neuroscience: Making connections
2009 Nature news feature

Wired: Connectomics aims to map the atlas of the brain
2009 Economist feature

Mapping the Most Complex Structure in the Universe: Your Brain
2008 Wired article

TR10: Connectomics
2008 Technology Review story

Multimedia Resources
DNA Learning Center: The brainbow
Professor Lichtman explains brainbow technology

Connectomics: Mapping the Nervous System
2008 Scientific American podcast

Building a Brainbow
2007 Science Friday interview and slide show

Imaging the Nervous System in Fluorescent Mice
2005 Harvard Life Sciences/HHMI Outreach video