Discovering the Wiring Diagram of the Brain

8/9/2019 Discovering the Wiring Diagram of the Brain

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HEALTH AND WELLBEING

Discovering theWiring

Diagram of the

Brain

hebrain, theseatofourcognitiveabilities, is perhapsthe most complex puzzle in all of biology. Every second

in the human brain, billions of cortical nerve cells trans-

mit billions of messages and perform extraordinarily

Jeff W. LichtmanR. Clay ReidHanspeter fister

Har!ard "ni!ersity

#ichael $. C%hen

#icr%s%ft Research

complex computations. How the brain workshow its function

follows from its structureremains a mystery.

he brain!s vast numbers of nerve cells are interconnected at

synapses in circuits of unimaginable complexity. "t is largely as-

sumed that the specificity of these interconnections underlies our

ability to perceive and classify ob#ects, our behaviors both learned$such as playing the piano% and intrinsic $such as walking%, and

our memoriesnot to mention controlling lower-level functions

such as maintaining posture and even breathing. &t the highest

level, our emotions, our sense of self, our very consciousness are

entirely the result of activities in the nervous system.

&t a macro level, human brains have been mapped into re-

gions that can be roughly associated with specific types of activi-

ties. However, even this building-block approach is fraught with

complexity because often many parts of the brain participate incompleting a task. his complexity arises especially because most

behaviors begin with sensory input and are followed by analysis,

decision making, and finally a motor output or action.

&t the microscopic level, the brain comprises billions of neu-

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rons, each connected to other neurons by up to several thousand synaptic connec-

tions. &lthough the existence of these synaptic circuits has been appreciated for

over a century, we have no detailed circuit diagrams of the brains of humans or any

other mammals. "ndeed, neural circuit mapping has been attempted only once, and

that was two decades ago on a small worm with only 122 nerve cells. he central

stumbling block is the enormous technical difficulty associated with such mapping.

*ecent technological breakthroughs in imaging, computer science, and molecular

biology, however, allow a reconsideration of this problem. 3ut even if we had a wir-

ing diagram, we would need to know what messages the neurons in the circuit arepassingnot unlike listening to the signals on a computer chip. his represents

the second impediment to understanding4 traditional physiological methods let us

listen to only a tiny fraction of the nerves in the circuit.

o get a sense of the scale of the problem, consider the cerebral cortex of the

human brain, which contains more than 562 trillion synaptic connections. hese

connections originate from billions of neurons. Each neuron receives synaptic con-

nections from hundreds or even thousands of different neurons, and each sends

information via synapses to a similar number of target neurons. his enormous

fan-in and fan-out can occur because each neuron is geometrically complicated,possessing many receptive processes $dendrites% and one highly branched outflow

process $an axon% that can extend over relatively long distances.

(ne might hope to be able to reverse engineer the circuits in the brain. "n other

words, if we could only tease apart the individual neurons and see which one is

connected to which and with what strength, we might at least begin to have the

tools to decode the functioning of a particular circuit. he staggering numbers

and complex cellular shapes are not the only daunting aspects of the problem. he

circuits that connect nerve cells are nanoscopic in scale. he density of synapses in

the cerebral cortex is approximately 122 million per cubic millimeter.'unctional magnetic resonance imaging $f*"% has provided glimpses into the

macroscopic 1- workings of the brain. However, the finest resolution of f*" is

approximately 5 cubic millimeter per voxelthe same cubic millimeter that can

contain 122 million synapses. hus there is a huge amount of circuitry in even the

most finely resolved functional images of the human brain. oreover, the size of

these synapses falls below the diffraction-limited resolution of traditional optical

imaging technologies.

7ircuit mapping could potentially be amenable to analysis based on color cod-

ing of neuronal processes 859 and:or the use of techni;ues that break through the

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diffraction limit 8?9. +resently, the gold standard for analyzing synaptic connections

is to use electron microscopy $E%, whose nanometer $nm% resolution is more than

sufficient to ascertain the finest details of neural connections. 3ut to map circuits,

one must overcome a technical hurdle4 E typically images very thin sections $tens

of nanometers in thickness%, so reconstructing a volume re;uires a @serial recon-

structionA whereby the image information from contiguous slices of the same vol-

ume is recomposed into a volumetric dataset. here are several ways to generate

such volumetric data $see, for example, 81-09%, but all of these have the potential to

generate astonishingly large digital image data libraries, as described next.

Some Numbers

"f one were to reconstruct by E all the synaptic circuitry in 5 cubic mm of brain

$roughly what might fit on the head of a pin%, one would need a set of serial images

spanning a millimeter in depth. )nambiguously resolving all the axonal and den-

dritic branches would re;uire sectioning at probably no more than 12 nm. hus the

5 mm depth would re;uire 11,222 images. Each image should have at least 52 nm lateral

resolution to discern all the vesicles $the source of the neurotransmitters% and synapse

types. & s;uare-millimeter image at 0 nm resolution is an image that has BC x52

52

pixels,or 52 to ?2 gigapixels. Do the image data in 5 cubic mm will be in the range of 5 petabyte

$?02B 5,222,222,222,222,222 bytes%. he human brain contains nearly 5 million cubic

mm of neural tissue.

Some Successes to Date

iven this daunting task, one is tempted to give up and find a simpler problem.

However, new technologies and techni;ues provide glimmers of hope. >e are pursuing

these with the ultimate goal of creating a @connectomeAa complete circuit diagram of

the brain. his goal will re;uire intensive and large-scale collaborations among biologists,engineers, and computer scientists.

hree years ago, the *eid and


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synapsethe physical connections that underlie neuronal function.

he problem of separating and tracking the individual neurons within the vol-

ume remains. However, some successes have already been achieved using exotic

means. ith this

approach, it is possible to track individual neurons as they branch to their eventual

synaptic connections to other neurons or to the end-organs in muscle. he multi-

color labeled nerves $dubbed @brainbowA%, shown in 'igure 5, are reminiscent ofthe rainbow cables in computers and serve the same purpose4 to disambiguate

wires traveling over long distances.

3ecause these colored labels are present in the living mouse, it is possible to track

synaptic wiring changes by observing the same sites multiple times over minutes, days, or

even months.

*eid!s lab has been able to stain neurons of rat and cat visual cortices such that they

@light upA when activated. 3y stimulating the cat with lines of different orientations, they

have literally been able to see which neurons are firing, depending on the specific visual

stimulus. 3y comparing the organization of the rat!s visual cortex to that of the cat, theyhave found that while a rat!s neurons appear to be randomly organized based on the

orientation of the visual stimulus, a cat!s neurons exhibit remarkable structure. $Dee

'igure ?.%

&chieving the finest resolution using E re;uires imaging very thin slices of

neural tissue. (ne method begins with a block of tissueG after each imaging pass, a

Figure 1.

3rainbow images showing individual neurons fluorescing in different colors. 3y tracking the neurons

through stacks of slices, we can follow each neuron!s complex branching structure to create the treelike

structures in the image on the right.

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Figure 2.

=eurons in a visual cortex stained in vivo with a calcium-sensitive dye.


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This tissue ribbon is collectedby a submerged conveyor belt

Tissue rotates

Knife

advances Knife&s aterlevel ad!usted viathis inlet tube

These synchroni"ed motions #roducea s#iral cut through the tissue bloc$%yielding a continuous ribbon oftissue in the $nife&s ater boat

Figure &.

he &utomatic ape-7ollecting


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Figure '.

H Iiew allows interactive exploration of this ?.0-gigapixel image.


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*eferences

859 J. eissman, H. Kang, *. >. raft, J. . . 7.

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Discovering the Wiring Diagram of the Brain