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Opinions diverge on whether mapping the synaptic connectivity of the brain is a good idea. Here we argue
that albeit their limitations, such maps will reveal essential characteristics of neural circuits that would
otherwise be inaccessible.
Neuroscience is in its heyday: large initia- not surprisingly, see the problem in struc- ficient justification for such studies. But
tives in Europe1 and the United States2 are tural terms. The nervous system is a physi- not everyone agrees. First, connectomics
getting under way. The annual neuroscience cal tissue that is quite unlike other organ can require an industrialized effort that is
2013 Nature America, Inc. All rights reserved.
meetings, with their tens of thousands of systems4. For one thing, it contains far more akin to initiatives that allowed genomics
attendees, feel like small cities. The num- types of cells. The retina alone has more to flourish. In light of present severe bud-
ber of neuroscience research papers pub- than 50 different kinds of cells5, whereas the get limitations, connectomics might be
lished more than doubled over the last two liver has closer to five. Second, neurons, by ill-advised. Moreover, some have argued
decades, overtaking those from fields such virtue of their complicated geometry, con- that pursuing connectomics would be a
as biochemistry, molecular biology and cell nect (via synapses) to many more cellular waste of money, even if it were free. They
biology3. Given the number of momentous partners than the limited associations of have argued that anatomical maps fun-
advances we hear about, surely must we not immediately adjacent cells in other organs. damentally do not reveal how the brain
be on the threshold of knowing how the Third, the neuronal contacts give rise to works. Below we address some of these
healthy brain works and how to fix it when directional circuits that have no analogs in arguments.
it does not? other tissues. Fourth, the fine structure of
Alas, the brain remains a tough nut to these neural circuits is quite diverse and dif- Top ten arguments against connectomics
crack. No other organ system is associ- fers from the marked structural redundancy Number ten: circuit structure is different
ated with as long a list of incurable diseases. in other organs where the same multicellu- from circuit function. One argument put
Worse still, for many common nervous sys- lar motif (for example, the renal nephron) forward is that the nervous systems mac-
tem illnesses there is not only no cure but no is iterated many times. Fifth, perhaps the roscopic functions (that is, behaviors) are
clear idea of what is wrong. Few psychiatric most intriguing difference between neural derived directly from the functional (that
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illnesses, learning disorders or even severe tissue and other organs is that the cellular is, electrical) properties of the neurons
pain syndromes such as migraine have structure of neural tissue is a product of rather than the anatomical connections
pathognomonic signs: no blood tests, radio- both genetic instruction and experience. between neurons. Hence it is the relation-
graphic or electrophysiological findings, or Thus, the structure of each of our nervous ship between the firing patterns of action
even brain biopsies enable diagnoses. This systems is personalized by our own set of potentials of neurons and function that is
predicament is unlike that for other organ experiences. the key to bridge the gap between the cells
systems, where disease is nearly always The special structural features of the of the nervous system and behavior. The
associated with tissue pathological and/or nervous system are likely the reason why it recent proposal of an initiative to get a brain
biochemical signs. A patient may come for is more difficult to understand than other activity map reflects this view, as do many
help because of pain in their belly, but the organs are. We contend, however, that a more initiatives for Ca2+ imaging from ever larger
physician discovers the cellular or molecu- complete rendering of neural circuit synaptic numbers of nerve cells.
lar cause of the pain before a treatment regi- connectivity (that is, connectomics6) would Although no one doubts that neural
men begins. Why is this so different for the go a long way to solving this problem. With connections underlie signaling between
brain? this understanding, diseases that manifest as nerve cells, the focus on neuronal function
Those of us with an interest in a deeper abnormalities of behavior, thought or learn- (action potentials) is based in part on the
understanding of the structure of the brain, ing, or as pain might become as clearly linked belief that the structural wiring details per
to underlying pathological structure, as is se are insufficient to derive the firing pat-
Joshua L. Morgan and Jeff W. Lichtman are in the the case for diseases in other organ systems. terns. Part of the problem is that the spik-
Department of Molecular and Cellular Biology and Knowing what is wrong is a good first step to ing properties of a neuron come not only
The Center for Brain Science, Harvard University,
Cambridge, Massachusetts, USA. finding a solution. from the electrical signals they receive from
e-mail: joshmorgan@fas.harvard.edu or For some proponents of connectomics, their presynaptic partners but also from
jeff@mcb.harvard.edu the potential clinical payoffs provide suf- the distribution and characteristics of their
decades or longer. The physical instantia- ing in the adrenal cortex have effects on monal milieu via blood flow or cerebrospi-
tion of such stable traces of activity is not brain function as do those from sex organs. nal fluid would still remain invisible unless
known, but it seems likely to us that they Growth hormone, thyroid hormone, insu- the effects of diffusible factors on behavior
are embodied in the same way intrinsic lin, leptin and many others also affect brain had a structural correlate12.
behaviors (such as reflexes) are: that is, in function. Furthermore, some forms of neu- There are also anatomical approaches to
the specific pattern of connections between rotransmitter release do not rely on classi- deal with the problem of synapses without
nerve cells. In this view, experience alters cal synapses8. Lastly, neurons often release signals. Some of the earliest evidence for
connections between nerve cells to record peptides that act over large areas, using vol- a class of silent synapses came from serial
a memory for later recall. Both the sensory ume transmission as opposed to restricted electron microscopy reconstructions13, and
experience that lays down a memory and its transmission at adjacent synapses9. All of we imagine that such information might
later recall are indeed trains of action poten- the aforementioned examples show that become available for glutaminergic synaps-
tials, but in-between, and persisting for long brain function is profoundly affected by es as well. If silent synapses are structurally
periods, is a stable physical structural entity chemical cues in ways that would be diffi- different from transmitting ones by virtue
that holds that memory. In this sense, a map cult or impossible to infer from anatomical of the neurotransmitter receptor, then in
of all the things the brain has put to memory wiring diagrams. principle that difference can be revealed.
is found in the structurethe connectional Conversely, it is generally accepted that a Immunolabeling for AMPA-type glutamate
map. An activity map of the brain that only substantial fraction of excitatory synapses receptors should solve this problem.
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shows trains of action potentials would cer- can be structurally present but functionally
tainly be an incomplete map, as most behav- silent10. These synapses can be switched on Number eight: junk synapses. Given the
iors and memories will not be visible in any via a Hebbian learning step. Obviously in trillions of synapses in a human brain, most
finite recording session. Decoding the way the absence of knowing which synapses are individual synapses are functionally negli-
experience via electrical activity becomes silent, a connectome provides a distorted gible. The brain is probably organized such
stably embedded in physical neuronal net- picture of the functionally useful connec- that the precise number and identity of syn-
works is the unmet challenge that connec- tions in the brain. apses are unimportant, and what really mat-
tomics attempts to solve. ters is the general likelihood of connectivity.
In our view, more challenging perhaps Response. It is true that that a map of syn- Thus, some fraction of the synaptic connec-
will be ferreting out the relationships aptic connectivity is not identical to a map tions could rightly be called junk: they have
between neural circuits and behaviors that of the signaling pathways of the brain. In no functional role but have so little cost that
are intrinsic and unlearned. In most ani- terms of signals without synapses, there is such scraps persist. If junk synapses are com-
mals, the behavioral repertoire is mostly no denying the importance of the brains mon, then going to the trouble of itemizing
genetically encoded. Such inherited circuits chemical milieu on behavior. The ability of all the synaptic connections is both a waste
may have arbitrary features that came about pharmacological agents to rapidly induce of time and a distraction from more impor-
accidentally at some instant in an animals sleep, tranquility, excitement, hallucinations tant functional questions.
evolution. We therefore think that geneti- and so on means that the behavioral state
cally encoded behaviors could be instanti- can be dramatically altered probably with- Response. Our view is that it is premature
ated in quite diverse ways compared to a out any modification to the connectome. to assign an influence to individual synaps-
more limited number of rules governing Therefore, we should be careful not to es in wiring diagrams when so few complete
experience-dependent formation of circuits. confuse the goals of connectomics with wiring diagrams have been described. The
From this perspective, the structural under- the aims of maps of the activity patterns lesson from genomics is that many noncod-
as peptides, other neuromodulators or Figure 1 | Potential results from two approaches of each and every particles trajectory. Given
activity levels. Because of this flexibility, it to studying circuit connectivity. (a) Probing the trillions of synapses in a brain, is there
is really not possible to assign a neuron to pairs of neurons in multiple subjects determines really any alternative except to take a statis-
a function without knowing the behavioral the probability that neighboring neurons are tical approach to synaptic connectivity?
connected. (b) Connectome of the same tissue
statesomething that is invisible in con- Members of the European Unions initia-
reveals network motifs.
nectomics. tive on Future and Emerging Technologies
have decided, for example, to fund the large
Response. Without an understanding of lar function, it will be impossible to relate Human Brain Project. In this case, the
the physiological responses of neurons to structure to function. connectional associations will be deter-
various chemical messengers such as pep- mined by characterizing ...the morpholo-
tides, we agree it will be difficult to define Response. In mammals, at least, variabil- gies of different types of neuron present in
the roles of neurons that switch their func- ity seems to be the rule. Even the pattern different regions of the human brain.
tion depending on the chemical milieu. The of nerve-muscle connections in the same Combined with modeling, the results
extent to which this kind of switching is a muscle is quite different from one instan- would enable the project to predict a large
general feature of nervous systems is not yet tiation to the next16. However, variability in proportion of the short-range connectiv-
known. connections does not necessarily mean that ity between neurons, without measuring
But whatever the case, it is important to the result is incomprehensible. In muscle, the connectivity experimentally1. That is,
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emphasize one limitation of connectomics: for example, there is a skewed distribution they will create the wiring diagram without
it is not a replacement for insights gained of the size of motor units that is the same having to go to the trouble of obtaining an
by physiological or pharmacological stud- in each muscle even though the exact loca- anatomic connectome.
ies. Rather, connectomics may associate tion and branching pattern of each axon is
specific physiological phenomena with unique. Thus, each instantiation appears to Response. Because of the heterogeneous
specific neural-circuit motifs so that the be a variation on the same common theme, nature of brain tissue, statistical approach-
next time that motif is observed in the just as every chess match is different, but es to studying neural-circuit wiring are, of
same tissue, it will signify a physiological they all obey the same rules. One of the rea- course, much more difficult than those for
process without the requirement of repeat- sons we believe connectomics is necessary, a homogeneous gas. For a statistical model
ing the physiological analysis each time. is that it is the only way to derive network to capture how brains actually generate
Because in many nervous systems the same principles despite variability in the connec- behavior, ideally it would need to include
neuron types are duplicated many thou- tivity of individual neurons. all the neuronal connectivity motifs.
sands or millions of times, it seems likely Indeed, deriving network principles Unfortunately, the number of ways the
that the same motifs will be repeated mul- without connectomics may be nearly dozens of different cell types are intercon-
tiple times. Thus, a little physiology may impossible in some cases. Without connec- nected, and especially how these connec-
go a long way. tomics, neural circuit diagrams can only be tions are contingent on the full cohort of
assembled by identifying connected pairs synaptic partners of each cell, is presently
Number six: same function, many struc- of cells in many different subjects. This unknown. But the advocates of statistical
tures What if there is great variability in the approach, although accurate as far as it approaches to studying connectivity are
circuits that give rise to a single behavioral goes, cannot reveal wiring rules as simple not unduly concerned because they believe
output? Without a stereotyped pattern of as cell A only connects to cell C when cell that models that combine a limited amount
neural circuits that underlie a particu- B connects to cell C. Such conditional rules of connectivity data with the right set of
emanate from even the best and the bright- Response. The Hubble telescope, archae- (unlike the situation for mammals), reduc-
est brains? Although some may hope that ology, the human genome and much of ing the overall power of the wiring diagram
there are organizing principles and regu- structural biology are also merely descrip- to reveal new concepts. In addition, there
larities that will permit substantial com- tive, but few would argue that they have are particular challenges in interpreting a
pression of the connectional information not provided fundamental insights. The map of connectivity in a highly differenti-
into a simpler framework, is there really hope of descriptive approaches is that they ated nervous system where each neuron has
any biological reason such regularities provide specific data that lead us to general many subcellular compartments, where all
are inevitable? Could the most succinct hypotheses (inductive reasoning). They can the signaling is due to local potentials, and
description that embodies all that a brain reveal associations and frameworks that evolution has specialized nearly every cell
does be the brain itself? If so, then there were not readily apparent before. In a vari- into a unique type. This specification con-
is little point in mapping the connections ety of fields, big-data initiatives are being trasts to the millions of cells of a single class
in great detail because in the best case, used to challenge the sacrosanct hypothesis found in many parts of the (perhaps less
one would end up with a description that first world view of scientific investigation. evolved) vertebrate nervous system. Thus,
would be as complicated and intractable as the worms nervous system may use a fun-
the brain itself. Number two: not much was learned from damentally different strategy than the one
the connectomes we have. The 10-year predominating in much larger nervous sys-
Response. The proximate goal of connec- effort to generate the connectome of tems in which cell types reflect populations
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tomics is to generate detailed renderings of C. elegans20 is widely cited, but it has had of neurons whose connectivity is organized
the connections between neurons in large less utility than had been imagined origi- by experience.
volumes of the brain. The purposes that nally. No one can claim that the relationship As to the Human Connectome project,
such connectional maps could be put to are between structure and function has been this is an important and ambitious multi-
numerous. Comparisons between healthy settled in this very small nervous system. In institution study to gain information about
and diseased brains might point to the phys- some respects, connectomes distract from the organization of the brains of many indi-
ical underpinnings of psychiatric diseases. more mechanistic analyses because they viduals including many twins. One of its
Comparisons between young and old brains reveal many more synaptic interconnections goals is to map the pathways that project
might provide an understanding of what between neurons than would seem neces- between various brain regions (projec-
kinds of network changes are associated sary. Given the struggle to make sense of the tomics). However, none of its many goals
with development and aging. Comparisons mind of a worm with about 300 neurons, it relate to describing the synaptic connectiv-
between human and other primate brains is very unlikely that we will get anywhere ity of the brain.
may provide insight into what underlies trying to fathom a mammalian nervous
intelligence. So even if understanding the system that could be roughly a billion times Number one. If you want to Google on
brain is not likely to be an early triumph of bigger. connectome and look [it] up, you can see
connectomics, there are potentially many Speaking of big brains, there is already a some gorgeous pictures that are being made
fundamental things that this kind of data big Human Connectome project21, so why of the wiring diagram of the human brain,
will reveal. To put it perhaps a bit too blunt- bother with maps of mice and flies? showing you how the wires move from front
ly, we think that understanding big data, to back and up and down, side to side. But
may be overrated as a goal. Connectomes Response. At the very least the worm con- again, its a static picture. Itd be like, you
can immediately provide insights even if nectome has been helpful in constraining know, taking your laptop and prying the
understanding lags. circuit analysis by providing for each neu- top off and staring at the parts inside, youd
thoughts while behaving. Unfortunately, we overwhelming but nonetheless holds fun- these diagrams include arrows that harken
are a long way from such technologies; so damental truths. back to the arrows found in the original
what do we do in the meantime? To quote Francis Collins referring to Cajal diagrams (Fig. 2a).
We think the computer analogy gives us the human genome project: When you The sense one might take from these
a lead. The computer can be turned off and have for the first time in front of you this kinds of diagrams is that this kind of struc-
on without losing much data because the 3.1-billion-letter instruction book that tural class-wise connectivity information
instructions that make it work are embed- conveys all kinds of information and all explains the way a neural circuit works.
ded in its static physicality. A deep under- kinds of mystery about humankind, you One may quibble over the extent to which
standing of how information is stably stored cant survey that going through page after the details of these connectional maps have
in the structure of hard discs, the input and page without a sense of awe. I cant help been worked out, but the implication is that
output wires of each chip, the physical struc- but look at those pages and have a vague knowing this kind of neuronal-class con-
tures that explain the working of those chips sense that this is giving me a glimpse of nectivity is sufficient to get some under-
and so on would be enormously helpful in Gods mind23. We likewise feel that the standing about how neurons process infor-
making sense of a computer. Might the same static maps of the brain may engender awe mation.
be said of nervous systems? and it might not be so unrealistic to hope In certain cases, this view is probably
We think that the static connectivity of that in staring into such a map we might correct. In an animal in which the major-
the brain has embedded within it much get a glimpse of the human mind. ity of neurons are each genetically unique
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of the instruction book that guides the and each has a stereotyped connectivity,
billions of impulses through networks of Why we still want to do connectomics connections of individual neurons are the
neurons to ultimately generate outward The large (but we are sure still incomplete) same thing as a class-wise wiring diagram
behavior. We see a connection between list of arguments above might seem discour- (because to a first approximation each cell
the relationship between the connectome aging enough to put a damper on all but the is its own class). Thus, one can imagine a
and the brains functional properties to not most irrationally enthusiastic proponents of detailed map describing exactly which
only computers but also to the way the static connectomics. In addition to the reasons we cells are connected, and that map would be
human genome encodes much of how an provided in our rebuttals, we remain com- exactly the same as what actually exists in
organism works. mitted to pursuing connectomics because the animal.
Structural defects in the genome that of the absence of one fundamental kind of But in other cases these diagrams are
give rise to a range of diseases are perhaps information about nervous systems that we quite different from the actual connec-
a good analogy for defects in wiring that do not think is attainable in any other way. tional array. They lack both quantitative
give rise to diseases of brain function. information and ignore the different wir-
In each case, tracing the causal linkages What Cajal did not do for neuroscience. ing patterns of the cells of the same class.
between the static structure (be it genotype Thanks to both his genius and the extraor- Thus, a retinal schematic diagram shows
or connectotype) and the ultimate pheno- dinary power of the sparse labeling of the what classes of cells are interconnected
type (be it cancer or schizophrenia) is dif- Golgi stain, Cajal developed a view about but does not show critical details such as
ficult. But this difficulty has not deterred neurons that has had a dominating effect on how many different amacrine cells con-
cancer biologists from seeking the ulti- the way in which we imagine neural circuits verge on each retinal ganglion cell or which
mate causes (the physical genes) that affect to work. Schematic textbook diagrams of particular amacrine cells are making those
the likelihood of cancer, and we think retinal circuits, cortical circuits, cerebellar connections. A cortical schematic diagram
should not deter neuroscientists from circuits, among many others, provide stu- does not show whether two interconnected
circuits. Because the vertebrate brain is of Cajal and more like modern renderings of
mostly composed of many copies of each social networks (Fig. 2b). How to compare Proteome meets the connectome. The
of many cell types (unique neurons such and analyze these connectional graphs of structural mapping of connections will
as the Mauthner cell in teleosts are quite the brain is a new challenge that will require only be useful if the cell type of each of
exceptional), this aspect of neural circuit new mathematical techniques for analyzing the neurons involved in a circuit is known.
organization cannot be ignored. In sum, graphs, new statistical tests to compare one Serial reconstruction of a neurons shape
Cajals use of sparse labeling did not pro- circuit with another and finally a cadre of and location will in some cases be suffi-
vide a means for coming to grips with the neuroscientists who will find mining big cient for the type of neuron to be identi-
way redundant populations are used in cir- data appealing. Ultimately, however, these fied. But it is likely that there is hetero-
cuits. Connectomics, however, does. tools will only be useful if connectomes can geneity among neurons that look alike.
be produced easily. Fortunately the past few decades have seen
Engramics? In 1904, Richard Semon, a an explosion in knowledge of the molecu-
German evolutionary biologist, coined Faster data collection. There are two rea- lar classes of nerve cells31. What remains
the term engram as the physical mem- sons to collect connectomics data faster. to be done is finding ways to insert that
ory trace that is somehow embedded in First, the production of connectomes must kind of information into mapping stud-
an organism after an experience. He was eventually be easy enough so that multiple ies. Correlative fluorescence immunos-
motivated to think about the physicality experimental conditions can be compared taining with electron microscopy is one
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of memory in an attempt to formulate a and findings can be replicated. Second, approach32. Other techniques are certainly
means of inheritance of acquired char- the variety of questions that can be asked on the horizon.
acteristics 28. Although this Lamarckian increases as volumes enlarge and multiple
notion is refuted for gene-based inheri- samples can be processed. If a complete Conclusion
tance, there is little doubt that humans do map of every synapse in a human brain is Despite the many arguments against
acquire information (by learning) during wanted, a serious obstacle is the fact that undertaking a connectomics analysis, we
their lives that affects their behaviors and at current speeds it would take 10 million think it must be done for three reasons.
then pass this information on to their chil- years to complete. First, the conditional patterns of synaptic
dren (among others) to alter their behav- connectivity generated during develop-
iors in nongenetic ways. A longstanding How fast can we go? The best technol- ment and by experience are inaccessible
goal of neuroscience is to determine the ogy currently available for producing con- to techniques that sample from only a
physical basis of an engram. nectomics data sets is high-throughput few cells at a time. Second, neuroscien-
An interesting feature of the highly electron microscopy. Large-scale electron tists cannot claim to understand brains as
redundant populations of neurons in microscopy data sets are now being pro- long as the network level of brain organi-
mammalian nervous systems is that they duced that are about 300 cubic microm- zation is uncharted; without this detailed
undergo dramatic changes in their connec- eters. For many circuits, this size is large information, neuronal physiology is
tivity in early postnatal life. Because these enough to encompass multiple com- connected to systems physiology by a
alterations are activity-dependent and plete axonal and dendritic arbors. There black box. Third, there is a high likeli-
transform diffusely connected networks are a number of ways that this technol- hood that such exploration will reveal
into many distinct subnetworks, this pro- ogy could be modified to produce a unexpected properties by shining a
cess could be the physical underpinnings 1050 fold increase in data-acquisition light (or electrons) on this most mysteri-
of memory14. rates in the next few years. However, the ous tissue.