B RA I N RE SE A R CH RE V I EW S 55 ( 20 0 7 ) 4 1 1–4 2 1
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v
Review
Relating the neuron doctrine to the cell theory. Should
contemporary knowledge change our view of the
neuron doctrine?
R.W. Guillery
Department of Anatomy, School of Medicine, University of Marmara, Haydarpaşa, Istanbul, 34668, Turkey
A R T I C LE I N FO
AB S T R A C T
Article history:
The neuron doctrine, formulated in 1891, attacked in 1906 by Golgi and fiercely defended by
Accepted 16 January 2007
Cajal, provided a powerful tool for analyzing the pathways of the brain. It has often been
Available online 20 January 2007
described as though it were merely the cell theory applied to nervous systems. In this essay I
show that the neuron doctrine claims more than does the cell theory, and that in many
Keywords:
instances, where it goes beyond the cell theory, it can no longer be defended on the basis of
Nerve cell
contemporary evidence. The neuron doctrine should be seen as a practical tool that is
Reticular theory
particularly useful for understanding the long pathways of the brain; it cannot be regarded
Synapses
as providing an accurate account of what nerve cells in general are really like.
Golgi
© 2007 Elsevier B.V. All rights reserved.
Cajal
Contents
1.
2.
3.
4.
5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .
How are the neuron doctrine and cell theory related? . . .
The strength of the neuron doctrine. What was the neuron
3.1. The synapse . . . . . . . . . . . . . . . . . . . . . .
3.2. The motor unit . . . . . . . . . . . . . . . . . . . . .
3.3. Neural degeneration and axonal transport . . . . . .
3.4. Developmental studies. . . . . . . . . . . . . . . . .
3.5. Molecular markers . . . . . . . . . . . . . . . . . . .
Some problems with the neuron doctrine . . . . . . . . . .
4.1. Fused neurons . . . . . . . . . . . . . . . . . . . . .
4.2. Gap Junctions. . . . . . . . . . . . . . . . . . . . . .
4.3. Serial synapses . . . . . . . . . . . . . . . . . . . . .
4.4. Some other issues . . . . . . . . . . . . . . . . . . .
Where does the neuron doctrine stand today? . . . . . . .
Postscript . . . . . . . . . . . . . . . . . . . . . . . . . . . .
E-mail address: [email protected].
0165-0173/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainresrev.2007.01.005
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412
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412
B RA I N R E SE A R CH RE V I EW S 55 ( 20 0 7 ) 4 1 1–4 2 1
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
1.
Introduction
The 1906 Nobel Prize recognized the advances that Golgi and
Cajal had made to our knowledge of nervous systems. Golgi’s
discovery of a new method and Cajal’s exploitation of it played
major roles in these advances, particularly in the development
of the neuron doctrine. The two laureates occupied opposing
positions in the fierce debate about the doctrine that long
preceded the award of the Prize. The debate continued during
the Prize ceremony and was to continue for many years after.
The present volume provides an opportunity for a new, contemporary look at the doctrine.
Both Golgi and Cajal made many important contributions
that extended into areas far beyond the neuron doctrine, but
for this brief essay I focus on the doctrine. I will argue that the
neuron doctrine, even though it still has major importance for
many areas of neuroscience, appears to be losing the central
position that it once held. The neuron doctrine recognized the
nerve cell as the developmental, structural, functional and
trophic unit of the nervous system and insisted that nerve cells
communicate at sites of contiguity not continuity. Together
with the law of dynamic polarization, which is often included
as a part of the doctrine and which recognized the dendrites
and the cell body as the receptive surface of a nerve cell with
the axon serving as the (single/unitary) effector portion of the
cell, the neuron doctrine formed a powerful tool for analyzing
the nervous system. Yet, today there are many younger
neuroscientists who know little about the doctrine, and
many of the fundamental points strongly defended by the
neuronists are no longer seen to be valid (Shepherd, 1991;
Bennett, 2002; Bullock et al., 2005; Guillery, 2005). Although the
doctrine is often presented as though it were simply the cell
theory applied to nervous systems, there are significant
differences, and it is now important to ask whether aspects
of the classical neuron doctrine that go beyond the cell theory
can still be defended.
all nervous systems are ‘really’ like. The tools will continue to
be useful even where the doctrine can be challenged.
The cell theory, announced for plants by Schleiden in 1838,
and extended to animals by Schwann in 1839 (Schleiden, 1838;
Schwann, 1839) recognized that animals and plants are made
up of distinct cells, each characterized by a nucleus, surrounded by cytoplasm and bounded by a cell membrane. New
cells arise from existing cells, and the division of the nucleus
plays an essential role in the production of new cells. For a
realistic view of the neuron doctrine in relation to the cell
theory it is important to recognize that the first description of
‘Schwann cells’ appeared in Schwann’s 1839 publication on the
cell theory (Fig. 1). This is important because the possibility
that nerve fibers are formed by the fusion of several of the
Schwann cells was maintained by many in later years and is
often referred to as the ‘catenary’ theory. Such a view of the
origin of axons is in direct opposition to the neuron doctrine,
which recognizes nerve fibers as the outgrowth of individual
nerve cells (His, 1886, 1889 and later Harrison, 1908, 1910, 1924),
but we will see that it is not, strictly speaking, contrary to the
cell theory, and did not become a contentious issue until the
basic concepts of the neuron doctrine were defined.
In 1861, Max Schultze, who was described by Cajal (1954) as
a “wise precursor of the neuron doctrine”, wrote a paper
(Schultze, 1861) that questioned exactly what should be
regarded as a cell. He focused on muscle cells and, noting
that the several nuclei in a single muscle cell are not separated
by membranes, suggested that a cell could be regarded as the
region around the nucleus, forming the unit for the generation
2.
How are the neuron doctrine and cell theory
related?
The neuron doctrine was formally proposed in 1891, more than
50 years after the cell theory, and many who have written
about the doctrine considered that it was merely a late
recognition of the fact that the cell theory applies to nervous
systems as much as to other tissues. In the following essay I
will argue: 1) that the neuron doctrine proved to be far more
restrictive than the cell theory; 2) that a number of observations made during the past 50 years appear to be against the
neuron doctrine without directly challenging the cell theory; 3)
that it may be useful to recognize the features of the neuron
doctrine that go beyond the cell theory, and 4) that, today,
aspects of the neuron doctrine that provided practical tools for
a reductionist approach to nervous systems in the past must be
distinguished from those that might appear to describe what
Fig. 1 – “Schwann cells” illustrated by Schwann in 1839.
These cells were often, but wrongly, regarded as the cells
responsible for producing the axons (the so-called catenary
view of the origin of nerve fibers; more details in text and in
Harrison, 1924).
B RA I N RE SE A R CH RE V I EW S 55 ( 20 0 7 ) 4 1 1–4 2 1
of further cells and not necessarily bounded by a membrane. It
is perhaps, therefore, not surprising that Schultze in other
studies (Schultze, 1863, 1871) described fusions of processes
arising from separate nerve cells in the olfactory and visual
pathways. In Stricker’s influential Handbuch (Schultze, 1871)
he stated: “There are fusions between neighboring nerve cells,
although it is very difficult to come to a certain conclusion
about the constancy or the frequency with which they
occur”.1 In 1872 in an account of the retina (Schultze, 1872)
he included a very rough drawing of the inner plexiform
layer, which leaves the relationships established by the
dendrites of the retinal ganglion cells entirely undefined
(Schultze, 1872). Schultze mentions a report by Corti of
anastomoses between the dendrites of retinal ganglion cells
in the elephant, where presumably the individual elements
are larger and easier to trace, and speculates that such
connections should perhaps be regarded as a regular occurrence in other species.
From the point of view of the connections he claimed
between nerve cells, Schultze must, therefore, be regarded as a
precursor of the reticular theory. Whereas in later years the
neuron doctrine would establish the discontinuity between
nerve cells, and stress the structural and functional unity and
independence of the individual nerve cell, the reticularists,
arguing from many different lines of evidence, favored the
continuity between adjacent nerve cells and their processes,
claiming to see fusions of the type described by Schultze in
many different parts of the nervous system of many different
species.
The long interval between the first statement of the cell
theory and the appearance of the neuron doctrine was due in
large part to the difficult problem of demonstrating that nerve
fibers are formed as the outgrowth of nerve cells (see
references to His and Harrison above) and are not formed by
the fusion of several distinct cells such as the cells of
Schwann. Further, the crucial observation that nerve cells
communicate at points of contiguities, not continuities
between individual nerve cells depended largely on the
development of the Golgi method and its exploitation,
particularly by Ramón y Cajal. The difficulties of demonstrating these relationships delayed the appearance of the neuron
doctrine by half a century, and when Waldeyer-Hartz formally
presented the neuron doctrine in 1891, it looked to many as
though, finally, the cell theory could be extended to the
nervous system. This has, as I will show, been a widely
accepted but mistaken view of the neuron doctrine ever since.
Waldeyer-Hartz produced, and Cajal demonstrated and
expounded something far more important than a simple
extension of the cell theory: a powerful way of looking at
distinct functional units in terms of which one could analyze
nervous systems.
The view of the neuron doctrine as an extension of the cell
theory to nervous systems was mistaken for two reasons. The
first and perhaps most important reason is that the neuron
doctrine claimed far more than did the cell theory. The cell
theory accepts multinucleate cells, so that today Schultze’s
view of muscle cells as consisting of many single elements
lacking a membrane is modified and treats muscle cells as
1
My translation.
413
multinucleate. The cell theory, even more significantly,
accepts fusions between cells to form syncytial structures,
such as the syncytial trophoblast of the placenta.
It is particularly relevant to note that Kölliker writing in
the fourth edition of his famous text-book (Kölliker, 1867),
having laid out the importance of the cell theory, went on to
consider how it might be that the sensory nerve fibers of the
dorsal root could communicate with the motor cells of the
ventral horn. He stated clearly that he was unable to see
continuities between nerve cells, recognizing that the resolution of the problem was beyond the methods that were
available to him. In spite of this, he proposed the connections
shown in Fig. 2, showing cells communicating at points of
continuity, which is an essentially reticularist view of the
spinal reflex, and he seems to have had no problem about
fitting this with his presentation of the cell theory in the
same book. Kölliker would later, influenced by Cajal and
convinced by his own Golgi preparations, change his view
about the reticular structure of the nervous system and
become a strong supporter of the neuron doctrine, but
initially he presented a reticularist view, perhaps the first
clear expression of such a view in terms of the structure of
individual nerve cells, and does not appear to have regarded
it as contrary to the cell theory.
Many years later it was still possible for a widely used and
highly respected textbook (Maximow and Bloom, 1930) to
present the basic structure of the cell theory and the neuron
doctrine itself and also to introduce multinucleate muscle
cells and syncytial epithelial structures. That is, the rule
against nerve cell fusions established by the neuron doctrine
went beyond anything that was implied by the cell theory for
muscle cells or for syncytial epithelial structures.
According to Young (1939) his earlier account of a fusion of
nerve fibers to form the squid giant axon was viewed in the
1938 edition of Maximow and Bloom as against the neuron
doctrine. Young wrote: ‘It is not necessary to delay over the
question of whether we should save the letter of the neuron
theory by saying that such cells are, by definition, not neurons
(see Maximow and Bloom, 1938). It is important to recognize
that the occurrence of such fusions does not invalidate the neuron
theory in general’ (Young’s italics). For Young the importance of
the neuron doctrine was as a tool for a reductionist analysis of
the nervous system, it was not necessarily an account that
must fit all nerve cells. For Maximow and Bloom, in contrast,
the neuron doctrine was a statement about the structure of the
real world. It strictly limited what a nerve cell could be like, and
seemed to exclude fused cells as neurons even though fused
cells were clearly acceptable to the cell theory.
In more recent years the view of the neuron doctrine as
merely the cell theory applied to nervous systems has been
expressed repeatedly by neuroscientists. Brodal (1969) in his
highly influential textbook wrote: “The neuron doctrine is in
reality nothing more than the cell theory applied to nervous
tissue.” In their 1976 text, Kuffler and Nicholls (Kuffler and
Nicholls, 1976) stated that: “the cell theory won general
acceptance and most biologists started to think of nerve cells
as being similar to other cells.” More recently Cowan and Kandel
(2001) again expressed this view when they wrote that the
reticularist view of the nervous system “challenged both the cell
theory in general and the neuron doctrine in particular.”
414
B RA I N R E SE A R CH RE V I EW S 55 ( 20 0 7 ) 4 1 1–4 2 1
particularly useful tool for studying nervous systems, and it
is important to understand where it can do this without going
beyond the cell theory.
There is a second reason for seeing the neuron doctrine as
including more than the cell theory. For many authors the
neuron doctrine has included the law of dynamic polarization,
the law that recognizes dendrites and cell bodies as the
receptive surface of nerve cells and the axon as the effector
surface. It can be argued that, strictly speaking, the neuron
doctrine as formulated by Waldeyer-Hartz in 1891 does not
include the law. The law was formulated later, after discussions between Van Gehuchten and Cajal (see Van Gehuchten,
1891; Van Gehuchten and Martin, 1891; Cajal, 1911) and added
very significantly to the analytical power of the neuron
doctrine because it provided crucial clues regarding the
direction in which messages pass through the nervous system
from one cell to another (see Figs. 3 and 4). The beginning of
Golgi’s attack on the neuron doctrine in his 1906 Nobel prize
lecture (Golgi, 1908) was an attack on the law, which he
probably saw as more vulnerable to attack than the doctrine as
laid out by Waldeyer-Hartz (1891). Although a polarized
structure is common in cells other than nerve cells, the cell
theory includes nothing about a polarized structure and the
Fig. 2 – Illustration used by Kölliker (1867). Although Kölliker
was clear that he could not see the relevant connections in
his own material, this schema represents a theoretical
view of how messages might be passed from the sensory
fibers of the dorsal root to the motor cells of the ventral horn
in order to produce a spinal reflex. It is essentially a
‘reticularist’ view of neural connectivity even though Kölliker
in the same book presented a clear view of the cell theory.
a, Axons of the motor root; b, motor cells in the ventral horn;
c, ‘motor conducting cell’; d, ‘motor conducting fibre’; e, the
process for connecting to the other half of the cord. All cells
are connected by Networks (Netze), of their branching
processes. a′–e′ indicate the corresponding sensory
components. Note that the arrows in this figure are based on
the law of Bell and Magendie (see Clarke and O’Malley, 1996),
which recognized the dorsal roots as afferent and the
ventral roots as efferent. The arrows do not relate to the
polarized structure of neurons, with the dendrites forming
the receptor and the axons the effector surfaces. This
distinction was recognized later, and expressed as the law of
dynamic polarization. The arrows in Fig. 4 are based on the
law of dynamic polarization.
Today it is important to recognize that there are aspects of
the neuron doctrine that are not part of the cell theory and go
beyond the cell theory. The neuron doctrine provides a
Fig. 3 – Cajal’s view of the connections between the dorsal
root and the ventral horn. This neuronist view is clearly
different from Kölliker’s view shown in Fig. 2, with each
nerve cell shown as a distinct unit.
B RA I N RE SE A R CH RE V I EW S 55 ( 20 0 7 ) 4 1 1–4 2 1
415
that go beyond the cell theory relegated to secondary
importance and subject to a separate evaluation. This would
allow for relationships between neurons that are acceptable
under the cell theory for cells in other tissues, would remove
several concerns about contemporary observations that
appear to go against the neuron doctrine (see e.g. Bullock et
al., 2005 and Section 4 of this essay), and would allow a
necessary discussion of what exactly it is that we should
expect our students to understand about the importance of
the neuron doctrine itself. It would recognize that neuroscience is a part of biology, and does not stand apart with
its own special rules. However, before presenting the arguments in favor of such a view it is necessary to ask what the
neuron doctrine offered to those who formulated and
defended the doctrine against attacks from many different
directions by the reticularists, and what it can still offer today.
3.
The strength of the neuron doctrine. What
was the neuron doctrine for?
Fig. 4 – Cajal’s view of some of the connections of cells in
the cerebral cortex (from Cajal, 1911). Notice that whereas in
Figs. 2 and 3 the arrows can be drawn in on the basis of the
law of Bell and Magendie, which recognizes the dorsal roots
as the inputs and the ventral roots as the outputs, in this
figure the arrows have to depend on the law of dynamic
polarization.
law of dynamic polarization, often included broadly as a part of
the neuron doctrine (e.g. Golgi, 1908; Shepherd, 1991; Guillery,
2005; Bullock et al., 2005), goes well beyond the cell theory.
In this essay I argue that where modern evidence appears
to be contrary to the neuron doctrine it is not contrary to the
cell theory. This leads to the suggestion that the neuron
doctrine should perhaps now be formally recognized as simply
an application of the cell theory to nerve cells, with aspects
The neuron doctrine provided a powerful tool for arriving at a
reductionist account of neural pathways. The doctrine, which
recognized the nerve cell as an independent unit, developmentally, structurally and functionally, when it was
combined with the law of dynamic polarization, provided a
view of how messages could be sent from one nerve cell to
another along the individual pathways and circuits of the
brain (see Fig. 4). This was something that the reticularist
view could not provide. Cajal expressed this weakness of the
reticularist view when he wrote: “The reticular theory offers
an attractive and convenient explanation… the inestimable
one of explaining in a simple manner the propagation of the
nerve impulse from one neuron to another and the diffusion
throughout the gray substance in a number of directions.”
(Cajal, 1954). It is hard to miss the sarcasm here, and important
to relate this statement to a contrary view expressed by Golgi
(1908) when he wrote: “one becomes convinced that one single
nerve fibre may have connections with an infinite number of
nerve cells.”
Golgi went on to argue more generally against the cerebral
localization of function: “I cannot abandon the idea of a unitary
action of the nervous system.” Here it is worth recalling that in
the interval between the formulation of the cell theory and the
neuron doctrine, Broca, Hughlings Jackson, Brown-Séquard,
Ferrier, Fritsch and Hitzig (references in Clarke and O’Malley,
1996), among others, had all contributed to a view of the brain as
having distinct functional parts. Golgi’s ‘unitary view’ had by
1906 already lost against a reductionist view that was expressed
by localization of function in the parts of the brain on the one
hand, and by the discrete connections of individual nerve cells
dictated by the neuron doctrine on the other. Golgi’s view made
the brain unanalyzable in reductionist terms, and this was
probably one of its attractions for many reticularists, who
favored a holistic approach. We have to recognize that two
issues were being confronted as the neuronists battled the
reticularists. One was about what the nervous system was
‘really’ like, and the other was about the best way in which to
understand the brain: reductionist or unitary and holistic. The
two issues are often confused.
416
B RA I N R E SE A R CH RE V I EW S 55 ( 20 0 7 ) 4 1 1–4 2 1
It is important to recognize that the neuron doctrine has
provided a powerful reductionist tool for many years, and as
such it has had a remarkable success. The power of this tool
will continue, and it would be an error to see criticisms of
the neuron doctrine as a denial of the continued use of these
practical aspects of the doctrine. It is beyond the scope of
this essay to provide details of the many ways in which the
neuron doctrine has provided a useful tool for the study of
nervous systems generally, but it is important to stress the
wide range of issues that have been, and continue to be
addressed successfully on the basis of concepts based on the
neuron doctrine. Figs. 3 and 4 illustrate the power of the
neuron doctrine (together with the law of dynamic polarization) for an analysis of the circuitry of the brain. As both
Golgi and Cajal recognized, such an analysis is impossible on
a reticular theory of neural connections. There follow a few
examples of conceptual structures that are dependent on the
neuron doctrine, structures that have played an important
role in experimental approaches to neuroscience in the past,
and that will no doubt continue to do so.
3.1.
The synapse
Perhaps most strikingly, Sherrington’s introduction of the
concept of the synapse (Sherrington, 1897), immediately dependent on the neuron doctrine, provided a further essential tool
that has served, and still serves as a vital concept for understanding how nerve cells function and communicate with each
other (see especially the recent volume: Cowan et al., 2001 ‘The
Synapse’ for a summary of much contemporary work on
synapses). Without the neuron doctrine it would have been
difficult to arrive at modern views of the synapse.
3.2.
The motor unit
An additional concept introduced by Sherrington (1906), of the
motor unit, was also clearly dependent on Cajal’s view of a
neuron, and today the functional view of single nerve cells
having a single axon with possibly multiple output terminals,
all transmitting essentially the same message, underlies much
of our basic understanding of neural functions, including
interpretations of vast numbers of highly informative ‘single
unit’ recordings, in vivo or in vitro. Much of our knowledge
about the functions of nerve cells rests on single and multiple
unit recordings that assume the functional unity of the nerve
cell. The view of nerve cells as units of function that deliver
essentially the same message at all of their axon terminals still
has much to offer neuroscience, although we will see in
Section 4 that modern evidence does provide some caveats.
3.3.
Neural degeneration and axonal transport
Studies concerned with changes produced by damage to axons
or cell bodies depend heavily upon conceptual structures
based on the neuron doctrine. The axon is a part of the single
unit, the nerve cell, and depends for its sustenance and
survival upon the integrity of the cell. Our views of pathological changes in the nervous system, and our interpretations
of great numbers of tract tracing studies have depended on the
trophic relationships between the axon and the cell body of
single nerve cells. Methods for tracing fiber pathways have
depended on the degenerative changes that occur in an axon
when it is cut (e.g. Brodal, 1969; Nauta and Ebbesson, 1970) and
on axoplasmic transport of proteins produced in the cell body
(anterograde transport) or taken up by the axon terminals
(retrograde transport). Examples can be found in Grafstein and
Murray (1969), LaVail and LaVail (1975), Lasek et al. (1984),
Kuypers and Ugolini (1990) or Bolam (1992).
These methods are all based on the conceptual structure of
the neuron doctrine and would have been hard to interpret or
exploit on any other basis. Certainly, a reticularist view would
have provided an inadequate guide for understanding the
effects of neural injuries or the changes due to axoplasmic
transport. Interpretations that lead us to a clear view of central
pathways and connections would have been difficult to
achieve on the basis of Gerlach’s or Golgi’s reticularist views
of neural connections.
3.4.
Developmental studies
Modern studies of neural development and axonal growth,
particularly those concerned with the developmental identity
of individual nerve cells or with the structure and guidance of
growth cones are essentially based on the neuron doctrine
(see for example, Marcus and Mason, 1995; Gordon-Weeks,
2000; Panzer et al., 2006). Contemporary studies generally
assume that the neuron doctrine applies, although the issue is
rarely discussed. It is difficult to conceive of basic principles
derived from a reticularist view that might serve contemporary developmental neuroscientists.
3.5.
Molecular markers
Many contemporary studies that involve the labeling of
individual nerve cell classes with particular molecular markers (see e.g. Fig. 5) not only assume the distinct unity of
individual nerve cells, but also serve to confirm this unity.
These are just some important examples that demonstrate the continuing power of the neuron doctrine. A
reticularist view of nerve cells would have produced
difficulties for each area of study, and would often have
made a functional analysis impossible. Each example
depends on seeing the nerve cell as a single unit that fits
the cell theory. The essential question from the point of view
of the present essay is whether the cell theory, allowing for
some secondary fusions of neural processes, for cells not
polarized in the classical pattern, or for cells with several
distinct functional parts (see below), can provide all that
these several areas of study need. The question merits more
detailed discussion than is possible here. I am inclined to
conclude that the cell theory will suffice for all practical
purposes and to hope that by raising the issue here I will
stimulate the necessary discussion.
It is important to recognize the fundamental power of the
neuron doctrine before looking at problems that might indicate
a need for a modified view of the doctrine (see e.g. Shepherd,
1991; Bullock et al., 2005; Guillery, 2005). The importance of the
neuron doctrine is widely recognized, but the nature of its
power as an experimental tool is rarely explored. The neuron
doctrine has to be seen as a tool, and should not to be regarded
B RA I N RE SE A R CH RE V I EW S 55 ( 20 0 7 ) 4 1 1–4 2 1
Fig. 5 – Figure to show the extent to which particular
molecular markers can identify a single type of neuron and
be limited to individual nerve cells or glial cells, as would be
expected on the basis of the neuron doctrine. The figure,
kindly provided by Dr. C. Cepko, shows a confocal image of a
section of a rat retina that had been electroporated in vivo on
the day of birth with three reporter constructs: rhodopsin
promoter-ECFP (photoreceptor cells, cyan), calcium binding
protein 5 promoter-EYFP (bipolar cells, yellow) and cellular
retinaldehyde binding protein-DsRed2 (Müller glial cells,
red). The tissue was analyzed on postnatal day 14. Cell nuclei
are stained with DAPI (blue). Figure reproduced with
permission from Matsuda and Cepko (2004).
merely as an accurate and single view of what all neurons are
‘really’ like. The doctrine has proved particularly useful in the
analysis of long pathways, and where it seems to be weakest
today is in the study of local circuits. We have to recognize that
the neuron doctrine has been extremely useful in the past, that
it continues to serve us as a practical conceptual tool today
especially for the study of long pathways and their development, and that its role in providing a general abstract view of
some ideal that would fit all nerve cells has never been an
important practical part of its function.
4.
Some problems with the neuron doctrine
4.1.
Fused neurons
We have seen the fused neurons that produce the giant axons
of squid as one early, well-documented example of a situation
that is against the strict letter of the neuron doctrine but can fit
easily into the cell theory. I shall say no more about this.
4.2.
Gap Junctions
In 1956 it appeared to many that the final evidence in support
of the neuron doctrine had been provided by the electron
417
microscope when De Robertis and Bennett (1955) and Palay
(1956) had confirmed earlier light microscopic accounts of a
membranous separation of neural processes at the synaptic
junction (the synaptolemma of Bodian, 1942). Just one year
later, when Furshpan and Potter (1957) described electrical
transmission at a synaptic junction, the door was opened to a
problem at some of these membranous junctions, because
before long it became apparent that such electrical transmission involved ‘gap junctions’, junctions that allowed transport
of small molecules across a synapse (see Bennett, 1972, 2002;
Bennet and Zukin, 2004; Saez et al., 2003, for details). Small dye
molecules injected into one cell could be seen to stain adjacent
nerve cells by passing through small holes in the gap
junctions, a point that is directly counter to the view of
contact by contiguity, not continuity, proposed by the neuron
doctrine. Loewenstein (1981) has suggested that this property
of gap junctions is also against the cell theory, but this is not a
view that has had significant support, and it would appear
that the cell theory remains essentially untouched by junctions leaky to small molecules.
Demonstrations of nerve cells linked by gap junctions can
now be found at many sites (Bennett, 1972, 2002) and include
recent accounts of inhibitory interneurons joined to each
other as an inhibitory ‘network’ in the cerebral cortex
(Galarreta and Hestrin, 2001; Gibson et al., 2005), which today
raise little concern as to how this network might relate to the
neuron doctrine or the reticular theory, even though it can
serve as an example where functional links across the synapse
produce ‘reticular’ structures of the sort denied by the neuron
doctrine. It should be recognized that one of the reasons why
these ‘reticular’ structures do not necessarily produce the
unanalyzable “diffusion throughout the gray substance in a
number of directions” described by Cajal (1954) is that they
relate to a population of other cortical neurons that seem still
to be in accord with the neuron doctrine and are analyzable in
relation to this proposed inhibitory network. A reductionist
approach to the nervous system need no longer be threatened
by such networks.
4.3.
Serial synapses
In so far as the law of dynamic polarization can be treated as a
part of the neuron doctrine, serial synapses, which have one
synaptic terminal synapsing upon another, clearly present a
problem. If dendrites are necessarily and exclusively postsynaptic, and axons are necessarily and exclusively presynaptic, as they are according to the law, then serial synapses
should not be found. In 1962 Kidd (Kidd, 1962) presented
electron microscopic evidence for serial synapses in the
retina, which were later shown to be the dendrodendritic
synapses of amacrine cells, and Gray (1962) demonstrated
serial synapses in the spinal cord. The latter provided a
morphological basis for axo-axonal contacts that Eccles et al.
(1961, 1962) had earlier postulated on the basis of a presynaptic inhibition of dorsal root axons demonstrable in the dorsal
horn of the spinal cord. Subsequently, serial synapses were
also demonstrated at other sites, including the thalamus
(Szentágothai, 1963; Colonnier and Guillery, 1964), the posterior column nuclei (Walberg, 1965) and the olfactory bulb
(Hirata, 1964; Rall et al., 1966).
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These and other serial synapses raise a problem not merely
for the law of dynamic polarization, but also for the neuron
doctrine in the narrow sense as formulated by Waldeyer-Hartz
(1891), because they produce an opportunity for the parts of a
nerve cell to have independent actions. If an axon terminal
receives presynaptic inputs, or has receptors that are local, not
shared by the other axon terminals belonging to that same
nerve cell, and not producing a depolarization that is
transmitted to all of the other axon terminals of that cell,
then the several axon terminals will not provide that nerve
cell with a single ‘unitary’ output function. Depending on the
distribution of the terminals that are presynaptic to any one
axon and its branches, some of the postsynaptic axon
terminals may be subjected to one action whereas other
axon terminals from the same axon will be subjected to
another, and thus the two branches will have different
actions; the functional unity of the neuron would be lost.
The same holds for the postsynaptic dendrites at dendrodendritic junctions. If these do not conduct the local membrane
change produced at an individual dendrodendritic synapse
back to the cell body and to other dendrites of the same
postsynaptic cell, then each postsynaptic dendrite will have
an action that is independent of the other parts of the cell, and
the unitary function of the nerve cell is, again, lost (e.g. Zhou et
al., 2006). Perhaps the most spectacular demonstration of this
capacity of a single vertebrate nerve cell to serve several
distinct functions is seen for the starburst amacrine cells of
the rabbit’s retina, which have a central cell body and
dendrites radiating out in all directions. Each of these
dendrites is capable of signaling to the retinal ganglion cells
and through them to the brain, a different direction of motion
of a stimulus in the visual field, corresponding to the direction
of the dendrite (Taylor and Vaney, 2003; Dong et al., 2004;
Poznanski, 2005; Masland, 2005). This is a capacity that is
entirely unacceptable on a standard view of the neuron as the
functional unit of the nervous system, but can be readily
accommodated in the cell theory.
4.4.
Some other issues
There are several other examples of situations where it has
been suggested that contemporary knowledge challenges the
classical view of the neuron doctrine. One example, the
‘trophic’ independence of neurons, has been discussed more
fully by Guillery (2005). This was introduced into the early
discussions of the neuron doctrine by Forel (1887), was
included by Waldeyer-Hartz in his 1891 account, and is widely
taken to imply that nerve cells have no trophic interactions
with each other (see Cowan and Kandel, 2001). Today we know
enough about the actions of trophic substances to understand
that nerve cells do depend upon other cells (nerve cells as well
as glia). The trophic unity of a nerve cell today can only refer to
the fact that axons are trophically dependent upon the
perikaryal region of the same cell, and that the perikaryal
region will often react to damage of its axon. The trophic unity
of the neuron cannot imply more than this in terms of current
knowledge. When the nerve cell is viewed in terms of the cell
theory, the degree to which the parts of a single nerve cell may
depend upon each other, or one cell may be dependent upon
another does not appear to be counter to the cell theory, even
where transneuronal (or trans-synaptic) degenerative changes
may appear to be a problem for the original neuron doctrine
expressed by Waldeyer-Hartz (1891) (see, Cowan, 1970; Cowan
and Kandel, 2001).
The functional independence of nerve cells as viewed by
the neuron doctrine is sometimes taken to imply that glial
cells can have no actions on nerve cells (see Bullock et al.,
2005). Today it is clear that glia do have actions on nerve cells
(Takano et al., 2005; Verkhratsky and Toescu, 2006), and the
functional dependence of nerve cells on other cell types
should not be regarded as contrary to the neuron doctrine as it
was originally formulated, nor, of course, can it be regarded as
contrary to the cell theory.
Bullock et al. (2005) raise the interesting issue of how
different types of conduction, decremental or all-or-none,
relate to the neuron doctrine. Whereas for many years the
former was thought of as characteristic of dendrites and the
latter of axons, this distinction is no longer valid. This
functional distinction between axons and dendrites relates
to the law of dynamic polarization but goes beyond it, and
where the distinction breaks down it appears to be contrary to
the law. However, it is a distinction that does not really
challenge the neuron doctrine and fits easily within the cell
theory.
Dale’s law (Dale, 1935), which stated that a single nerve cell
produces the same transmitter at all of its axon terminals,
clearly depended on the neuron doctrine. The law had to be
modified when it was discovered that a single nerve cell could
produce and release more than one transmitter (summarized
by Cowan and Kandel, 2001), but that still could be seen as in
accord with the neuron doctrine. However, the suggestion that
there are nerve cells that can release distinct transmitters at
different terminals (Sossin et al., 1990) has to be seen as
contrary to the neuron doctrine. It is not clear whether such
cells are common. The mechanism of their action must be
distinguished from cells whose terminals produce different
actions by relating to different postsynaptic receptors. A cell
that itself produces different functional outputs at each of its
terminals is not a functional unit and it cannot reasonably be
regarded as fitting the neuron doctrine.
5.
Where does the neuron doctrine stand
today?
Exactly how one views the neuron doctrine today depends on
what one expects the doctrine to do. If the doctrine is to
provide rules that apply to all nerve cells then it is probable
that no single generalization that is more stringent than the
cell theory will be applicable at the level of the single neuron. It
may well be necessary to break the neuron up into smaller
units, as proposed, for example by Shepherd (1974, 1991, 1999),
who has suggested that the individual synapse be recognized
as a useful unit for analysis. Although it is clear that neither
the neuron doctrine nor the cell theory can provide an ultimate
level for analysis, the next level from the neuron, down to
smaller units for analysis has not received much attention to
date. It may be doubted whether the synapse will provide a
useful, long-term, intermediate concept for analysis. At an
early stage we have to expect a further breakdown, producing
B RA I N RE SE A R CH RE V I EW S 55 ( 20 0 7 ) 4 1 1–4 2 1
an analysis at the level of individual units such as those
represented by transmitters, receptors or ion channels. Then
the theoretical basis for understanding nervous systems will
be seen to be at the molecular level, which is the level at which
much of contemporary neuroscience operates today. At this
level, the molecules generally provide an appropriate ‘unit’ for
a reductionist analysis and the power of the neuron doctrine
becomes less relevant. That is, we have to recognize the level
at which the neuron doctrine can be expected to operate and
to ask whether we want an accurate account of what the world
at that level is really like, or a generalization that provides a
useful framework for interpreting experimental results at the
cellular level. Do we want a view of a postulated reality or a
useful tool?
We have seen that for many contemporary experimental
approaches dealing with central pathways the neuron doctrine, where it does not represent more restrictions than does
the cell theory, can still provide a powerful tool. This is true for
studies of single cells or populations of cells, particularly for
long pathways as opposed to local circuitry involving axonless
cells and glia. Generally this tool works well. For some
purposes a reductionist analysis of neural pathways and
circuits (that is, an analysis at the cellular level), can usefully
employ a more restrictive model, including nerve cells that are
not leaky at junctions, or nerve cells that are clearly polarized
with distinct receptor (dendritic) and effector (axonal) parts.
Where such nerve cells can be identified they can lead to
important conclusions in terms of the full, unrestricted neuron
doctrine, and about the nature of the circuitry of which those
cells form a part. This was one of the great achievements of the
neuronists, and the method does not have to be abandoned
provided that one recognizes that exceptions occur. It is a
method, not an account of reality. There is no “ideal” neuron;
neurons, like cells in the rest of the body vary greatly in the
details of their structural and functional organization, and
when we recognize the strength of the neuron doctrine as an
analytical tool we must also recognize its limitations.
6.
Postscript
One question that is often raised, and hard to answer,
concerns the terminology. Why do we have the alternatives
of neuron ‘doctrine’ and neuron ‘theory’, coupled to a ‘law’ of
dynamic, or functional, polarization? Whereas a doctrine
generally relates to religious or political ideas that cannot be
questioned, a theory has a more natural place in science as
something that should be questioned, and a law generally has
a wider range of meanings. Cajal in 1899 in the original
Spanish version of his famous textbook (Cajal, 1995) contrasted the facts and doctrine (‘los hechos’ and ‘la doctrina’)
with imperfect observations based on fallacious methods and
risky theories (‘las observaciones imperfectas, basadas en
métodos falaces’, and ‘las teorías harto aventuras’). Yet the
English translation of Cajal’s summary essay on the neuron
doctrine, ‘Neuronismo o Reticularismo’ (see Cajal, 1954) was
rendered as ‘Neuron Theory or Reticular Theory’ and the first
line of the text reads: ‘…the doctrine of the individuality of the
constituent elements of the gray substance.’ The term
doctrine seems to be most widely used in accounts written
419
in English, although “theory” and “doctrine” are often interchangeably used. Van Gehuchten in 1897 wrote about the
‘théorie des neurones’ and Barker, in 1898 on the “Neuron
Doctrine”, giving both terms a long history.
Acknowledgments
My thanks to Murray Sherman, Luis Populin (who also helped
with the Spanish of the postscript), Daniel Lllano, Carmen
Varela, Richard Wingate and Emil Toescu for helpful comments on an earlier draft of this essay. The departments of
anatomy at the University of Wisconsin, Madison and at the
University of Marmara, School of Medicine, Haydarpaşa,
Istanbul, provided generous hospitality while this manuscript
was in preparation.
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