Download CONTROL OF CELL NUMBER IN THE DEVELOPING MAMMALIAN

Progress in NeurobiologyVol. 32, pp. 207 to 234, 1989
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Copyright © 1989 Pergamon Press plc
CONTROL OF CELL N U M B E R IN THE DEVELOPING
M A M M A L I A N VISUAL SYSTEM
BARBARA L. FINLAY a n d SARAH L. PALLAS*
Department of Psychology and Section of Neurobiology and Behavior, Cornell University, Ithaca,
NY 14853, U.S.A.
*Present address: Department of Brain and Cognitive Sciences, E25-618, M.LT., Cambridge,
MA 02139, U.S.A.
(Received 15 September 1988)
CONTENTS
I. Introduction
208
1.1. Conceptual frameworks in which the control of cell number has been investigated
208
1.2. Comparative approaches to the control of cell number
2O8
1.3. Numerical relationships of visual system components in mammals
2O9
1.4. Variability in convergence ratios of cells within the visual system
210
2. Developmental studies of control of cell number
211
2.1. The retina: retinal ganglion cells
211
2.1.1. Normal cell addition and loss
211
2.1.2. Generational control of retinal ganglion cell number
211
2.1.3. Efferent and afferent control of cell number
211
2.1.3.1. Target control of cell number
212
2.1.3.2. Afferent control of cell number
213
2.1.4. Error correction
213
2.1.5. Sculpting
214
2.2. The retina: amacrine cells, bipolar cells, horizontal cells and photoreceptors
214
2.2.1. Normal cell addition and loss
214
2.2.2. Efferent and afferent control of cell number
214
2.2.2. !. Photoreceptors
214
2.2.2.2. Amacrine cells and bipolars
215
2.3. Superior collicuhis
215
2.3.1. Normal cell addition and loss; sculpting
215
2.3.2. Efferent and afferent control of cell number
215
2.4. Lateral geniculate nucleus
216
2.4.1. Normal cell addition and loss; sculpting
216
2.4.2. Afferent and efferent control of cell number
216
2.5. Parabigeminal nuclei: efferent and afferent control of cell number
216
2.6. Visual cortex
217
2.6.1. Normal variability in adult neocortical cell number
217
2.6.2. Normal cell generation and death in the visual cortex
217
2.6.2.1. Generation and migration
217
2.6.2,2. What is the normal pattern of cell death in visual cortex?
218
2.6.3. Efferent and afferent control of cell number
218
2.6.3.1. Error correction
218
2.6.3.2. Target availability
218
2.6.3.3. Afferent availability
219
2.6.3.4. Generation of cytoarchitectonic differences (sculpting)
220
3. Physiological consequences of changes in afferent and efferent convergence ratios
220
3.1. Effect of decreased afferent activity on physiology of target cells
220
3.2. Effect of decreased afference/excess target on physiology
221
3.3. Effect of excess afference/decreased target on physiology
222
4. Summary and overview
224
4.1. What is the function of cell death in the developing visual system?
224
4.2. What features of connectivity or convergence are regulated in the early development of the visual system? 225
4.2.1. Cell generation
225
4.2.2. Afferents
226
4.2.2.1. Cell number
226
4.2.2.2. Presynaptic axon arbor size
226
4.2.3. Target availability
226
4.2.3.1. Cell number
226
4.2.3.2. Postsynaptic dendritic arbor size
227
207
208
B.L. FINLAY and S. L. PALLAS
4.2.4. Afferent/target ratios
4.2.4.1. Cell number ratios
4.2.4.2. Synaptic density
4.2.5. Summary
4.3. Some evolutionary considerations
Acknowledgements
References
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1. INTRODUCTION
the evolutionary history of the animal. Comparative
and evolutionary biologists might point to the size in
the lateral geniculate in closely related species of
comparable body size as the reason for the particular number of geniculate cells in the species of
interest. Finally, the nature of the animal's development might be given as the reason. Developmental
neurobiologists might argue that because of competition for terminal space in the visual cortex, only
a certain number of lateral geniculate cells might
receive enough trophic substance to survive, thus
determining their number.
These explanations represent different aspects of
biological argument and are not contradictory, but
are too often kept separate. In the following review,
we will principally discuss information from developmental neurobiology on control of cell number in
the visual system, and we will attempt to begin an
integration of this information with comparative and
evolutionary approaches. The contrast between these
two fields is interesting, because for evolutionary
biology the individual is a unit of variability, and the
data to be explained are the variations in brain size
and organization across individuals and species. For
the developmental neurobiologist, a typical research
approach is to determine what developmental processes conserve or stabilize the cell number of a
particular brain area, or defend a constant ratio
relationship between cells in interconnecting populations in the nervous system: i.e. how, in individual
animals, development is regulated against variability.
Since species variations in brain organization must
arise out of variations in developmental programs,
these two approaches could profitably be integrated
(Finlay et al., 1987; Wikler and Finlay, 1989). In
particular, we will ask if there is any information
from the developmental neurobiology of the visual
system which might shed light on the patterns
observed in visual system evolution.
Cells are the fundamental units for the organization and transmission of information in the
nervous system. The number and density of photoreceptors limits the grain with which the visual world
can be sampled. The inescapable limitation imposed
by cell number and related processing capacity constrains the form of the visual system and the nature
of visually guided behavior. For example, Hughes
(1977) has calculated that if the ganglion cell density
of the entire Cat retina was the same throughout as
the peak of cell density in its area centralis, and the
visual cortex were also proportionately increased, the
visual cortex (area 17) of the cat would have to be five
times larger than the human visual cortex. Rather
than processing high resolution views of the visual
world in parallel, with a uniformly high receptor
density, high resolution views of the visual world in
animals specialized for high-acuity vision are processed serially using head, eye and body movements
for successive fixations. The evolution of the neural
machinery for producing, processing and comparing
successive views of the world through eye movements
can be thought of as a consequence of the constraints
imposed by limitations of cell number and processing
capacity. The nature of cellularly economical ways of
organizing visual information is clearly important for
understanding the paths of visual system evolution.
Cell number in the visual system must also be
understood in terms of the more general constraints
on cell number in the entire developing vertebrate
brain (Williams and Herrup, 1988). In the following
review, we will summarize evidence about the specific
mechanisms of control of cell number for a variety of
components of the visual system and evaluate the
consequences of these mechanisms in the larger
domain of visual system function and control of cell
number in the brain overall.
1.1. CONCEPTUAL FRAMEWORKS IN WHICH THE
CONTROL OF CELL NUMBER HAS
BEEN INVESTIGATED
In answering the question of why organisms have
come to be in their current state or, in this case, why
the visual system of a certain animal contains a
certain number of cells, a variety of types of explanations can be offered. First, an explanation could
be given in terms of the function of the visual system
and its optimal design: why a feature is necessary
for proper visual functioning. For an example of
this type of explanation, typically used by neuroanatomists, physiologists or psychophysicists, the
number of cells in the lateral geniculate nucleus
should equal the number of transmission cells in the
retina so as not to lose spatial resolution. Alternatively, an explanation could be given in terms of
1.2. COMPARATIVE APPROACHES TO THE CONTROL
OF CELL NUMBER
The nature of developmental control of cell
number for an entity like the "visual system" is
poorly understood. The central issue is; what units of
the visual system or brain independently vary from
species to species? At what level of organization in the
nervous system can cell number vary independently,
so that a change might be selected for? There are a
variety of approaches to this question that come from
comparative anatomy, all of which account for part
of the variations between species. Some emphasize
overall brain-body or metabolic relationships, some
particular organ systems (like the cortex or cerebellum) and some functional systems (like the visual
system).
Students of allometric relationships of brain and
CELL NUMBER CONTROL IN DEVELOPING VISUAL SYSTEM
body point to the lawful relationships of brain and
body size (for a comprehensive review see Eisenberg,
1981). Within any vertebrate radiation, overall brain
size is an exponential function of body size. Both of
these variables in turn can be related to length of
gestation, to rate of growth and to other metabolic
constraints in v a r y development. The relative constancy of this function across vertebrate radiations
has suggested that if an animal is selected for a
certain body size or rate of development, a certain
brain size is concurrently specified by whole-animal
genetic constraints. It is also possible, however, that
these allometric regularities represent stable, multifactorial solutions to selection pressures encountered
repeatedly and not direct genetic control of both
body size and brain cell number as a single specifiable
unit (Mann et al., 1988).
At any particular body size, however, there is a
large residual variation in brain size unaccounted for
by allometric regularity, as much as 5-10 to 1 in
mammals (Northcutt, 1981). To account for this
residual variability, a second description of the nature
of change in the vertebrate brain is "encephalization"
(Jerison, 1973): that complex system shows increases
in the relative importance of the telencephalon, particularly neocortex (or the cerebellum, Northcutt,
1981). The underlying hypothesis of encephalization
is that particular structures like the neocortex are
particularly likely to show an increase in size over
evolution, within a functionally defined system like
the visual system, and perhaps across several
functionally-defined systems.
Residual variation in brains could also be accounted for in part by hypertrophy or atrophy of
particular functional systems. For example, animals
are often described as "more visual" or "less visual"
based upon the extent to which they depend upon
vision in their behavior, and their corresponding
anatomy is often thought to show this distinction
throughout, from size of eye to corresponding visual
cortex to visuomotor components, as in the traditional testbook comparisons of rat and monkey.
However, it is not known whether "the visual
system" is a genetic unit all of whose parts might
become smaller or larger in concert: a systematic
study of the relative size and number of components
in animals classified as more or less visual has not yet
been done. Visual system components might only
change in a piecemeal fashion.
To resolve and integrate these approaches, information on the numerical relationships of numbers
of cells in different visual system structures in a
variety of species is necessary. However, this information is quite sparse, and developmental investigations
sparser still. We will first list what is known about the
numerical relationships of visual system structures
in a few widely studied mammals for a preliminary
sense of what, if anything, is conserved across the
visual system in the numerical relationship of components. Next, we will review developmental investigations of control of cell number to determine
what regulatory forces exist, and how they might
account for phylogenetic trends in visual system
organization.
1.3. NUMERICAL RELATIONSHIPS OF VISUAL SYSTEM
COMPONENTS IN MAMMALS
Very few mammals have been assessed comprehensively for the number of neurons in their retinae and
associated central structures. Since exising studies are
not systematic and overrepresent rodents, definitive
conclusions about phylogenetic trends, or regularities
in ratio relationships between visual system structures are difficult. Nevertheless, inspection of these
data can produce some useful initial observations
(Table 1).
For closely related animals that differ in body size,
how does the visual system differ? The most systematic data available come from a recent study of Hallet
(1987), who studied scaling relationships in the visual
system for the mouse and rat, animals which have
similar overall morphology and visual ecology, but
different body size. He concludes that the two species
have linearly scaled optics (i.e. cross sections of their
eyes are superimposable with an appropriate scaling
TABLE 1. NUMBERSOF CELLSIN THE RETINAAND PRINCIPALVISUALNUCLEI
Animal
Photoreceptors
RGC
LGN
SC
VC (17)
Hamster ~
-72
36
100
760
Gerbil2
-160
140
--Mouse 3
6,412
50
21
90
440
Rat 3
23,570
110
120
394
1,100
Cat4
150
29,000
Monkey5
127,000
1,300
1,400
-150,000
Human 6
1,100
--538,000
Entry = cells x 1000.
Legend: RGC, retinal ganglion cell; LGN, lateral geniculate nucleus; SC,
superior colliculus; VC, visual cortex.
1. Mesocricetus auratus: RGC, from Linden and Esberard, 1987; LGN, Finlay
et al., 1985; SC and VC, unpublished results, this laboratory.
2. Meriones unguiculatus: RGC, unpublished results, this laboratory.
3. All mouse (C57Bl/6J pigmented) and rat (Long-Evans) as reviewed in
Hallet, 1987; also Peters, 1987 for VC.
4. Domestic cat: RGC, Williams et al., 1986; VC, Beaulieu and Collonier,
1983.
5. Macaccamulatta: RGC, Rakic and Riley, 1983; LGN, Williams and Rakic,
1988; VC, Peters, 1987.
6. Homo sapiens: RGC, Provis, 1985b; VC, Peters, 1987.
JPN 32/3~C*
-
-
-
-
209
-
-
-
-
210
B. L. FINLAYand S. L. PALLAS
factor), and equal photoreceptor spacings. Since the
retinal area is four times larger in a rat than a mouse,
the rat has thus four times as many photoreceptors.
Note, however, that while photoreceptors and central
structures change their numbers by a factor of four
between these animals, number of ganglion cells
changes only by a factor of two (Table 1), and central
structures change variable amounts between two and
four.
For closely related animals of the same body size
but different visual capacity, how does the visual
system differ? Gerbils (Meriones unguiculatus) and
hamsters (Mesocricetus auratus) present such a comparison. First, visual system size is obviously dissociable from body size: the gerbil has more than
twice the retinal ganglion cells of the hamster, and 3.5
times more cells in the lateral geniculate body. Interestingly, the scaling relationships are quite comparable to that seen in the mouse/rat comparison. This
suggests that the visual system can in fact change as
a unit, but does so without preserving 1:1 ratios of
cells in its components as the visual system becomes
larger or smaller.
For the more distantly related species shown here,
the number of ganglion cells is peculiarly unrepresentative of either intuitions about the animal's
visual capacity or known information on their visual
acuity (Wilkinson, 1984); the topographic arrangement of these cells is quite different, however, and
does correspond to behavioral acuity (Hughes, 1977).
For any one species the numbers of cells in these
various brain areas do roughly covary, as might be
expected from gross allometric studies of the relationship of brain to body size (Eisenberg, 1981).
However, there is little to suggest a constant ratio
relationship between the numbers of cells in these
visual nuclei. The ratio of ganglion cells to number of
cells in subcortical target nuclei does vary less than
ratios involving the cortex. Particularly striking is the
variability of absolute numbers of neurons in primary
visual cortex, and the varying ratios of the number of
cells in primary visual cortex and the lateral geniculate nucleus, which in this data set ranges from 2.5 : 1
(rat) to about 100:1 (human). Humans have only 10
times the number of ganglion cells as do rats, but 400
times the number of cells in primary visual cortex
(Hallet, 1987; as reviewed in Peters, 1987). In addition, extreme individual variability in the area of
striate cortex in macaques has been described (Van
Essen et al., 1984): in a study of 31 monkeys, the area
of striate cortex ranged from 690 mm 2 to 1560 mmL
Failure to find a constant ratio relationship
between these areas is not surprising in that each of
these nuclei connect to other brain areas, and the
neurons that compose them vary in a number of
ways, including somal conformation and size, and
axonal branching patterns. Attempts to assemble
information like that contained in Table 1 are instructive, however, in demonstrating how little is
actually known about fundamental regularities in
system organization across animals, or what sources
of developmental variability produce the eventual
differences in neuron number seen here. Of particular
interest for this review is whether experimentallyinduced differences in convergence ratios between
visual nuclei in any single animal can account for
cross-species variability, particularly the extreme
variation in visual cortex.
1.4. VARIABILITY IN CONVERGENCE RATIOS OF CELLS
WITHIN THE VISUAL SYSTEM
The convergence ratio between cells in the visual
system has been the subject of much study. Differential convergence between rods and cones and onto
the bipolar cells in the retina, variable convergence of
cones onto bipolar cells from the center to the
periphery of the retina, and the nature of convergence
from thalamus to cortex have been studied particularly well in cats and monkeys (Sanderson, 1971;
Mcllwain, 1975; Wilson and Sherman, 1976; Peichl
and Wassle, 1979; Connolly and Van Essen, 1984;
Schein and de Monasterio, 1987).
Central to this discussion is the fact that functional "streams" (Van Essen, 1979; Van Essen and
Maunsell, 1983) in the visual system preferentially
magnify different areas of the visual field, as expressed as cells per visual angle. This is most notably
true for rods and cones, but is also true for the major
cell classes of the ganglion cell layer. X cells (cats)
or P cells (monkey) preferentially represent central
retina, while Y, W (cat) and M cells have flatter
distributions (Wilson and Sherman, 1976; Schein and
de Monasterio, 1987). Yet, these "streams" must be
accommodated in the same coordinate system of
visual space laid out in primary visual cortex, and in
fact must often be represented by the same cells. This
requires that convergence ratios between pre- and
postsynaptic cells be systematically altered for particular cell classes across the visual field. An example of
this is the convergence of magnocellular (M) and
parvocellular (P) geniculate laminae onto striate cortex in the macaque (Schein and de Monasterio, 1987).
They argue that across the visual cortex, the ratio of
presynaptic P cells to striate cortical cells remains
constant. However, the proportional number of M
cells is higher in the periphery, so the convergence
ratio increases for M cells from center to periphery by
about a factor of 7. How does the structural basis for
this difference in convergence ratios (for example, by
change in axonal arbor size or alteration in the
number of presynaptic cells contacting postsynaptic
cells) come about during development?
This representational problem occurs numerous
times within the visual system; For example, area 17
preferentially represents the center of the visual field,
the superior colliculus comparatively represents the
periphery, and area 17 projects to the superior colliculus, in spatial register. This problem is almost
certainly not unique to the visual system, and the
constraints on the mechanisms by which arrays of
variable cell number are mapped onto each other
would be of extreme interest.
In the following sections we will review the literature, with particular emphasis on our own studies, on
experimental manipulations of the developing visual
system. Of interest will be how adult cell numbers are
produced through processes of cell generation and
death, and whether ratios of cell numbers are regulated. The mapping problem of variable convergence
ratios, and the issue of what features of interconnecting populations are stabilized during devel-
CELL NUMBER CONTROL IN DEVELOPING VISUAL SYSTEM
opment are the fundamental questions which guide
this study.
2. DEVELOPMENTAL STUDIES OF
CONTROL OF CELL NUMBER
2.1. THE RETINA" RETINALGANGLIONCELLS
2.1.1. Normal cell addition and loss
Retinal ganglion cells are the first cells produced in
the developing mammalian retina (Sidman, 1961;
reviewed in Policy et al., 1989). Several species show
a central to peripheral wave of retinal ganglion cell
production, while others show a flat distribution
(Sengelaub et al., 1986; Wikler et al., submitted). The
presence or absence of spatial gradients in initial cell
production is related to the eventual cell distribution
of the retina: whether its growth will be uniform, to
produce a uniform cell distribution, or non-uniform,
producing the growth pattern characteristic of an
area centralis or visual streak (Wikler and Finlay,
1989). As retinal ganglion cells leave the mitotic
cycle, differentiate and begin to establish central
connections, cells in the ganglion cell layer begin to
degenerate and die (Sengelaub and Finlay, 1982;
Sengelaub et al., 1986). Since the ganglion cell layer
consists of two neuronal populations, ganglion cells
and displaced amacrine cells, much effort has been
expended to determine the identity of the cells lost.
These include morphological and ultrastructural investigation (Young, 1984; Cunningham et al., 1982;
Wong and Hughes, 1987a,b; Provis, 1987; Penfold
and Provis, 1986); labelling retinal ganglion cells
retrogradely with HRP, and counting the changes in
labelled cell number (Perry et al., 1983; Henderson et
al., 1988); labelling of degenerating debris by its
birthday with tritiated thymidine (Sengelaub et al.,
1986); and comparison of changes in numbers of
axons in the optic nerve with changes in cell number
and distribution in the ganglion cell layer (Braekevelt
et al., 1986; Provis et al., 1985a,b; Chalupa and
Williams, 1984; Williams et al., 1986). Taken together, these studies conclusively show a major loss
of ganglion cells, between 50 and 90% in every
mammalian species studied (quokka, Braekevelt et
al., 1986; albino rat, Crespo et al., 1985; rat, Dreher
et al., 1983; Henderson et al., 1988; Jeffrey and Perry,
1982; cat, Ng and Stone, 1982; monkey, Rakic, 1983;
hamster, Sengelaub and Finlay, 1982, Sengelaub et
al., 1986; cat, Shatz and Sretevan, 1986; gerbil,
Wikler et al., submitted; rabbit, Robinson et al.,
1986). There is some indication that different subclasses of ganglion cells may die in different proportions: the earliest generated, large ganglion cells in the
hamster and gerbil retinae show the greatest proportional loss (Sengelaub et al., 1986; Wikler et al.,
submitted); in the cat, cells of different types show
different patterns of death associated with their
projection laterality (Leventhal et al., 1988).
Enough species have been studied that it is reasonable to look for phylogenetic trends, or functional
variations in visual systems associated with greater or
lesser amounts of death. There are intrinsic problems
associated with these studies, however, which make
any conclusions tentative. The principal method by
211
which total cell loss has been ascertained is to compare the peak of axon numbers with mature axon
numbers in the optic nerve. Since axon addition and
loss are coincident in the optic nerve, and since the
rate of addition and loss must vary between species,
this method almost certainly yields inaccurate comparisons. In addition, in some species, the presence of
substantial axon branching confounds this estimate
(Braekevelt et al., 1986; but see Lia et al., 1985).
Nevertheless, taking these estimates uncritically, the
largest demonstrated axon losses are 80% in the cat
(Williams et al., 1983, 1986; review in Shatz and
Sretevan, 1986) and the quokka, a rabbit-sized marsupial (Braekevelt et al., 1986). The other species
cited previously show a range between 50 and
70%. No obvious relationships between the amount
of cell death and any feature of visual system organization, such as visual system complexity or
degree of binocular overlap, are obvious.
2.1.2. Generational control o f retinal ganglion cell
number
There is no evidence that retinal ganglion in mammals may be induced to proliferate early in development by reduction of their numbers, as has been
demonstrated for amacrine cells in amphibians (Reh,
1987), or that the hormonal milieu influences the
number or type of cells generated, as has also been
shown in amphibians (Hoskins, 1989). Neither, however, have there been systematic tests of these possibilities. A hypothesis that a retinal ganglion cell with
a centrally projecting axon might retract that axon
and become an amacrine cell (Hinds and Hinds,
1983), has been largely discounted (Perry, 1981; Perry
et al., 1983). Therefore, the number of ganglion cells
originally generated is viewed to be unmodifiable,
and developmental cell death has been the sole factor
investigated for potential alterations in adult retinal
ganglion cell number.
Several studies in non-mammalian vertebrates now
indicate that the ventricular cells of the retina are
pluripotent, giving rise to retinal neurons of all types
(Wetts and Fraser, 1988; Holt et al., 1988). How the
relative proportion of each cell type is fixed in the
mammalian retina is unknown. The reciprocal relationship of the densities of some cell types in some
retinas, for example, retinal ganglion cells and displaced amacrine cells of the ferret retina (Henderson
et al., 1988), raises the interesting possibility that an
increased density of a particular cell class might be
"bought" at the expense of fewer divisions producing
an alternate cell class for cell groups that are clonally
related.
2.1.3. Efferent and afferent control o f cell number
The three functional roles for cell death that
have been systematically considered are numerical
matching of retinal ganglion cells with their target
and afferent availability, correction of errors of
early connectivity, and sculpting of topographical
inhomogeneities.
212
B.L. FINLAYand S. L. PALLAS
2.1.3.1. Target control o f cell number
Retinal ganglion cells require efferent targets for
their survival at all but the earliest stages of their
development. Section of the optic nerve in any mammal studied results in the eventual death of all
ganglion cells (see Allcutt et al., 1984). In tissue
culture, retinal ganglion cell survival is improved by
conditioning of the medium with appropriate target
tissue (Amson and Bennett, 1983). Early in development, however, Miiller ceils and not central targets
are critical for cultured cell survival, indicating that
trophic requirements change with the maturational
state of the cells (Raju and Bennet, 1986).
Final cell number in the ganglion cell layer may be
increased or decreased by increases and decreases in
target availability respectively, much as the survival
of motoneurons in the spinal cord reflects target
availability (Hamburger and Levi-Montalcini, 1949;
Hollyday and Hamburger, 1976). Initial enthusiasm over this positive result for a time masked the
further observation that the details of the behavior of
spinal cord motoneurons and retinal ganglion cells
are quite different: in normal development (Sperry,
1987) and in several experimental manipulations
(Hamburger and Levi-Montalcini, 1949; Hollyday
and Hamburger, 1976), spinal motoneuron number is
related quite linearly to target availability (but see
Lamb, 1980). Retinal ganglion celt number is related
much more loosely to target availability. We will
argue that branching of optic axons and considerable
malleability in their terminal arbor size can account
for this observation.
Increased target: early enucleation o f one eye. Removal of one eye in development in the hamster
provides greater terminal area and presumably lesser
competition for terminal area for the remaining eye.
This manipulation reduces the incidence of degenerating cells in the remaining eye (Sengelaub and
Finlay, 1981), and at maturity there are greater
numbers of cells of ganglion cell morphology in that
eye (16%; Sengelaub et al., 1983). These "rescued"
cells derive principally from the temporal retina in
which, in the hamster as in other rodents, both the
ipsilateral and contralateral projections arise. In addition, a component of this increased projection
comes from ipsilaterally projecting cells of the nasal
retina, an early aberrant projection which is stabilized
by the early eye removal, to be discussed in more
detail below (Insausti et al., 1984). This rescue effect
has now been demonstrated numerous times by optic
nerve counts after prenatal eye removals in monkeys
(35% sparing; Rakic and Riley, 1983) and in cats
(20% sparing; Williams et al., 1984; Chalupa et al.,
1984; however, another less extensive study reports
no sparing; Shatz and Sretavan, 1986). Rats also
show similar stabilized projections, though a change
in axon number has not been observed probably due
to its small absolute magnitude (Crespo et al., 1985).
The substantial species differences in the percentage of cells rescued do not yet have a complete
explanation. The relative number of spared cells is
larger in monkeys, which has been attributed plausibly to their greater potential for binocular competition due to their greater binocular overlap (Rakic,
1986). However, the number of cells saved in the cat
is considerably less, if all studies are taken together,
despite the fact that the cat has binocular overlap not
much less than the monkey. In the quokka, which
also has large binocular overlap, no difference in cell
survival in the remaining eye after early monocular
enucleation is seen (Coleman and Beazley, 1986).
Note also, as in every case of sparing of cells after
provision of greater terminal area, cell death is
reduced but not eliminated, even in the case of
the cat and monkey where available target area is
nearly doubled for the remaining eye by the early
enucleation.
Decreased target: striate cortex and lateral geniculate ablations. If lesser target is available for ganglion
cells, cell loss is only sometimes increased, depending
upon the particular postsynaptic structure damaged
and the maturational state of the animal at the time
of the damage. In rodents, removal of the visual
cortex, which results in the complete transneuronal
loss of the lateral geniculate nucleus, has no effect
on retinal ganglion cell survival, as measured from
numbers of cells in the ganglion cell layer (Perry and
Cowey, 1979a,b, 1981; Linden et al., 1983; Raabe et
al., 1986). The lateral geniculate nucleus in rodents
accounts for about 15-20% of the total terminal
volume of the combined tectum and geniculate, as
measured in numbers of cells (Table 1), and most if
not all cells projecting to the lateral geniculate nucleus in rodents also send a branch to the superior
colliculus. Whether the small absolute volume of the
cell loss or the presence of axonal branching, or both
is the factor responsible for the lack of response to
geniculate ablation is not known. In monkeys and
cats, removal of primary visual cortex results in the
selective loss of X cells, thought to occur since this
class of cells projects exclusively to the lateral geniculate (minor projections to midbrain structures have
been demonstrated but are apparently inadequate to
sustain retinal ganglion cells), whereas Y cells branch
to innervate the superior colliculus (Tong et al., 1982;
Payne et al., 1984; Weller and Kaas, 1984).
Decreased target: superior colliculus ablations.
Damage to the superior colliculus, the major target of
the retinal ganglion cells in rodents, has variable
effects which can principally be accounted for by the
animal's maturational state at the time of damage. In
the hamster, removal of an average of 70% of the
superior colliculus at birth, prior to the ingrowth of
most optic fibers, results in only an 8% increase in
cell loss (Wikler et al., 1986). In rats, if the damage
occurs at birth, about 30% of the normal ganglion
cell population is lost. If the tectum is destroyed at
5 days postnatal, 60% of the population is lost
(Perry and Cowey, 1979a,b, 1981). Similar studies in
the rat using kainic acid injections into the superior
colliculus which have the advantage of not directly
damaging axons, confirm this approximate magnitude (Carpenter et al., 1986). Since the hamster is
substantially less mature than the rat at birth, the
hamster results are a plausible extrapolation of the
rat results. In both the hamster and the rat, a
progressive lack of reorganization of retinal arbors
after early tectal lesions has been demonstrated to
occur during this time period (So and Schneider,
1978; Perry and Cowey, 1982) which could account
for the difference in retinal cell loss at different ages.
CELL NUMBFAtCONTROLIN DEVELOPINGVISUALSYSTEM
Structure
Investigated
Type and Magnitude
of Manipulation
RGCL
~fflation-"]
.ao~.
~h,,,,o.'l
Magnitude of
Effect
---
Branching
of Axons
YES
213
cell loss, if there is enough time for retinal ganglion
cell axons to establish a new terminal arbor of
reduced size in the decreased target area. Ganglion
cell survival thus reflects aspects of target availability,
but there is little evidence for linear matching of
ganglion cell number to target availability through
developmental cell death.
YES
Lo'~J ' ~
2.1.3.2. Afferent control of cell number
Developing neurons may also require interactions
with their afferents in order to survive; such trophic
interaction has been demonstrated for the spinal cord
(Okado and Oppenheim, 1984). The afference to
II
LGNd
r ~blati°n'']
.o
retinal ganglion cells, the various amacrine and biL of vc ..J
polar cells of the ganglion cell layer and the inner
nuclear layer, has been the subject of fewer studies
Neocortex
j corpus J
....
YES
than the target control of cell survival, principally due
Ea,os.~
to the difficulties of selectively manipulating the
amacrine/bipolar population. In order to explore the
lJof
-ablati°n
7 ~7
role of afference, experimental studies have prinNeocortex
superiorJ
---YES
cipally made use of the fact that enucleation, optic
LcolliculusJ
tract section and target ablation have different conFIG. 1. Qualitative summary, of results from our laboratory
sequences for the ratios of afferents to target retinal
on the effects of various developmental manipulations of ganglion cells than they do for the ratio of retinal
target nuclei on patterns of cell death and correspond- ganglion cells to their targets.
ing adult cell number. The direction and size of the arrows
Evidence that afferent input may in part regulate
(of three sizes) indicate the direction and size of the manipulation and the induced change in cell number through cell survival comes from the observation of the effects
changes in cell death. Large black arrow: complete ablation of early unilateral superior colliculus ablation in rats
or major addition of excess target; complete reactive cell loss (Linden and Perry, 1982; Perry and Linden, 1982).
or savings. Medium gray arrow: partial target ablation; sub- Unilateral tectal lesions cause a loss of ganglion cells
stantial, but not total cell loss or savings. Small gray arrow: in the contralateral retina, as described previously
small to negligible reactive cell loss. Whether axons branch (Perry and Cowey, 1979a,b). However, this loss is
with respect to the target of interest is also included. RGCL, confined to the contralaterally projecting ceils of the
retinal ganglion cell layer; LGNd, dorsal lateral geniculate
retina contralateral to the lesion: the numbers of
body; SC, superior colliculus; VC, visual cortex, area 17.
ipsilaterally-projecting cells in this retina go up in
number. The authors argue that these ipsilaterallyprojecting cells, whose targets have not changed, are
Several types of reorganization are possible. Reti- in a privileged position for access to afference, due to
nal arbors could stabilize their early diffuse con- the loss of contralaterally projecting cells in the same
nectivity or sprout new connections in anomalous area of retina. Their finding that retinal ganglion cell
locations, or reconform and reduce their arbors dendrites extended toward depleted areas lent supwithin their normal terminal zones, or both. Both port to this argument. While other explanations
stabilization of diffuse connectivity and reactive involving rerouting or selective loss of cell types
sprouting after combinations of early manipulations might also account for these results, as these authors
have been demonstrated in hamsters (Frost, 1986). note, the likelihood that afference does modulate
After the particular manipulation of early tectal early cell survival is high, and developmental deablation, although the retina does establish new pletions of particular amacrine and bipolar cell
projection fields in the thalamus as a result of this populations with selective toxins will eventually
manipulation (Crain and Hall, 1980a,b), the volume disambiguate these results. Dendritic competition
of the new terminal fields is very small compared to and competition for targets may interact to determine
the extent of the tectal loss. The probability that the final distribution of cells across the retina (Linden
single axon arbors must be reduced in the tectum and Serfaty, 1985).
is thus quite high (to be discussed in Sections 3.3
and 4).
2.1.4. Error correction
A schematic version of the results described so far
appears in Fig. 1. Retinal ganglion cells respond to
Errors, defined as projections observed in neonates
increased target availability in most cases with a
not observed in adults, occur in the early choices of
reduction in normal cell death. Complete loss of a
laterality, target nucleus and topography for retinal
target nucleus produces variable effects: if a particuganglion cells. It has been conclusively demonstrated
lar target nucleus is the sole target of a particular that it is cell death that removes early errors of
ganglion cell class, loss of that nucleus will result in
projection iaterality (Sengelaub and Finlay, 1981;
loss of the appropriate ganglion cells. If a ganglion
Jeffrey and Perry, 1982; Insausti et al., 1984; Cowan
cell projects to several targets, loss of one target
et al., 1984). Errors of choice of target nucleus are
can be sustained by collaterals in other targets.
also observed in early development, but it is unknown
Partial losses of a target can be met without major
if cell death removes them (Frost, 1984).
.oo
E'n:°',:q "1"
~
NO
214
B.L. FINLAY and S. L. PALLAS
It has been established that aberrant ipsilateral
projections establish synapses (Jeffrey et al., 1984)
and that normal neuronal activity is required for their
removal (Fawcett et al., 1984). Blockade of normal
activity also alters the pattern of retinal ganglion cell
survival in vitro (Lipton, 1986). Thus, the mechanism
of ejection of aberrant ipsilateral projections is likely
to be activity-dependent sorting, which results in the
death of the projecting neuron. Why this type of
target loss results in the death of neurons, while
major target ablations often do not result in neuronal
death will be discussed in conclusion.
The absolute magnitude of errors of projection
laterality is small, with estimates ranging from 1-4%
(Jeffrey and Perry, 1982; Sefton and Lam, 1985).
While the number of errors of target choice has not
been determined, qualitative estimates would also
make this number quite small (Frost, 1984). Thus, the
removal of gross lateral and targeting errors can only
account for a very small fraction of naturallyoccurring cell loss. A somewhat larger magnitude of
error correction has been described in the developing
retinotectal system at the level of order in topographic projections (O'Leary et al., 1986; Catsicas et
al., 1987). A role of cell death in the local ordering
of projections may contain the key to the reason for
the large magnitude of cell death in various developing vertebrate systems (Section 4.1).
2.1.5. Sculpting
During the period of retinal development when cell
death occurs, the retinal ganglion cell layer begins to
change from a sheet of cells of roughly uniform
density, to a surface showing the local specialization
of areas of high cell density such as an area centralis
or visual streak (some of this specialization also
occurs after the period of cell death, through differential retinal growth; reviewed in Wikler and Finlay,
1989). Early excess cell death in the periphery might
thus initiate or at minimum contribute to the production of local specializations (Sengelaub and Finlay,
1982). Proportionately greater cell loss in the retinal
periphery has been demonstrated in the hamster and
quokka (a marsupial), using the method of comparing distributions of tritiated-thymidine labeled
cells before and after the period of cell death
(Sengelaub et al., 1986; Beazley et al., 1989). In the
human retina, a very much greater incidence of
degenerating cells in the retinal periphery suggests the
same effect (Provis, 1987). In other species, the presence of differential cell loss is controversial (cat, Lia
et al., 1987; Stone and Rappaport, 1986 vs Wong and
Hughes, 1987a,b,c; Shatz and Sretavan, 1986), or
ambiguous (ferret, Henderson et al., 1988; gerbil,
Wikler et al., submitted) or demonstrated to be a
minor effect (rat, Perry et al., 1983; rabbit, Robinson
et al., 1986). The variability across species is not
accounted for by the type of retinal specialization
possessed by the animal, nor by the degree of
center/periphery density disparity. No sensible phylogenic analysis can be made with the small number
of species sampled.
We suggest that the marked topographical inhomogeneities seen in cell loss in the early devel-
opment of the retina may well reflect a solution to the
convergence problem arising from mapping cell
groups with different spatial distributions onto single
terminal area, such as the distribution of X and Y
cells discussed previously (Section 1.4). If the competition for retinotopically-defined terminal sites varies across the visual field for different cell classes, the
probability of death would be higher for certain cell
classes in particular retinal locations. As a hypothetical example, if W cells are comparatively more
numerous in the visual periphery than Y cells but
must share retinotopically defined terminal sites in
the superior colliculus, the W cells would be at a
disadvantage claiming terminal sites in the periphery of the visual field compared to their success in
the center, and peripheral W cells might show a
higher incidence of death. The fact that different cell
classes do show different absolute amounts of cell
death (Sengelaub et al., 1986) is consistent with this
hypothesis.
2.2. THE RETINA: AMACRINECELLS, BIPOLAR CELLS,
HORIZONTAL CELLS AND PHOTORECEPTORS
2.2.1. Normal cell addition and loss
The neural retina is generated in several overlapping gradients: the first, retinal ganglion ceils,
amacrine cells and cones, and second, bipolar cells
and rods (see review by Policy et al., 1989). For
mammals, there is no evidence as yet that the amount
of generation of any of these cell classes may be
influenced by the number of pre-existing cells of
the same class as has been shown in the amphibian
(Reh, 1989). Transection of the optic nerve in the rat
results in no changes in the ongoing rate or pattern
of mitosis in the ventricular zone (Beazley et al.,
1987).
Following the termination of generation of each
retinal cell class, a period of cell death occurs (mouse:
Young, 1984; rat: Kuwabara and Weidman, 1974;
Spira et al., 1984; Cunningham et al., 1982; cat:
Wong and Hughes, 1987c; Horsburgh and Sefton,
1987; Robinson, 1988; human: Penfold and Provis,
1986). Cell death in all of these cell classes has been
inferred from the presence of pyknotic cells in the
appropriate location, with ultrastructural confirmation in most cases. For amacrine cells, the absolute
number of cells has been shown to decline (Perry
et al., 1983; Wong and Hughes, 1987a,b; Henderson
et al., 1988). Other cell classes have not yet
been investigated for alterations in absolute neuron
number.
2.2.2. Efferent and afferent control o f cell number
2.2.2.1. Photoreceptors
A specialized type of cell loss has been hypothesized for the photoreceptor cells. Photoreceptor cells
located ectopically in the inner nuclear layer in early
development show a pronounced and specific degeneration (Spira et al., 1984; Robinson, 1988) which has
been interpreted as a consequence of a migrational
disorder resulting in failure to make connectivity
appropriate to that cell class. However, a direct
CELL NUMBERCONTROL IN DEVELOPINGVISUAL SYSTEM
demonstration that photoreceptors must make
synaptic contact to survive has not been made.
2.2.2.2. Amacrine cells and bipolars
Both the displaced amacrine cells of the ganglion
cell layer and the amacrine cells of the inner nuclear
layer normally show a substantial amount of cell loss
(Perry et aL, 1983; Sengelaub et al., 1986; Wikler et
al., submitted; Henderson et al., 1988; Horsburgh
and Sefton, 1987). The cause of this loss is unknown,
in that this cell class has been repeatedly shown to be
resistant to complete removal of its principal target,
the ganglion cell population, during development or
at adulthood (Miller and Oberdorfer, 1981; Perry,
1981). Neither total cell number, nor the location and
number of pyknotic cells, nor the incidence of particular amacrine cell subclasses known to be directly
presynaptic to ganglion cells has been shown to
change after optic nerve section (Osborne and Perry,
1985; Beazley et al., 1987; Horsburgh and Sefton,
1987). Similar independence has been indicated for
bipolar cells (Beazley et al., 1987). In transplant
studies where ganglion cells fail to make connections
with their host tissues and die, amacrine and bipolar
cells survive (McLoon and Lund, 1984). Manipulation of afference to these cells has not yet been
done, and the relationship of amacrine and bipolar
survival to afferent innervation would be very useful
information.
The reason for the independence of retinal interneuron number from their targets is unclear, and the
cause of the substantial cell death in this cell class is
a further mystery. In few other structures has a
contrast between interneurons and projection neurons been investigated. In the cerebellum, however,
interneurons show a higher rate of cell loss than
projection neurons (Caddy and Biscoe, 1979). Several
useful avenues for investigation suggest themselves.
Since many or most interneurons do not have the
problem of distant target acquisition or topographic
mapping to solve, the nature of their trophic requirements might be quite different: residual intrinsic
connectivity with other interneurons might be enough
to sustain cells in early development. Whether death
in these cell classes is related to normal synaptic
activity is unknown. The often non-spiking nature of
much interneuronal transmission may require a
different mechanism for activity-dependent sorting, if
it in fact occurs.
2.3. SUPERIOR COLLICULUS
2.3.1. Normal cell addition and loss; sculpting
Neurons that compose the retinorecipient zones in
the superior colliculus are generated over approximately the same period of time that retinal ganglion
cells are generated. The first autoradiographic
demonstration that histogenesis in the mammalian
brain is largely unaffected by its afferent input was
made for the superior colliculus by DeLong and
Sidman (1962): early enucleation partially deafferenting the superior colliculus did not change the rate
of cell generation in the colliculus.
Pyknotic cells in early collicular development have
215
been described several times (Arees and Astrom,
1977; Giordano and Cunningham, 1978; Finlay et al.,
1982; Cunningham et al., 1982), and the amounts of
cell loss observed in hamsters probably correspond to
about 20°/, of the originally generated cell cohort of
the superficial cell layers, and about 40% of the lower
layers (Finlay et al., 1982). The pattern of cell death
corresponds to the maturitional gradient of retinal
innervation of the superficial layers of the superior
colliculus (Cunningham et al., 1982).
The incidence of pyknotic cells is much higher
in the retinotopically defined periphery of the superficial gray layer of the superior colliculus, over all
developmental stages (Finlay et al., 1982). In the
intermediate and deep gray layers, the incidence of
pyknotic cells is higher centrally. This spatially inhomogeneous distribution of cell loss may relate to
the developmental problem of mapping together representations of the visual field that differentially
magnify or represent different parts, as discussed
previously. However, this hypothesis has not been
directly demonstrated, and there is partial evidence
against the hypothesis that retinotopic gradients in
the density of afferents produce this effect: the gradient persists at an elevated level of cell loss if the
superior colliculus is denervated by early enucleation
(Walker et al., 1986). The retina therefore does not
impose its spatial inhomogeneity in cell loss directly
upon its target.
2.3.2. Efferent and afferent control o f cell number
No study of cell survival in the colliculus after
manipulation of its targets has been made. Instead,
interest has centered on afferent control of cell
number, principally because of the relative ease of
deleting inputs to the superior colliculus. Denervation of the superior colliculus by early monocular or binocular enucleation increases early cell
death and decreases adult cell number (DeLong and
Sidman, 1961; Finlay et al., 1986). The only changes
observed in early cell death, however, occur in
regions that are nearly totally denervated of their
retinal input: after monocular enucleation, elevated
cell loss is seen only in the monocular section of the
colliculus contralateral to the enucleation (Fig. 2).
The partial denervation occurring in binocular
zones has no effect. (This is also seen in the lateral
geniculate body, to be discussed in Section 2.4.2.)
One report linked a possible increase in innervation
(produced by an early visual cortex lesion, which
causes degeneration of the lateral geniculate body
and potential rerouting of afference from the lateral
geniculate to the superior colliculus) to a decrease in
cell loss in the superior colliculus (Cunningham et
al., 1979). Our attempts to replicate this phenomenon
failed, however (Raabe et al., 1986). Another attempt
to produce collicular hyperinnervation through
partial tectal lesions also produced no change in the
amount of coUicular cell loss (Wikler et al., 1986). We
interpret these results in the following manner:
afferents are normally in excess and compete for
terminal space. Thus, only major denervations of
afferent input are detectable by the target tissue, and
increases in afferent availability are also ineffective,
since afferents are normally in excess.
216
B.L. FINLAYand S, L. PALLAS
Structure
Investigated
Magnitude
of Manipulation
Type and
LGNd
removeat"]
7contratater
L- retina ._.]
LGNd
removeal'~
Fcontralater
L._ retina ._l
(contralateral
projection zone)
(ipsllateral
projection
zone)
LGNv
Magnitudeof
Effect
~
,~
,~
,~
In both the hamster and monkey, the cell loss
within the lateral geniculate nucleus is strikingly
inhomogeneous, with the greatest concentration of
degenerating cells seen in the ventral margins of the
nucleus, corresponding to the retinoptic periphery.
Whether this represents a solution to the mapping
problem for projections with intrinsically different
magnification described previously, or the deletion of
a particular cell class is as yet unknown (Sengelaub
and Finlay, 1985; Williams and Rakic, 1988).
retina __1
SC
(contralateral
projection zone)
I"-coremoveal'-'l
ntralater
L-- retina ._l
SC
(ipsilateral
projectionzone)
rem°veal"--~
~'contralater
!.__ retina
~7
SC
E artiat
vctectal
or --II
z~
Neoco~ex
[--~ectioo
--1 ~Z
corpus /
lesion __J
callosum._J
Neocortex
F thalamic
'\
FIG. 2. Qualitative summary of results from our laboratory
on the effects of various developmental manipulations of
afference on patterns of cell death and corresponding adult
cell number. The direction and size of the arrows (of three
sizes) indicate the direction and size of the manipulation and
the induced change in cell number through changes in cell
death. Large black arrow: complete ablation or major
addition of excess target; complete reactive cell loss or
savings. Medium gray arrow: partial target ablation; substantial, but not total cell loss or savings. Small gray arrow:
small to negligible reactive cell loss. Whether axons branch
with respect to the target of interest is also included. RGCL,
retinal ganglion cell layer; LGNd, dorsal lateral geniculate
body; LGNv, ventral lateral geniculate body; SC, superior
colliculus; VS, visual cortex, area 17.
2.4. LATERAL GENICULATE NUCLEUS
2.4.1. Normal cell addition and loss: sculpting
As in all other visual structures, neurons are overproduced and eliminated in the early development of
the lateral geniculate nucleus. This cell loss occurs
early in the establishment of the efferent and afferent
connectivity of the lateral geniculate, during the
period of establishment of retinotopic maps, but well
before the segregation of ocular dominance columns
(Williams and Rakic, 1988). The presence and spatial
distribution of cell loss has also been described in
several rodents (mouse: Heumann and Rabinowicz,
1980; rat: Matthews et al., 1982; Satorre et al., 1986;
hamster: Sengelaub et al., 1985). Amounts of cell loss
reported are in the 25-40% range for all species. In
the monkey, the amount of cell loss is laterally
asymmetric, with significantly less cell loss on the
right side, raising the interesting possibility that
thalamic cell death might produce or reflect some
aspects of lateralization of the neocortex.
2.4.2. Afferent and efferent control o f cell number
The lateral geniculate nucleus critically depends
upon the integrity of its efferent target, the visual
cortex, for its survival. Damage to the visual cortex
early in development results in nearly complete loss
of the lateral geniculate body, particularly in rodents
where the projection from the lateral geniculate body
to striate cortex is exclusive (Perry and Cowey,
1979a,b; Cunningham et al., 1979; Raabe et al., 1986;
Pearson et al., 1981). The lack of multiple targets for
the lateral geniculate nucleus, combined with absence
of reorganization or redirection of the geniculocortical pathway after cortical damage (Miller et al.,
1987) may account for this exceptionally high sensitivity to target availability. Recently, a diffusible
protein associated with the visual cortex has been
shown to prolong the survival of lateral geniculate
neurones after cortical ablation (Cunningham et al.,
1987).
After deafferentation by monocular or binocular
enucleation, the lateral geniculate body shows a
pattern of induced cell loss much like that already
described for the superficial layers of the superior
colliculus. Unlike target removal, cell loss produced
by deafferentation is not total: values ranging from
30-50% cell loss have been reported (Finlay et al.,
1986; Heumann and Rabinowicz, 1980; Rakic and
Williams, 1986). Partial deafferentations in areas of
binocular overlap produce little or no increase in cell
death. The interpretation of these results we offer is
as above (Section 2.3.2): afferents are normally in
excess, and only substantial removals are detectable
by target tissues.
2.5. PARABIGEMINAL NUCLEI: EFFERENT AND
AFFERENT CONTROL OF CELL NUMBER
The parabigeminal nucleus, a midbrain site of
reciprocal connectivity between the eontralateral and
ipsilateral superior colliculus, offers an interesting
opportunity to both dissociate the effects of afferent
and efferent connectivity and also to examine their
interaction because it has divisions that are purely
afferent to the superior colliculus, purely efferent, or
both (Linden and Perry, 1983; Linden and Pinon,
1987). Moreover, the nucleus has very few connections with structures other than the superior colliculus, and thus the deafferentation and target removal produced is effectively total. Consequent to
unilateral colliculus lesions, both areas efferent and
afferent to the colliculus show increased cell death
(though not total cell loss). The time course of targetand afferent-induced death is different, however, with
CELL NUMBER CONTROL IN DEVELOPING VISUAL SYSTEM
afferent-induced death protracted with respect to
both normal cell death and target-induced death.
Target and afferent effects interact so that no cells
survive a combined target and afferent denervation.
2.6. VISUAL CORTEX
2.6.1. Normal variability in adult neocortical cell
number
Different species vary greatly in cortical area and
in total number of cortical neurons (Table 1). In
addition, there is significant variability between individuals within a species in the size of striate cortex
(Van Essen et al., 1984), and presumably in the size
of other cortical areas as well. It is unknown whether
these individual differences arise from differences in
cell generation or cell loss.
In contrast to the variability seen in total cortical
cell number, there is some evidence for conservation
of the number of neurons in a "unit column" of
cortex. Studies by Rockel et al. (1980) have suggested
a uniformity in neuron number per column across
various areas of the lateral convexity of neocortex.
(It should be noted here that in most cases discussed
below, the investigators used criteria for counting
that would include only neurons, and not glial cells.)
These authors counted the number of cells in a
30/~m cortical column in several different cortical
areas; motor (area 4), somatosensory (area SI),
frontal (area 9), temporal (area 22), parietal (area 7)
and striate (area 17) cortex in several different species
(mouse, rat, cat, monkey and human). They found
that despite the variation in cortical thickness
between areas and species, the number of cells
in a cortical column remained relatively constant
(approximately 110 cells/column). In agreement with
this finding, Beaulieu and Colonnier (1983, 1985)
confirmed that in areas 18, PMLS, and the monocular portion of 17 in the cat, the number of cells
per column varies by less than 10% between them.
However, although there may be uniformity between
some areas within a species, other authors do not
agree that there is uniformity between species. In
particular, data from several laboratories indicates
that the cat has about half the number of neurons per
cortical column as the macaque (see Peters, 1987, for
review).
An exception to the uniformity among the areas
Rockel et al. (1980) studied was in the binocular
portion of area 17 in the macaque, which had 2.5
times the number of cells per column compared to the
other areas (Rockel et al., 1980; see also O'Kusky and
Coionnier, 1982; and the excellent review by Peters,
1987). In the cat, Beaulieu and Colonnier (1983,
1985) reported 30% more cells per column in the
binocular area of 17 than in the monocular region of
17, area 18, or the posteromedial suprasylvian cortex.
Cragg (1967), in an earlier comparative study, also
found that the number of neurons per unit volume in
the binocular portion of 17 in the macaque is much
greater than that in the monocular portion of 17 in
the cat or rat. The monocular region of the macaque
area 17 was not counted. Peters (1987) has recently
confirmed this observation. Thus, while it is not clear
whether there is an overall uniformity in cell number
217
between species, it is well established that the number
of cells per column in the binocular portion of 17 is
much expanded compared to other areas in both the
monkey and the cat.
Investigators who have examined a wider array of
cortical areas disagree with Rockel et aL's idea of
constancy in the number of cells in a cortical column
as outlined above. The particular areas which Rockel
et al. (1980) examined (all resided in the lateral
convexity) do not reflect the full extent of variability
in thickness seen between various neocortical areas.
For example, Finlay and Slattery (1983) (see Section
2.6.3.4) investigated areas outside the lateral convexity in the hamster (29b, 29d, and 27) and found
more variability in the number of cells per column
between different areas than did Rockel et al., challenging the concept of strict uniformity. Area 17 had
the highest number of columns per column, suggesting that there may be an upper limit: that thickness and cell number per cortical column can vary to
some extent but never exceed a certain limit which is
reached in the binocular part of 17. In addition, they
found that in the medial cortex, values fall well below
this value (cf. Bok, 1959). One might still postulate,
however, a basic pattern on which cortical areas are
constructed (within a species) that maintains the
number of cells per cortical column in most portions
of the lateral convexity, but with a potential for
variation both above and below this value. This
variation might depend on such factors as differential
generation or death of neurons between different
cortical areas.
2.6.2. Normal cell generation and death in the visual
corlex
2.6.2.1. Generation and migration
Cortical neurons are generated from columnar
epithelial cells residing in the ventricular zone
(Boulder Committee, 1970; Sidman et al., 1959).
After their birth (last cell division) neuronal cells
migrate out to form the cortical plate, with each wave
of cells coming to reside nearer the pial surface than
the previous generation; thus the cortex is said to
develop in an "inside out" sequence (Rakic, 1974;
Angevine and Sidman, 1961, 1962; Luskin and Shatz,
1985; see McConnell, 1988, for review). Rakic suggested that the cells migrate along radial glial fibers,
in part because the migrating neurons remain in very
close apposition to the radial glia until they reach
their destination (Rakic, 1971, 1972, 1974).
Rakic (1988) has recently proposed a "radial unit
hypothesis of cortical parcellation" to explain how
the generation of different cytoarchitectonic areas
occurs. According to this hypothesis, prospective
cytoarchitectonic areas arise from a number of proliferative units generated from progenitors at the ventricular layer. Each proliferative unit would generate
a single "ontogenetic column". If each proliferative
unit is given approximately the same amount of
gestational time to generate all of its daughter cells,
and the rate of cell division and death does not differ
between areas, the thickness of the cortex would
remain relatively constant. In contrast, longer generation times would lead to thicker cortices. Indeed,
218
B.L. FINLAYand S. L. PALLAS
neurogenesis in Area 17 lasts twice as long as in
cingulate cortex (Rakic, 1974, 1982), which may at
least in part explain the increased thickness of area
17. Rakic (1988) proposes that changes (evolutionary
or developmental) in the total size of a cytoarchitectural area are accomplished by changing the
number of proliferative units.
Thus, differences in generation of cortical cells
between different cortical areas are one factor in the
"sculpting" of the cortex. However, the differences in
the pattern of lamination between areas are more
striking than the differences in thickness, and cannot
be explained by the radial unit hypothesis as presently
interpreted. This issue will be discussed further in
Section 2.6.3.4.
2.6.2.2. What is the normal pattern o f cell death in
visual cortex?
Cell death in the neocortex is a very significant
event during the development of the neocortex. Absolute cell counts indicate cell losses in layers II-IV of
up to 50% (Heumann and Leuba, 1983). (This measure is confounded, however, by the simultaneous
occurrence of migration and cell loss, and actual
incidence of death is probably greater than 50%).
Finlay and Slattery (1983) have examined cell death
in five areas of hamster neocortex: Areas 17, 18b,
29b, 29d and 27. These areas were chosen because
they show a great deal of variation in their final
thickness and density. They found that nearly all cell
death occurs in the last generated, upper layers
(II-IV), and particularly in II-III. Very little degeneration was seen in layers V-VI. This was also noted
by Heumann and Leuba (1983). Furthermore, the
amount of degeneration seen during development in
these upper layers predicted the eventual cortical cell
number in each of the five areas.
The above results suggest that differential patterns
of cell death are another factor which serve to
"sculpt" the cortex and thus give rise in part to the
differences in cortical cell number between various
cortical areas. This is done primarily by variation in
the extent of neuron death in the upper layers I-III.
However, there is still a substantial amount of death
seen even in area 17 (approximately 30%), which is
the area that has the greatest final number of neurons
per column, suggesting that cell death may serve
some function in addition to sculpting.
Luskin and Shatz (1985) have described a population of cells termed the subplate cells, which were
generated quite early in development. They reside just
underneath the cortical plate at the time when thalamocortical afferents have sent their processes into
the subplate area. The thalamic afferents remain in
the subplate area while their potential targets, the
layer IV cortical cells, migrate past them. After
migration is complete and the thalamic afferents have
contacted their target cells, the subplate cells die.
Luskin and Shatz suggested that the subplate cells
serve as temporary targets for the thalamic cells to
sustain them until the cortical targets are in place.
This phenomenon is reminiscent of the programmed
cell death observed in invertebrates (Horvitz et al.,
1982), where certain cells or populations of identified
cells survive only transiently. Some of the cortical cell
death that serves in the sculpting process may be
"programmed" in a similar sense.
2.6.3. Efferent and afferent control o f cell number
2.6.3.1. Error correction
In non-cortical systems, cell death has been demonstrated to operate in correction of early errors of
projection (Lamb, 1976, 1977; Bennett and Lavidis,
1981; Cowan et al., 1984; O'Leary et al., 1986;
Catsicas et al., 1987; see review in Section 2.1.4).
However, the removal of cortico--eortical and
cortico-subcortical connections is brought about by
collateral elimination rather than by cell death. Cortical cells are known to exhibit early patterns of
diffuse or "exuberant" connectivity. For example,
callosal neurons originate from the entire visual
cortex in kittens, but are restricted to a specific area
by adulthood (Innocenti et al., 1977; Innocenti and
Caminiti, 1980). Similarly, projections from occipital
cortex to the pyramidal tract are present in newborn
rats but are absent in adults (Stanfield and O'Leary,
1985; Stanfield et al., 1982). Innocenti (1981) showed
by means of injections of HRP and long-lasting
fluorescent tracers in areas 17 and 18 of kittens that,
although the cells labelled by this process are still
present 2 months later, their callosal axons become
progressively more restricted with age. Reinjection at
2 months with a second tracer shows that at this age
only cells near the 17/18 border, parts of 19 and of
suprasylvian cortex are double-labelled by retrograde
transport. Similar experiments on the transient pyramidal tract projection in rats (Stanfield and
O'Leary, 1985; Stanfield et al., 1982) and hamsters
(O'Leary and Stanfield, 1986) show a complete elimination of corticospinal axons from occipital cortex
without the death of the cortical cells.
Thus, early "errors" in connectivity in visual cortex
(as well as in other cortical areas; see Ivy and
Killackey, 1982) found to date are eliminated, not by
the loss of the cells, but by retraction of collaterals.
Presumably the cells are sustained by collaterals
projecting to other, permanent targets. It is not
known if these sustaining collaterals are present
before collateral elimination occurs, or what factors
trigger the collateral withdrawal. The results suggest
that error correction is not a major factor in the
normal cell death seen in the cortex.
2.6.3.2. Target availability
Another function of cell death in noncortical
systems is the matching of afferent and target
populations (Hamburger and Levi-Montalcini, 1949;
Hollyday and Hamburger, 1976; Pilar et al., 1980;
O'Leary and Cowan, 1984; but see Lamb, 1984).
Studies on the effect of target removal on cortical cell
survival are rare. Ramirez and Kalil (1985) have
demonstrated that neonatal lesions of the pyramidal
tract in the hamster have no effect on the final
number of pyramidal cells in motor cortex, although
they did observe that the somata of target-deprived
cells were smaller in size than normal. This is apparently not due to the selection of a population of cells
with smaller somata; rather a large-celled population,
CELL NtrMI~R CONTROL IN DEVELOPING VISUAL SYSTEM
which in the adult projects to the spinal cord, is
arrested in its growth (but see Tolbert and Der, 1987).
We have explored target dependence of visual
cortical cells in the hamster (Pallas et aL, 1988).
Neonatal unilateral deletions of the superior colliculus, a major target of layer 5 pyramidal cells in the
primary visual cortex, were made to assess the effects
of target loss on conical cell death. The incidence of
pyknotic cells during the major period of cell death
(postnatal days 5-10) and in adults was monitored,
as well as the total number of cortical cells in layer
5 and in all cortical layers combined. The target
deletions were found to have no effect on either cell
death incidence during development, or on final cell
number, either in layer 5 alone or in all cortical layers
combined. In addition, there was no effect on soma
size, in contrast to the results of Ramirez and Kalil.
Thus, at least for cells in layer 5, availability of
the primary target, the superior colliculus, does not
influence cell death, indicating that the primary
purpose of cortical cell death is not population
matching.
The independence from the primary target does
not imply, however, that cortical cells do not require
some minimum amount of target space. In fact there
is evidence that the reason cortical cells are not
affected by target deletions is that they have sustaining collaterals in other targets. For example, many
cells in layer 5 of area 17 send collaterals to both the
pontine nuclei, the lateral posterior nucleus of the
thalamus (LP) and the superior colliculus. In the rat,
Hallman et al. (1988) have reported that at least 60%
of corticoteetal cells also project to the pons, as
shown by double-labelling studies. Baker et al. (1983)
obtained a similar result in the cat using antidromic
activation. Klein et al. (1986) could antidromically
activate 50% of corticotectal cells from LP in the
hamster thalamus. It is not known how many collaterals (synapses) are required for survival, and
whether this differs in different cells. In addition,
some collaterals may be more essential for cell survival than others (Tolbert, 1987). Perhaps at least
some of the cells that normally die during neocortical
development are those which did not establish any
permanent targets. Thus the extreme case of collateral elimination results in cell death. There is no
evidence that cells can survive without some minimal
amount of axonal arbor and thus target space.
Another study in our laboratory demonstrated the
effect of loss of callosal targets on survival of cells in
several cortical areas, including the 17-18 border
(Windrem et al., 1988). Callosal projections were
prevented by the insertion of a barrier along the
cortical midline in neonatal hamsters. This target loss
had no effect on cell survival (number of neurons/unit
column) either in the caliosally-projecting layers
(II-III and V) or in the entire cortical column. These
results are in agreement with the superior colliculus
ablation study and suggest that target matching is not
the function of cortical cell death.
2.6.3.3. Afferent availability
Section of the corpus callosum also eliminates a
significant portion of the afference to cells in cortical
layers II-III and V. Thus the results discussed above
219
also indicate independence between conical cells and
their callosal inputs. Again, the reason for this independence between cortical cells and their inputs and
outputs is suspected to be the presence of sustaining
collaterals. Evidence that the callosally-projecting
cells also have ipsilateral collaterals was presented
above (Innocenti, 1981; Innocenti et al., 1986).
Other sources of afl'erence show a more substantial
effect. Lesions of thalamic input nuclei have a strong
effect on cortical cell survival. Windrem and Finlay
(1985, 1986) made unilateral thalamic lesions in
neonatal hamsters and measured resulting cortical
cell numbers in the cortical projection areas of the
thalamic nuclei affected by the lesions. Cell numbers
were measured in adults as well as in postnatal day
7 (P7) animals, just after the cessation of migration
to the cortex. No significant differences were found in
cell number per cortical column or in the laminar
composition of the cortex in the P7 animals. This
confirms that the cortex was not directly damaged by
the early thalamic lesions, and also demonstrates that
the thalamus is not required for the last phases of
cortical cell generation or for successful migration to
the cortex. By adulthood, however, there was a
significant reduction in the total number of neurons
per unit cortical column iby a mean of 13%). This
difference was due to the absence or substantial
reduction of an identifiable layer IV and reductions
in layer VI. Only layer V, which is neither afferent not
target for the thalamus, was unaffected. However, the
amount of increased cell death was not enough to
account completely for the loss of layer IV. It appears
that some of the cells which are normally destined for
layer IV according to their birthdate may not become
stellate cells but instead have a pyramidal morphology and reside in layer II-III (Windrem and
Finlay, in preparation). An alternate explanation is
that the lack of thalamic afference causes an increase
in death of presumptive layer IV cells which is
compensated by an increased survival of layer III
cells.
Rakic (1988) has done a similar study in monkeys,
where a reduction in the number of thalamic afferents
to visual cortex was made by removing both eyes.
This reduces the number of LGN cells by at least
50% if done by embryonic day 60. The result is a
reduction in the size but not the thickness of area 17,
which Rakic interprets as indicating that the number
of proliferative units has decreased as a result of
afferent deprivation without decreasing the number
of divisions of each proliferative unit. However, the
number of proliferative units is set before migration,
which is before the thalamic afferents can come into
contact with the cortical cells. Thus, it is difficult to
understand how the afferents could influence the
original number of units, or even the number of units
which survive to proliferate. In light of this difficulty,
Rakic raises the possibility that some units originally
destined for area 17 are respecified into area 18 units
by accepting the inputs typical of area 18 rather than
those for area 17, which in this experiment have been
largely removed by enucleation.
Thus, although cortical cells in layers II and III are
independent of their callosal afference and targets for
survival, and layer V cells are independent of at least
some of their subcortical targets, thalamic afferents
220
B.L. FINLAYand S. L. PALLAS
are of critical importance--in the pattern of cell
death, the formation of layer IV, and perhaps in the
total size of cytoachitectonic areas. The question
remains why it is only layer IV cells that are uniquely
dependent on their connectivity patterns for survival.
We can conclude that the primary reason cell
death occurs is not for error correction and target
matching. However, thalamic afference is important
in controlling the pattern of cell death. How is this
control achieved?
2.6.3.4. Generation of cytoarchitectonic differences
(sculpting)
The increase in thickness in the binocular portion
of area 17 discussed earlier is due primarily to an
increase in layers II-IV, but especially in layer IV.
However, there are differences between all cortical
areas in the number of cells per column in layer IV,
which are compensated for in all but the binocular
portion of 17 by changes in layers III, V and VI
(Rockel et al., 1980; Peters, 1987). Layers I and II
remain uniform between the different areas.
The magnitude of the difference in thickness of
layer IV in different cortical areas is correlated with
the amount of thalamic input an area receives. Those
areas of cortex which do not receive direct thalamic
afference (such as the medial wall) are those which are
agranular in appearance (meaning that they have a
reduced or absent layer IV). Conversely, areas which
receive heavy thalamic input (such as primary sensory
cortices) are distinguished by their thick granular
layers. The question remains, however, regarding
what developmental events control these differences.
Windrem et al. (1985, 1986) have shown that early
removal of thalamic afference leads to a decrease in
the final number of non-pyramidal ceils. It thus seems
possible that the thalamic afferents initiate the differentiation of migrating neurons into non-pyramidal or
granule-type cells. During the time that presumptive
layer IV cortical cells are migrating along the radial
glia, they can potentially come into contact with the
thalamocortical afferents which reside under the
cortical plate at this time (Lund and Mustari,
1977, Rakic, 1977, 1983; Shatz and Luskin, 1986).
Windrem and Finlay (1985, 1986) propose that the
cells which are generated during this time are pluripotent and can form either layer I I - I I I or IV. If they
do not come in contact with thalamic axons, they
would express a pyramidal morphology and form
layer II-III, but the contact with the thalamic axons
would specify their differentiation as non-pyramidal
(star pyramids or steilate cells) layer IV cells. Then
during the period of normal cell death which follows
migration (Finlay and Slattery, 1983; Heumann et al.,
1977, 1978), the excess cells in layer I I - I I I would die.
H~wever, it is unclear how certain cells could be
determined as "excess", since very little afferent or
target dependence is shown by cortical cells. It is true
that the variability in the amount of death between
different cortical areas is determined by the number
of cells specified as layer IV cells, such that areas with
a large granular layer have relatively little cell death,
more neurons per cortical column, and fewer II-III
cells. Other indirect evidence that laminar position is
specified by afference is the fact that cells generated
on the same birthdate, although they reside at the
same cortical depth, may be of different laminar
identity (Rakic, 1982). Also, in the lateral convexity
of the neocortex, the number of cells in a cortical
column is relatively constant, though the relative
proportions of pyramidal vs non-pyramidal cells
may vary (Rockel et al., 1980) as discussed above.
Beaulieu and Coionnier (1985) have shown that the
increased number of cells in the binocular zone area
17 (which receives increased afference compared to
the monocular zone) is due entirely to doubling the
number of non-pyramidal cells of layer IV.
If this hypothesis is correct, then the amount of
thalamic afference to each cortical area should predict the eventual number of cells per column, and if
there is an area which receives no thalamic input,
there should be little or no layer IV. There is evidence
on this point. The medial wall of the cortex receives
very little thalamic input, is the thinnest cortical area,
and shows the largest amount of cell death (Finlay
and Slattery, 1983).
3. P H Y S I O L O G I C A L CONSEQUENCES O F
CHANGES IN AFFERENT AND
EFFERENT C O N V E R G E N C E RATIOS
Insight into the question of what features of connectivity are conserved or defended during development can be obtained through studies of the effect
of changes in afferent/target ratios and axon arbor
size on the receptive field properties of the target cells.
Ultimately, the purpose of neural development, including regressive events such as cell death and
collateral elimination, as the establishment of appropriate patterns of synaptic connectivity, thus ensuring
the proper functioning of the nervous system.
The following is a summary of some of the information available concerning the physiological effects
of experimental manipulations of cell number and
connectivity patterns. Much of this literature is reviewed in Sherman and Spear (1982) and we will
cover only the points relevant to our argument here.
We will particularly emphasize effects on receptive
field size, because this property reflects changes in
convergence most directly. What is needed is an
understanding of how convergence changes that
occur naturally during development and evolution
affect acuity and thus how mechanisms for these
changes might be constrained. We suggest a twostage process whereby the target first accepts whatever inputs are available and then, secondly, sorts
these inputs on the basis of activity, accepting no
more than the usual number even when afferents are
in excess.
3.1. EFFECTSOF DECREASED AFFERENT ACTIVITY ON
PHYSIOLOGY OF TARGET CELLS
The manipulation of relative activity levels often
results in local alterations in the convergence ratios
between afferent axons and postsynaptic neurons.
Wiesei and Hubel (1963, 1965) studied the effects of
visual deprivation on the physiological properties of
cells in the LGN and striate cortex in kittens 9 weeks
of age or older. Monocular deprivation had no
CELL NUMBER CONTROL IN DEVELOPING VISUAL SYSTEM
apparent effect on most cells in the LGN in that they
showed normal receptive field sizes and configurations, although they were somewhat less excitable
than normal and their somata were smaller. More
recent studies have revealed that monocular deprivation does have an effect on Y cells, however.
Sherman et al. (1972) have shown that there are fewer
Y-type cells in the deprived laminae of the LGN
compared to both normal and non-deprived laminae
(although this could be due to electrode sampling
error given that the deprived somata are smaller than
normal). Physiological changes in the Y cells include
poor responsiveness and somewhat larger receptive
fields (Krantz et al., 1978). Morphologically, it has
been observed that Y-cell axons from the deprived
eye have shrunken terminal arbors in the A laminae
and in MIN (Suret al., 1982). The Y cells establish
their terminal arbors later than the X cells (Suret al.,
1984), and their lack of correlated activity under
conditions of monocular deprivation may prevent
them from pruning back the arbors of the X cells
(Garraghty et al., 1986).
At the cortical level, kittens monocularly deprived
from birth of patterned light exposure were apparently blind in the deprived eye, despite what was
reported by Wiesel and Hubel (1963, 1965) as the
relative normality of geniculate cell responses. Only
one cell out of the 84 recorded could even be driven
by the deprived eye and it showed no orientation
preference and was very sluggish. Responses of cells
driven by the non-deprived eye were normal. There
was an increased incidence of cells which could not
be driven by either eye. Substantial projections to
striate cortex from the deprived laminae of LGN
remain; however, these inputs are largely below
threshold (Kratz et al., 1976). The effects can be
lessened by normal visual experience prior to deprivation, and they exhibit a critical period; deprivation in adults has no effect. These results have
been confirmed repeatedly (e.g. Shatz and Stryker,
1978; Singer, 1977; Wilson and Sherman, 1977).
Binocular deprivation also decreases the responsiveness of cortical cells, indicating that some
non-competitive effects can occur as well. In lidsutured cats, which are deprived of pattern vision but
not deprived completely of light, fewer cells are
responsive to light, and receptive fields are larger with
more diffuse borders (Hubei and Wiesel, 1963; Singer
and Tretter, 1976; Watkins et al., 1978). Dark-rearing
also decreases the responsiveness of cortical cells to
light, but field sizes remain normal (Cynader et al.,
1976; Leventhal and Hirsch, 1980).
These results taken together indicate that monocular deprivation causes the disruption of retinogeniculate and geniculocortical connections from the
deprived eye that were initially present at birth,
without any effect on the responses of cells driven by
the non-deprived eye. Because binocular deprivation
causes a much less severe deficit than monocular
deprivation, it can be inferred that it is in large part
competition between projections from the two eyes
that restricts the extent of the geniculocortical fibers'
arbors. Any manipulation which changes the balance
of activity between the two eyes will put the deprived
eye at a disadvantage in "capturing" synaptic connections. Conversely, any manipulation which affects
JPN 32/3--D
221
the activity level of the two eyes equally has lesser
effect. Further evidence for the role of activity comes
from binocular TTX injections, which prevent the
formation of ocular dominance columns (Stryker and
Harris, 1986).
Although monocular deprivation has been studied
in detail, the consequences for afferent/target convergence ratios have not been addressed. For example, the projections of the deprived eye reflect a
greater reduction in Y-cell than in X-cell terminals
(Shatz and Stryker, 1978), and terminals of the
non-deprived eye expand in layer IV of striate cortex
so that they contact more target cells (Hubel et al.,
1977; Shatz et al., 1977; Shatz and Stryker, 1978;
LeVay et al., 1980). However, there is no apparent
increase in the receptive field sizes of the cortical
target cells receiving input from the non-deprived eye
(Wiesel and Hubel, 1963). It would be of interest to
know how this lack of change is achieved.
3.2. EFFECT OF DECREASEDAFFERENCE/EXcESSTARGET ON PHYSIOLOGY
Rhoades and Chalupa (1980) have studied the
effect of monocular enucleation in neonatal hamsters
on receptive field properties of visual cells in the
superior colliculus of adults. This manipulation leads
to an expansion of the ipsilateral retinotectal
projection, which is normally restricted to rostral
tectum, over the entire tectum. They found that the
receptive field properties of cells in the colliculus
contralateral to the remaining eye did not differ from
normal. However, several marked changes were observed in the properties of cells ipsilateral to the
remaining eye. Receptive fields of these cells were
abnormally large, and the field size was inversely
correlated with the density of the ipsilateral retinotectal projection as determined by anterograde transport of tritiated proline. This change is particularly
informative, as field size probably reflects the amount
of convergence from the retina. Direction selectivity
and surround suppression were rarely observed, in
contrast to normal animals. The responsiveness of the
cells in general was also related to the density of
innervation.
Anatomical results obtained by Wikler and Finlay
(1984; in preparation) are useful in interpreting the
physiological results described above. They demonstrated a 30% decrease in synaptic density with the
relative increase in target area caused by the monocular enucleation. The afferents, while able to expand
their terminal arbor to some extent, apparently cannot increase the number of synapses enough to
innervate the excess target up to its normal synaptic
density. This occurs despite a 2-fold increase in tectal
cell death in the ipsilateral tectum. Thus, the expanded receptive fields in these cells could be
explained by increased branching of the afferents due
to a decrease in competition for target sites. The
absence of direction selectivity and surround suppression may indicate disruption of the normal pattern of inhibitory connections, but could also be
due to decreased excitability. Because the innervation
of each target cell is reduced, some decreases in
excitability would be expected.
Monocular enucleation in kittens results in the
222
B.L. FINLAYand S. L. PALLAS
contralateral and ipsilateral L G N being innervated
completely by the remaining eye in the adult. White
et al. (1987) have studied the functional consequences
of this manipulation by recording from single cells
in the A layer of the L G N in these animals. They
examined several characteristics of the receptive fields
of these cells, including spatial resolution and the
size and shape of the field. They found that LGN-X
cells had larger receptive fields than normal and lower
spatial resolution. The authors suggest that these
differences could result from an induced mismatch
between retinal ganglion cell afferents and L G N
target cells resulting in changes in the pattern of
afferent arborization. Garraghty et al. (1986) have
shown that X and especially Y retinogeniculate
afferents have a much more extensive arbor in cats
enucleated at birth, supporting this interpretation.
They have postulated that X cells remain fairly
restricted to their eye-specific laminae, and Y cells
expand into the deafferented laminae. Because the
excess target availability decreases the amount of
competition between the X and Y cells within a
lamina, both types of cells can expand their arbors.
[It should be noted that the enucleation-dependent
expansion of X and Y arbors exhibits a critical
period. Cats enucleated at E23 (Sretavan and Shatz,
1986; Garraghty et al., 1988) show no change in X
and Y arbor size.]
A different result was obtained by Shook et al.
(1985) when they undertook a study of the physiological effects of monocular enucleation in the cat on
visual cortical cells. Kittens were enucleated in utero
at least 2 weeks before birth. Cortical units were then
recorded in area 17 of adult cats. All cells were driven
well by the remaining eye, in contrast to the lack of
responsiveness observed in some ipsilateral SC cells
in hamsters (Rhoades and Chalupa, 1980). However,
the cells did show a marked difference from normal
in the size of their receptive fields. Field size in the
monocularly enucleated cats is smaller than normal
(x = 1.76 degrees vs 2.67 degrees), in contrast to the
results from retinocollicular connections in monocularly enucleated hamsters and retinogeniculate connections in cats. In both these species, monocular
enucleation leads to an increased number of surviving
retinal ganglion cells in the remaining eye. Shook et
al., suggest that increased dendrodendritic competition between neighboring ganglion cells might result
in smaller dendritic trees and thus contribute to the
reduced field size. However, it is difficult to explain
how increases in LGN cell field size can occur simultaneously with decreases in cortical cell field size.
Perhaps the difference in time when the animals were
enucleated plays some role. It is also possible that
changes in intracortical inhibitory circuitry are responsible. More anatomical information is needed to
interpret these results, but future work on this system
could be very informative.
Unlike the kitten which has a large degree of
binocular overlap and thus a significant ipsilateral
retinogeniculate projection, the retinogeniculate projection in the rat is largely contralateral. Monocular
enucleation in the rat results in an expansion of the
ipsilateral retinogeniculate projection. Fukuda et al.
(1983) found that physiological responses of P (parvocellular) cells in the contralateral L G N do not
differ compared to samples from normal animals.
However, several differences were seen in the ipsilateral P-cell population in the enucleated rats as
compared to normal. Receptive field center sizes were
significantly larger in L G N cells ipsilateral to the
remaining eye. It was hypothesized that disruption of
the normal one-to-one connection between RGCs
and L G N cells could explain the change in receptive
field size.
In summary, challenges to the afferent/target
matching process in the case of increased target area
(monocular enucleation) cannot always be compensated for. In rat and cat L G N and in hamster SC, the
afferents cannot expand enough to fill the excess
target even by increasing their extent of branching,
despite some documented increases in cell survival in
the ipsilateral eye when competition from the contralateral eye is removed, and some increases in cell
death in the underafferented target. The increased
branching leads to increases in receptive field size,
perhaps because more afferents synapse with each
target cell. Thus, there is an upper value for target
size beyond which the afferents cannot expand their
arbor enough to fill the target adequately to maintain
field size. The extent to which the afferents can
expand their arbor in turn determines cell survival in
the target, as shown by the increased amount of tectal
cell death in enucleates. These two mechanisms serve
to regulate afferent/target cell ratios with a certain
range. However, in cat cortex, decreases in field size
result from monocular enucleation. This result is
difficult to interpret without further information.
3.3. EFFECT OF EXCESS AFFERENCE/DECREASED TARGET ON PHYSIOLOGY
What is the response of the visual system to an
increased number of afferents at the periphery? Does
this result in increased survival of target cells, and
thus a concatenated increase in the size of all visual
nuclei central to the increase in afference? If not, how
are the excess afferents accommodated functionally
and anatomically?
These questions have been addressed only rarely in
the mammalian visual system (Murphy and Kalil,
1979). Our studies using the retinotectal system of the
hamster (Pallas and Finlay, 1986, 1987, in press)
provided some interesting results that are relevant in
this regard. Partial unilateral tectal ablation in neonatal hamsters results in a compression of the entire
contralateral visual field onto the remaining tectal
fragment (Jhaveri and Schneider, 1974a; Finlay et aL,
1979a). Retinotopic order is preserved in these animals, with the compression of the central nasal visual
field being somewhat less than that in the far periphery (Finlay et al., 1979a). Multiunit evoked potentials
indicate that more retinal area is represented at each
location in the superior colliculus as well. Wikler et
al. (1986) found only a minor increase in cell death
in the retina with the neonatal partial tectal ablations,
and no change in cell death within the superior
colliculus (SC). Thus, for a lesion of the caudal half
of the colliculus, approximately twice the normal
number of retinal ganglion cells are potentially available to each tectal cell. This preparation provides a
convenient experimental system in which to study the
CELL NUMBER CONTROL IN DEVELOPING VISUAL SYSTEM
nm
NORMAL RETINOTECTRLMAP
RETINA
~CTHM
B.
C.
INCREASED CONVERGENCE
OF RETINAL PROJECTIONS
TO THE 'rECTUM
RETINA
TECTUM
o
o
REDUCTION OF
RETINAL ARBORIZATION
WITHIN THE TECTHM
RETINA
TECTUM
o
FIG. 3. A. Schematic figure of hypothesized normal retinotectal connectivity, reflecting the moderate divergence of
retinal axons in the tectum and convergence of retinal
ganglion cells onto single tectal cells described in the text.
B and C demonstrate two models by which an entire retina
might compress its propections onto a halved teetum. In
B, increased convergence of retinal axons onto tectal cells
is diagrammed, resulting in larger receptive field sizes for
postsynaptic tectal cells, which was not demonstrated in our
experiments (Pallas and Finlay, in press). In C, the model
consistent with our results, retinal axons reduce their arbor
in the tectum, preserving the convergence ratio of number
of presynaptic cells to postsynaptic cells, and retaining
normal receptive field size.
physiological effects of increased afference on single
target cells.
We studied the effects of the early lesions (removing 20-75% of the SC, mean = 38%) on several
different physiological properties in the tectal target
cells, including receptive field size. Responses of cells
from lesioned animals were compared to those
recorded from normal and sham-operated animals.
In lesioned animals with compressed visual maps,
an increased area of visual field is represented per unit
of tectum. One might expect then, that individual SC
cells would have increased receptive field sizes as a
result of the excess afferents (compare Fig. 3A and
Fig. 3B). However, our results show that this is not
the case. Receptive field size was not significantly
different between lesioned and intact animals. This
result is in contrast to the results of multiunit recordings (Finlay et al., 1979a), which showed increases in
field sizes proportional to the size of the lesion. Other
receptive field properties, such as velocity and size
tuning, were also unaffected.
These results suggest, then, that the increased
convergence of the visual field onto the SC is not
reflected in increased convergence at the level of the
single cell. This would mean that the model shown in
Fig. 3B is incorrect. How then can the two results,
increased field size with multiunit recordings and no
223
change in field size with single unit recordings, be
reconciled? We have proposed the model shown in
Fig. 3C as a possible interpretation of the results. The
model involves a simple arbor pruning of the RGC's
which maintains the original number of RGC's projecting to the rectum without a change in synaptic
density. This interpretation is supported by preliminary evidence from Wikler and Finlay (1984, in
preparation) that synaptic density remains constant
in the SC of hamsters with early partial tectal ablations. The model depicts a 50% ablation; in this
case, each tectal cell receives input from the same
number of RGC's as usual and these RGC's cover the
same amount of retinal area, but each RGC has half
its original arbor. The model does not exclude the
possibility that RGC collaterals project to alternate
targets, however. Multiunit recordings (e.g. recording
from two adjacent SC cells in the model) show
an increase in field size, but single unit recordings
do not.
There is some evidence for increases in retinal
projections to alternate targets in animals with early
partial tectal lesions. Udin and Schneider (1981)
reported a decline in the density of retinal ganglion
cells projecting to the tectum in hamster with early
lesions. Crain and Hall (1980a,b) demonstrated an
increased projection to the LP nucleus of the thalamus following partial tectal lesions in hamsters.
However, the extent of the projection to alternate
targets was not enough to account for the amount of
target loss, suggesting that some combinations of
arbor reduction and projection to other targets may
be occurring. To address this point, we are now
conducting a study in which the density of RGC
projections to the tectum is measured with varying
lesion sizes. Perhaps a reduction in arbor is the
response of the cell to small lesions, but if the amount
of available target drops below a threshold amount,
projections to other targets occur (Fig. 4).
In summary, the hamster retinotectal system is
remarkably resistant to increases in afferent availability in terms of its physiological properties. This
resistance appears to arise as a result of alterations in
circuitry which compensate for increased afference in
such a way as to maintain receptive field properties.
What prevents the excess afferents from superinnervating the tectal fragment? Or conversely, what
prevents the tectal targets from accepting more than
their usual number of inputs? Our results suggest that
the target cells can be quite selective about their
inputs; even in the presence of excess afferents, the
number of afferents innervating a single tectal cell
and the amount of retinal area they represent is held
at the normal value. This could be explained by an
activity-dependent sorting mechanism that is specific
enough to select down to the single cell level. That is,
when confronted with a larger number of potential
inputs with less-correlated activity patterns, the sorting mechanism does not adjust its selectivity. In our
experiments, each tectal target cell could potentially
be innervated by twice the usual number of afferents,
which would have half the overall amount of c o i n c i dence in their activity patterns. Instead, only the
usual amount of visual field is represented in each
target cell, by the same number of innervating ganglion cells as seen in the intact state.
224
B.L. FINLAYand S. L. PALLAS
O•
RETINA
NORMAL
TECTUM
SMALL
LESION
LARGER
LESION
~projectlon
to an
alternatetarget
LARGEST
LESION
topographi
map c
FIG. 4. Schematic figure of the progressive series of reorganizations hypothesized to result as a consequence of tectal
lesions of increasing size.
This explanation predicts that there will be a limit
to the amount of target that can be deleted while
still maintaining receptive field properties in their
normal state. In accordance with this prediction, we
(Finlay et al., 1979a,b; Pallas and Finlay, 1986, 1987,
in press) have observed, with very large lesions of the
superior colliculus, that only temporal retina is
mapped onto the SC. We suggest that this reflects the
limit to the amount of plasticity the system can
exhibit with increasing amounts of target loss. If
nasal ganglion cells cannot obtain enough target
within the tectum, they drop those collaterals and/or
project elsewhere. Thus, the solution of this particular system to an extreme lack of target is to make only
a partial topographic map (Fig. 3).
From these results, it is apparent that another
constraint operating is that of the conservation of a
minimum amount of axonal arbor by each presynaptic axon (see Devor and Schneider, 1975). The
results from the studies of monocular enucleation
suggest some additional constraints. In cases where
afferents are depleted, the target will accept afferents
which are spread out over a wider area of visual field
(indicated by increased field sizes). Thus, there seems
to be a two-stage selection process: when afferents are
in short supply, they can spread over larger distances
in the target because of decreased competition for
terminal space, and the target cells operate as if they
must accept whatever afferent input they can obtain,
regardless of the absolute amount of correlation in
afferent activity patterns. One does not often see
receptive fields that are patchy, however, so there
must be some constraint that maintains nearest
neighbor relations between the inputs. When afterents are more numerous than usual, a second stage of
selection operates that sorts inputs on the basis of
activity-dependent sorting, and target cells will not
accept other than the normal amount of coincidence.
What consequences does only an upper limit on
convergence have for evolutionary change in visual
systems? When more afferents are supplied as in a
partial target deletion, the target will not accept them
and circuitry is rearranged in order to maintain receptive field properties. Thus one can postulate that a
mutation which increased the number of afferents
could be compensated for. When more target is
provided as in monocular enucleation, there is an
increased sparing of cells in the remaining retina as
the retinal ganglion cells spread to innervate the
entire cortex. Rakic (1985) has found that vernier
acuity (which is thought to depend on the visual
cortex; Barlow, 1978, 1981) increases following monocular enucleation in monkeys. Such increased computational resources for a defined sensory input, as
evidenced by increased vernier acuity, could provide
the evolutionary pressure for increasing encephalization. However, as other experiments described
above show, monocular enucleation also can result in
decreased synaptic density, increases in receptive field
size in the target, and erratic responsivity of the cells.
These results are not consistent, and it is not yet clear
when excess target is advantageous and when it is
pathological. It is also unclear whether reconciliation
can be made between these results and the trend
toward encephalization over evolutionary time.
4. SUMMARY AND OVERVIEW
4. I. WHAT IS THE FUNCTION OF CELL DEATH IN THE
DEVELOPING VISUAL SYSTEM?
Cell death has now been shown to have multiple
functions in the developing visual system. However,
an exhaustive list of these functions, with generous
estimates of their total numerical contribution, does
not satisfactorily account for more than half of the
total estimated cell loss. This situation is quite comparable to what has been observed in the spinal cord:
a documented function is the numerical matching of
motoneurons to target muscle availability (no other
functions have been described). Yet, provision of
excess target of any kind can only reduce naturally
occurring cell loss to about half of its normal amount,
and the function of the residual loss thus remains a
mystery.
Taking the case of retinal ganglion cells, for which
the most quantitative evidence is available, we know
that 50-80% of ganglion cells are normally lost. Cell
death participates in the correction of errors of early
laterality (Insausti et al., 1984). Corrections of errors
of laterality account for no more than 1-3% of
normal cell death. In some animals, cell death prefer-
CELL NUMBER CONTROL IN DEVELOPING VISUAL SYSTEM
entially removes cells from the retinal periphery: in
hamsters, this sculpting can account for no more than
10% of normal cell death. For target matching, the
maximum induced sparing of cells after provision of
excess terminal field is 30% in monkeys, but in every
other animal, considerably less. For hamsters, the
only species in which all of these factors have
been estimated, totalling these sources of loss gives
an "accountable" loss of about 25% in a total
population loss of 50--60%.
More cell loss can be accounted for in the correction of errors of topography (O'Leary et al., 1986;
Catsicas et al., 1987). O'Leary and colleagues estimate that large topographical targeting errors in the
rat occur at about a rate of 12% and hypothesize that
if short-range "errors" were included, the error rate
could account for the entire population loss. We
propose a reinterpretation: that cell death in developing mammals and birds is an epiphenomenon of
the process of activity dependent sorting occurring
within a finite period. Activity dependent sorting
requires that "inappropriate" terminals be transiently
removed from their terminal areas. By this sorting
process, a fraction of neurons may be prevented, on
a statistical basis, from maintaining a stable synapse.
As activity dependent sorting ceases and connections
are stabilized, some neurons may be caught without
a terminal connection, much as in a game of musical
chairs. Neurons thus losing their connectivity could
be construed as making very local "errors" of connectivity in failing to gain a particular postsynaptic
neuron, but it is the transience of the plastic state that
defines them as error (Lamb, 1984). If activity is
prevented, cell death can be prevented (Oppenheim,
1981; Fawcett et al., 1984; O'Leary et al., 1986). This
argument is supported by the observation that in
animals with an unlimited plastic period, such as
the growing teleost retina, cell death has not been
reported.
Given this hypothesis, the amount of cell loss seen
in a particular structure in a particular species will be
a combination of several factors. First, since the
range over which an axon arbor may vary is apparently quite large, but with a defined minimum, the
initial ratio of generated presynaptic neurons to
postsynaptic neurons will specify where the system is
located in its potential axon range. This in turn will
specify (in part) the likelihood of failure to establish
the minimum arbor, and the response of the system
to afferent and target deletions.
Secondly, the number and nature of the axonal
branches that a neuron possesses will affect the
probability of the neuron's survival. Assuming that
the establishment of any branch is enough to
sustain a cell, consider the following situation: a
nucleus from which each neuron's axons bifurcate to
innervate two targets (for example, the hamster
retina/lateral geniculate/superior colliculus system),
compared to a nucleus in which the same number of
neurons does not branch and contacts either one
or the other target (for example, part of the cat
retina/lateral geniculate/superior colliculus system).
Suppose the probability of failing to establish a
synapse in each target is 0.5, and that the probability
of failing to establish a synapse in one or the other
target is independent. The probability of any individ-
225
ual cell being unable to establish a terminal in the
first, bifurcation situation is 0.5 x 0.5 = 0.25; in the
non-branching situation it is 0.5. Therefore, the absolute rate of cell loss should be lower in populations
containing many multiply-targeted axons. This generality receives some support across both structures
and species: the low rates of cell loss in the multiplytargeted cells of the cortex and cerebellum contrasted
with higher rates of loss in various subcortical
structures with singly-targeted axons.
There are several situations, however, in which the
probabilities of having an axon ejected are not independent in multiple terminal sites. Such a case occurs
in correction of errors of projection iaterality. It has
been established that a vanishingly small number, if
any, retinal ganglion cells bifurcate at the optic
chiasm in hamsters (Hsiao et al., 1984; Hsiao and
Schneider, 1984). Cells that project ipsilaterally "in
error" do so in toto. If we can assume that these cells
branch in the characteristic way of rodents to multiple targets, it might seem that one of these branches
might be capable of sustaining the cell. However, in
each terminal area, the aberrant ipsilateral axon
branch will be a topologically inappropriate minority
projection that will be evicted with a probability
close to 1.0. Thus, branching confers no advantage
if success in the various terminal areas are not
independent.
We have argued that the developmental "functions" or secondary adaptations of cell death in the
mammalian brain (or any brain not constantly growing) are best understood as epiphenomenal of the
basic process of activity-dependent sorting occurring
in a delimited critical or plastic period. The probability of cell loss in a population is a complex function
of both its initial afferent/target ratio, and the branching properties of its neurons. This causal scenario
in no way minimizes the magnitude of cell loss, or the
possibility that it might be secondarily employed,
over evolutionary time, as a reservoir of variability
giving rise to diversity in brains (Finlay et al., 1987).
4.2. WHAT FEATURES OF CONNECTIVITY OR CONVERGENCE ARE REGULATED IN THE EARLY DEVELOPMENT OF THE VISUAL SYSTEM?
The information presented here can now be summarized to determine what cellular features, if any,
are preserved or defended in early development.
Several features could potentially be regulated during
development in order to preserve certain aspects of
cell number or convergence ratios. In this section we
will generalize across structures and species to generate hypotheses about developmental processes which
constrain visual system development and evolution.
Figures 1 and 2 summarize much of the data from
which this discussion is drawn.
4.2.1. Cell generation
If cell generation is regulated or monitored in some
fashion to produce a certain initial state or number
of cells, then cell generation could be a constraint on
development in the sense described here. This regulation could occur indirectly or directly. For example,
in neuromuscular systems there is evidence that the
226
B.L. FINLAY and S. L. PALLAS
number of motoneurons produced is related to eventual muscle size. Sperry (1987) found a natural variation in body size in Xenopus tadpoles that was
correlated with the number of motor neurons and
muscle fibers in the lumbar lateral motor column
system (L-LMC) after metamorphosis. He measured
body size, motor neuron number, and muscle fiber
number before, during and after the period of natural
cell death. Contrary to the size matching hypothesis
(Hamburger and Oppenheim, 1982), the percentage
amount of cell death in the motor neuron population
was fairly constant (approximately 70%) regardless
of the number of neurons prior to the cell death
period or the number of muscle fibers. Thus it
appears that there is a regulation of motor neuron
production according to body size that serves to
match target and afferent populations. In the visual
system of amphibians, cell generation and early aspects of specification of cell type can be regulated by
the cellular milieu such that more cells of a particular
class will be generated if that class is experimentally
depleted (Reh, 1989).
For mammals, there is evidence for gross allometric regulation of visual system size (reviewed in
Wikler and Finlay, 1989). Eye size (diameter) is
grossly correlated to body weight (Hughes, 1977)
which is in turn correlated to brain weight (Jerison,
1973; Eisenberg, 1981). However, at any particular
body size across mammals, there is a 3- to 5-fold
variation in eye size and a similar variation in brain
weight. The relationship of eye size to brain weight
has not been described systematically, but the relationship is unlikely to account entirely for the
3-5-fold variation. Thus, gross allometric scaling is
likely to account for some basic visual system scaling,
but the residual variability is large.
There is little direct evidence for regulation of cell
generation as yet in mammals, either in the retina
(Beazley et al., 1987) or centrally (DeLong and
Sidman, 1962). In general, therefore, given the gross
allometric context, there is little evidence to suggest
that a target amount of cell generation is regulated or
defended as a developmental means for controlling
convergence.
4.2.2.2. Presynaptic axon arbor size
Cells in the visual system can survive with wide
variations in amount of axonal arbor, as was first
implied by the monocular eye closure experiments of
Wiesel and Hubel (1964) and more recently demonstrated directly by reconstruction of full terminal
arbors (Garraghty et al., 1986). Numerous experiments (reviewed in Sections 2.1-2.6 and in Sections
3.1-3.6) show that afferents appear to saturate target
space, both when the relative competitive ability of
afferents is altered by alterations in activity patterns
or when the number of afferents is changed by direct
deletions or additions. When target space is scarce, as
in the several target deletion studies we have described (Fig. 1), the cells do not die proportionally,
but appear to survive with lesser arbor or find
alternate targets to some lower limiting value.
Devor and Schneider (1975) have hypothesized a
principal of conservation of axonal arbor. Two interpretations of this principle are possible, one interpretation concerning the developmental "behavior"
of the cell, and the second concerning the survival
requirements of the cell. For the developmental
behavior of cells, conservation of arbor implies that
a ceil can in some way monitor or defend its
total axonal arbor: if part of the dendritic tree is
pruned back by lack of target space, other parts will
sprout in compensation. The difficulty in establishing
whether axons actually maintain their arbor in this
fashion is the necessarily confounded nature of target
availability manipulations in the richly interconnected visual system: most target deletion studies also
deafferent alternate targets, and thus free synaptic
space (e.g. Crain and Hall, 1980b).
Conservation of arbor might also mean that a
certain amount of arbor is required for cell survival,
and a particular arbor size is regulated and defended.
Stated more simply, in this view, the minimum
amount of arbor is equivalent to the maximum
amount of arbor. While there are certainly upper and
lower limiting values, as described above, it is clear
that most cells that have been investigated can survive with several-fold variability in their terminal
arbor size.
4.2.3. Target availability
4.2.3.1. Cell number
Afferent cell number has been shown to be linearly
4.2.2.1. Cell number
regulated to target availability over a substantial
Afferents are generally in abundance, and targets range in the neuromuscular system (Sperry, 1987;
are generally saturated with inputs. Deletions of reviewed in Hamberger and Oppenheim, 1982). This
afferents must therefore be fairly large to have any type of singly targeted system thus has its cell number
significant effect on target cell survival (Fig. 2). constrained by target cell number. Although similar
Similarly, we have been unable to show that a quantitative studies have not been done for similarly
developmental increase in input to a structure is connected pairs in the visual system, like the singlymatched by an increase in cell survival in that struc- targeted geniculocortical system, it is a reasonable
ture (Raabe et al., 1986; Wikler et al., 1986) or hypothesis that such pairs would also match linearly.
For multiply targeted cells, such as most retinal
anything but a transient alteration in volume of
neuropil (Wikler et al., 1986). Therefore, except in the ganglion ceils in rodents, or subeortically projecting
limiting case of massive afferent deletions, target cell cells of the neocortex, the total number of retinal
number is not matched to afferent cell number. ganglion cells is not matched to the total number of
Except for its role in establishing boundary condi- target cells summed over all targets; for example, in
tions for cell survival, afferent cell number is not rodents, the entire geniculate body can be removed
without change in retinal cell survival (Perry and
defended during visual system development.
4.2.2. Afferents
CELL NUMBERCONTROL IN DEVELOPING VISUALSYSTEM
Cowey, 1979a; Raabe et ai., 1986). Survival of these
cells may be regulated in the multifactorial way
discussed in Section 4.1.
Overall, therefore, in some singly targeted systems,
target cell number is a severe constraint on afferent
cell number, and afferent cell number is regulated
directly to target cell number. In multiply-targeted
systems, target availability in any one structure is
unrelated or loosely related to afferent survival.
4.2.3.2. Postsynaptic dendritic arbor size
Dendritic arbor size has been shown to be highly
malleable in situations related to gross cellular activity or function (Greenough, 1984; Turner and Greenough, 1985; Coss, 1979, 1980) or other functional
alterations such as hormonal state (Goldstein et al.,
1988). Dendrites also appear to compete with other
dendrites to establish arbors, and will increase their
size if competition is reduced, up to cell-type-specific
limiting sizes, and will decrease their size if cell
density is made higher than normal (Perry, 1989;
Leventhal, 1989).
There are several interesting cases where dendritic
arbor size does not change. In three-eyed frogs
(Constantine-Paton, 1982; Constantine-Paton and
Law, 1978), the size of the doubly-innervated tectum
does not increase as might be expected if arbor size
were increased to accommodate the extra afferents.
In our own work (Hatlee and Wikler, unpublished)
dendritic arbors of developmentally hyperinnervated
cells in the superior colliculus did not increase. [In
contrast, however, a report that hyperinnervation
increased the dendritic arbors of Mauthner cells has
recently been made (Goodman and Model, 1988).] If,
as is commonly believed from a wealth of evidence,
axons compete for a limited amount of terminal
space, it is a necessary assumption that axons do not
then determine the amount of terminal space.
We have suggested that there may be an upper
limit to the number of inputs accepted by a target cell.
At a cellular level, a simple explanation for this is that
if total dendritic arbor size does not change, there is
no room for extra inputs. This mechanism has been
suggested for both muscle cells and autonomic ganglia. Most muscle cells have only one endplate, but
larger fibers can have two or three, and these are
always separated by a minimum distance (Bennett
and Pettigrew, 1975, 1976). In autonomic ganglia, the
number of axons innervating the dendritic arbor is
directly related to the size and complexity of that
arbor. The cause and effect relationship is suggested
by the fact that early in development, each postsynaptic cell is innervated by about the same number
of axons regardless of its geometry, and these are
later pruned back according to dendritic arbor size
(see Purves, 1977, 1983, for reviews).
The distinction between the marked dendritic
growth mediated by activity, hormonal state, and
interactions with neighboring dendrites and the absence of dendritic growth to excess of afferents is
interesting, and may provide a mechanism by which
connectivity is regulated, but which can be reset
under appropriate environmental or physiological
conditions.
227
4.2.4. Afferent/target ratios
4.2.4.1. Cell number ratios
As we have described above, afferent/target ratios
of cell number appear to be closely regulated only in
the case of singly targeted systems. In the experiments
described here (Figs 1 and 2), afferent/target ratios in
cell number could vary over a wide range. In addition, individual and interspecific variations in this
ratio in various visual system structures can be
extreme (Table 1). Thus, afferent/target ratios are not
conserved during development, except for those
boundary conditions described previously.
4.2.4.2. Synaptic density
Synaptic density stays the same under at least some
conditions of increased afference, but declines when
the number of afferents is reduced (and target relatively increased). This suggests an upper limit to the
number of synapses that an afferent can maintain or
produce, or an upper limit to the number of synapses
the target will allow, or both. Our physiological
evidence suggests the latter plays a role (Pallas and
Finlay, in press).
4.2.5. Summary
The various constraints on cell number and arbor
size can now be summarized. Within the ranges
of gross allometric scaling, both the number of
afferent cells and target cells can be highly variable
in the visual system, as can the afferent/target ratio.
Cell death does not act to maintain a particular
afferent/target ratio, but is a function of the probability of establishing a viable terminal in any terminal
nucleus in a delimited plastic period. Synaptic density
shows a ceiling--it can decline when the number of
afferents is severely reduced developmentally, but it
cannot go above a certain limit when the number of
afferents is increased. Conversely, the presynaptic
axon arbor size has a lower limit--afferents must
acquire a minimum amount of target--but can increase substantially above that lower limit. Size of the
dendritic arbor of the postsynaptic cell is at a ceiling,
in that it has not been shown to change as a function
of excess afferent availability (although other factors
may modify dendritic size). Physiological experiments indicate there is an upper limit to the number
of inputs a postsynaptic cell will accept under conditions of increased afference, which may be due at least
in part to this limit on dendritic arbor, in conjunction
with early sorting processes.
What are the consequences of these observations
for normal developmental variability? If afferent/
target cell ratios were tightly coupled in development,
any variation in generated cell number might be
expected either to cascade throughout the visual
system, or be immediately damped, depending upon
the direction of the coupling. For example, an increase in the number of cells in the lateral geniculate
nucleus might spare a corresponding number of cells
from death in the retina and the cortex, which in turn
might alter the numbers of cells in the afferent and
target populations for the retina and cortex. However, given the developmental properties described
228
B. L. FINLAYand S. L. PALLAS
above and within small ranges of variability, such a
cascade could not occur. The change in cell number
will most likely be met with changes in the presynaptic axonal arbor of the lateral geniculate neurons, and perhaps, changes in the branching patterns
of individual axons. Constraints on the number of
inputs a postsynaptic cell will accept would insure
that the system would remain physiologically
stable over a wide variation in convergence ratios
(Section 3.3).
4.3, SOME EVOLUTIONARY CONSIDERATIONS
What are the evolutionary implications of these
constraints? First, the wide inter-species differences in ratios of cell numbers between interconnecting structures are easy to accommodate to the
wide experimentally-induced variations in these same
numbers in a single animal. Mapping rules which
allow a wide variation in afferent arbor size and
branching, but a limit on the number of separate
afferents a postsynaptic cell will allow seem to permit
a wide variation in developmentally stable systems.
The developmental imperturbility of the neocortex
to deletion of its targets, perhaps due to its widely
branching axons (Fig. 1), suggests a reason for the
extreme variation in its size in various species. If
major subeorticai or intracortical target zones of the
cortex can be deleted without modifying cell death in
the existing cortex then, conversely, more cortex
could be generated and remain viable even without
corresponding increase in the volume of subcortical
target zones.
Finally, the physiological experiments on the consequences of changes in convergence ratios reviewed
here present a paradox. If a mutation occurs which
increases the number of cells in the periphery, the
excess afferents can be accommodated without affecting the function of the system adversely. An increase
in the number of target cells, as seen in the experiments on monocular enucleation, has very damaging
effects on physiological responsivity. Yet the phylogenetic trend has been for increasing encephalization,
an increase in the number of and volume of central
nuclei. How the developmental mechanisms described here could be employed to make efficient use
of increases in the size of central nuclei or increases
in size of cortical areas remains unknown.
Acknowledgements--Empirical work described in this paper
was supported by NSF grant BNS 79 19491 and NIH grant
R01-NS19245 to B. Finlay and a Sigma Xi grant-in-aid to
S. Pallas while B. Finlay was supported by NIH career
development award K04 NS00783 and S. Pallas by NIH
traineeship T32 GM07469. We thank particularly Drs Paul
Katz, Anna Roe, Dale Sengelaub, Mriganka Sur and Susan
Udin for their helpful criticisms of this manuscript.
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