Figure 8. Schematic representation of the timing
of major processes in the development of the primary visual pathway in
the rhesus monkey based on the results of this study, Rakic (1976,
1977a, 1977b), and Rakic and Riley (1983a). A particularly important
observation is that the loss of neurons in the geniculate nucleus (black
line) is essentially complete by the time the number of optic axons in
the nerve begins to fall (gray line).
The sensitivity of ganglion cells to a reduction in the number of
geniculate neurons is not matched by an equal sensitivity of geniculate
neurons to a reduction in the number of ganglion cells. Although the
removal of one eye early in development causes a 50% drop in the number
of retinal axons innervating the geniculate nuclei, there is no evidence
for any substantial reduction in the number of geniculate neurons (P.
Rakic and R.W. Williams, in progress). The independence of geniculate
neurons to a substantial loss of retinal axons may be due to the major
projections the nucleus gets from cortex and brainstem.
Neuron death and lamination.
The development of cell layers in the geniculate begins around E85
and is complete by about E110 (Fig. 8). If lamination involved the
selective loss of neurons, one would anticipate that neuron loss would
continue after E100, and one would anticipate that neuron loss would be
as common in parvocellular as in magnocellular parts of the nucleus.
Neither of these predictions is correct, and consequently, the formation
of laminae is evidently not associated with appreciable neuron death.
Lamination is probably caused by the growth and redistribution of cells,
dendrites, and fibers.
Neuron death and the formation of retinotopic maps
There is good evidence that the formation of retinal projections
involves the selective elimination of ganglion cells that make incorrect
connections (McLoon, 1982; Insausti et al., 84; Jeffery, 1984; O'Leary
et al., 1986; Jacobs et al., 1984, Rakic, 1981; Rakic and Riley, 1983;
Williams et al., 1983; Rakic, 1986). In marked contrast, our results
demonstrate that neuron number in the geniculate nucleus is stable
during the entire period from E110 to E140 when geniculate axons grow
into the cortical layers and establish the geniculocortical projection
(Fig. 8). It is evident that this precise retinotopic projection is
established without the the benefit of cell loss. Thus at the level of
retina and its targets, the refinement of connections appears to be
achieved in part by the selective elimination of incorrectly connected
subsets of ganglion cells, whereas at the level of the geniculate
nucleus and its target, the refinement is achieved without any neuron
loss. [Footnote 3.]
Neuron loss and the development of ocular dominance columns
The segregation of ocular dominance stripes in the primary visual
cortex of the rhesus monkey begins during the last month of gestation
and is complete two months after birth (Rakic '76; Hubel et al., 1977;
LeVay et al., 1980). LeVay and Stryker (1978) have illustrated arbors of
individual Golgi-impregnated geniculocortical axons in neonatal cat that
extend uniformly over territories that in adults would occupy several
ocular dominance stripes. On the basis of this finding they concluded
that segregation results from "synchronous changes in the arborizations
of thousands of overlapping geniculocortical axons." Their result does
not rule out an alternative, namely, that the refinement is attributable
to the selective elimination of geniculate neurons that make incorrect
connections. Because, segregation occurs long after the period of neuron
death in the geniculate nucleus, we can now rule out this alternative.
Positional specificity of neuron loss
Degenerating cells in the fetal monkey geniculate nucleus are located
principally in ventral and ventro-medial parts of the nucleus. This zone
overlaps extensively with the prospective magnocellular layers. In
contrast, cell loss is light in the dorsal part of nucleus that gives
rise to the four parvocellular layers. There are several possible
interpretation of this finding:
- Ratios between the two major types of projection neurons in the
geniculate nucleus (magnocellular Y-type and parvocellular X-type) may
be adjusted by the elimination of young magnocellular neurons. An
effective way to adjust ratios would be to eliminate members of the
less numerous cell class—in this case the magnocellular Y-type
- The spatial segregation of the two major neuron classes may
involve the selective elimination of magnocellular Y-type cells
located in the parvocellular layers and of parvocellular X-type
neurons located in the magnocellular layers. However, it is important
to note that the segregation of cell types in the adult monkey is far
from perfect. About 1 in 50 neurons recorded in the parvocellular
layers is Y-type (Marrocco, 1982) and according to Shapley et al.
(1981) as many as 3 out of 4 cells in the magnocellular layers are
- The focus of necrosis in the ventral region may reflect the
elimination of a transient population of S-type neurons. This idea is
based on a suggestion of Kaas and colleagues (1978) that the ventrally
situated S layers are regressive in several primate species, including
- The ventro-medial bias in the incidence of cell degeneration
suggests that more neurons may die in the region that represents the
periphery of the visual field (eccentricities greater than 15 degrees)
than in the dorsocaudal region that represents the center of the
visual field (Malpeli and Baker, 1975). Sengelaub et al. (1985) have
previously reported that the loss of geniculate cells in hamsters in
greatest in a region that represents the periphery of the
contralateral visual hemifield.
Experimental and comparative approaches would be effective in testing
the validity of these ideas.
Neuron death and the cortical target
The dependence of young neurons on their target cells has been
demonstrated in several systems (reviewed by Hamburger and Oppenheim,
1982; Williams and Herrup, 1988). For instance, in the retinogeniculate
system, the reduction in neuron number in the central target—the
geniculate nucleus—may initiate a reduction in the number of neurons in
retina. This notion that the survival of retinal ganglion cells depends
on the number of geniculate neurons stands in contrast to the
somatosensory system, in which there is reason to believe that the
survival of the central neurons depends on the status of the periphery
(Johnson et al., 1972; Rowe, 1982; van der Loos and Welker, 1985).
Is the loss of geniculate neurons also regulated by interactions with
target cells? The principal targets of these thalamic neurons are cells
in striate cortex—stellate cells of layer IV, ascending dendrites of
layer V and VI pyramidal cells, and descending dendrites of layer III
pyramidal cells (Garey and Powell, 1971; Peters, et al., 1979; White,
1979). At the time the loss begins (ca. E48), only those cortical
neurons destined for the deep layers V and VI are being generated,
whereas the stellate cells of layer IVC and the pyramidal cells of layer
III are not generated until after E66 (Rakic, 1974). All these young
neurons migrate up into the cortical plate after passing through a
plexus of geniculate axons situated in the optic radiations and the
subplate (Rakic, 1977b). While contacts between geniculate axons and
migrating neurons during this period have not been demonstrated yet (Kostovic
and Rakic, 1980; Chun et al., 1987), it is nonetheless possible that
interactions between the two modulate the severity of neuron loss in the
thalamus; and it may be more than just coincidental that the period of
heaviest neuron death occurs when layer IV neurons migrate through the
plexus of geniculate axons. Interactions between thalamic axons and
young cortical neurons certainly exercise strong control over the size
and number of neurons in the visual cortex of primates. We have been
able to demonstrate that reducing the number of geniculate neurons
causes a matched reduction in the number of neurons in visual cortex (Rakic
and Williams, 1986). Work in progress suggests that the critical period
for this type of manipulation extends from E60 to E100, almost precisely
the period during which cortical neurons are migrating through the
subplate and the plexus of geniculate axons.
We thank Kathryn Ryder for helping us perform the analysis; Dr.
Patricia Goldman-Rakic for providing us with tissue; and Dr. Prabhat
Sehgal for surgery and acquisition of fetuses of known gestational age.
Supported by grant EY 02593 to PR. The fetuses were obtained through the
primate breeding colony (Yale University School of Medicine) supported
in part by program project NS 22807, and from the New England Regional
Primate Research Center, Southboro, MA.
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Footnote 1. High variability (up to 10-fold) in the index of necrosis
has been noted previously by Prestige (1970, his figure 2B) in the
spinal cord of Xenopus larvae, even though absolute neuron
numbers in the same animals show very little variation.
Footnote 2. Both humans and rhesus macaques have 1.2 to 1.5 million
retinal ganglion cells and about 1.0 to 1.5 million geniculate neurons (Chacko,
1948; Chow et al., 1950; Sullivan et al., 1958). Developmental changes
in the number of retinal ganglion cell axons are also remarkably similar
in these two primates (cf., Rakic and Riley, 1983; Provis et al., 1986).
Using the gestational age at which retinal axon number peaks in the two
species as a time standard (E90 in rhesus and E110 in human), we
estimate that the putative period of neuron loss in the human lateral
geniculate should extend from E60 to E120. Gestation is 165 days in
rhesus monkeys and 265 days in humans.
Footnote 3. A template of geniculocortical topography could
conceivably be established between geniculate axons and cells in the
subplate before the geniculate axons grow into the cortex. If this is
the case then the subplate may play a role in organizing or filtering
axons destined for visual cortex.