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The Journal of Neuroscience, December 1, 1998, 18(23):9896-9909
Morphology of Single Geniculocortical Afferents and Functional
Recovery of the Visual Cortex after Reverse Monocular Deprivation in
the Kitten
Antonella
Antonini,
Deda C.
Gillespie,
Michael C.
Crair, and
Michael P.
Stryker
W. M. Keck Foundation Center for Integrative Neuroscience,
Department of Physiology, University of California, San Francisco,
California 94143-0444
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ABSTRACT |
To investigate the possible anatomical basis for the functional
recovery of visual cortical responses after reverse monocular deprivation, we have studied the morphology of single geniculocortical afferents to area 17. In kittens reverse-sutured for 10 d after an
initial week of monocular deprivation, single-unit and intrinsic signal
optical recordings confirmed that the effects of the initial deprivation were largely reversed. Responses through the originally nondeprived (OND) eye were drastically diminished, but remained much
more selective for orientation than after an initial monocular deprivation (Crair et al., 1997 ). Responses through the originally deprived (OD) eye recovered completely. Geniculocortical afferent arbors in layer IV of area 17 were filled by iontophoresis of Phaseolus lectin into lamina A of the lateral geniculate
nucleus (LGN) and were serially reconstructed. Arbors serving both the OD and the OND eye were analyzed. The plastic changes of both OD and
OND arbors were evaluated by comparison with arbors reconstructed in
normal animals and in animals studied after an equivalent initial period of deprivation (Antonini and Stryker, 1996). These analyses demonstrate that closure of the OND eye caused a substantial shrinkage of the arbors serving that eye. Moreover, reopening the OD eye induced
regrowth only in some arbors, whereas others appeared to be largely
unaffected and continued to have the characteristics of deprived
arbors. Quantitatively, the initial and the second deprivation caused
similar proportional changes in total arbor length and numbers of
branches, whereas several other features were more severely affected by
the initial deprivation.
Key words:
area 17; reverse suture; axonal reconstruction; optical
imaging; critical period; monocular deprivation
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INTRODUCTION |
In many species of mammals, closure
of one eye during a sensitive period in early postnatal development
leads to a loss of normal binocular interactions in the visual cortex,
and the vast majority of neurons lose their responses to the closed,
deprived eye (Wiesel and Hubel, 1963, 1965; Hubel and Wiesel,
1970; Shatz and Stryker, 1978; LeVay et al., 1980; Sherman and
Spear, 1982; Fregnac and Imbert, 1984; Mitchell, 1991). However, a
substantial functional recovery of cortical responses through the
deprived eye can be obtained by forcing the use of the deprived eye by patch therapy or reverse lid suture. In this experimental paradigm, after the initial period of monocular deprivation (MD), the eye that
was originally deprived (OD) is reopened and allowed normal vision,
whereas the originally nondeprived (OND) eye is sutured closed (Hubel
and Wiesel, 1970; Chow and Stewart, 1972; Blakemore and van Sluyters,
1974; Movshon, 1976; Mitchell et al., 1977; Olson and Freeman, 1977;
Blakemore et al., 1978, 1981; Giffin and Mitchell, 1978).
In the cat, the rate and extent of the physiological changes produced
by reverse suture depend on the age of the animal and the length of the
original deprivation (Blakemore and van Sluyters, 1974; Movshon and
Blakemore, 1974; Dursteler et al., 1976; Movshon, 1976; Giffin and
Mitchell, 1978; van Sluyters, 1978; Blakemore and Hawken, 1982; Malach
et al., 1984). At the peak of the sensitive period, it is possible to
reverse completely the cortical ocular dominance to favor the OD eye,
even when the initial MD was initiated at eye-opening.
At present, we have some understanding of the anatomical changes
accompanying the physiological effects induced by the initial MD. These
include a substantial loss of geniculocortical terminals serving the
deprived eye in layer IV of the visual cortex (Hubel et al., 1977;
Shatz and Stryker, 1978; LeVay et al., 1980; Antonini and Stryker,
1993a, 1996) if the deprivation period lasts for 1 week or more.
However, an expansion of the nondeprived terminals was observed only in
animals deprived for many weeks starting from eye-opening and not in
animals deprived for 1 week around the middle of the critical period
(LeVay et al., 1980; Antonini and Stryker, 1993a, 1996). Together,
these results suggest that the processes responsible for new growth of
terminals are slower than those responsible for their removal. All of
these anatomical changes appear to take place more slowly than the
effect of MD on the physiological reorganization of cortical responses,
in which the loss of response to the deprived eye is almost saturating with 2 d of deprivation (Movshon and Dursteler, 1977; Freeman et
al., 1981; Crair et al., 1997).
The present experiments were undertaken to determine whether the loss
of function of the OND eye and the complementary recovery of responses
to the OD eye after reverse suture can be attributed to anatomical
changes the pruning and re-expansion of geniculocortical connections
serving the two eyes. Indeed, a partial new growth of connections
serving the OD eye has already been suggested by transneuronal
experiments in monkeys that were reverse-sutured after several weeks of
MD (LeVay et al., 1980; Swindale et al., 1981). These experiments show
geniculocortical terminals serving the OD eye in regions of layer IV
that were devoid of afferent connections after the initial MD.
To study the anatomical basis of the functional recovery, we have
serially reconstructed single geniculocortical arbors in reverse-sutured animals in which the length of the first MD and the age
at which it was performed were equivalent to those used earlier to
study the effects of an initial period of MD (Antonini and Stryker,
1993b, 1996). The anatomical data are preceded by an analysis of the
efficacy of the particular protocol of reverse suture used in these
experiments at restoring functional cortical responses, using intrinsic
signal optical imaging and single-unit recording.
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MATERIALS AND METHODS |
Seven normally pigmented kittens were used for this study. All
kittens were born at the University of California San Francisco cat
colony and were kept with their mother throughout the experiment. Six
kittens underwent the reverse-suture manipulation, and one was used as
an age-matched control. Among the reverse-sutured animals, two were
used exclusively for optical imaging of the visual cortex and single
unit recordings, three were used exclusively for single arbor
reconstruction, and finally, one was used for both the anatomical and
physiological experiments (see Tables 1, 2).
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Reverse suture |
The experimental paradigm consisted of performing MD for 6 or
7 d during the fifth week of age (first MD) followed by a reverse suture of the other eye for a subsequent 10 or 11 d period (second MD). Tables 1 and 2 list for each kitten the age at the time of each
procedure and the eye involved in the first or second MD. Monocular
deprivations were performed under halothane anesthesia (1-2%) in
N2O/O2 (1:1). For the first MD, the superior
and inferior eyelids were joined along the margins and sutured with
sterile surgical #4 Vicryl (Ethicon, Somerville, NJ). Ophthalmic glue (Nexaband, Phoenix, AZ) was applied to both of the eyelid margins and
to the Vicryl stitches to prevent reopening of the eye. For the second
MD, the eyelids were trimmed along the margins and then sutured with
sterile surgical #4 Vicryl. In both procedures, topical antibiotic
ointment was applied to the eye before the eyelids were sutured. A
small opening on the nasal end of the eyelid allowed lachrymal
drainage. Antibiotics were administered systemically, and the animals
were checked once or twice a day to ensure that no openings formed
along the eyelids.
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Optical imaging and single unit recordings |
The animal was initially anesthetized with halothane mixed with
N2O/O2 (1:1). This initial anesthesia permitted
the insertion of a catheter into the femoral vein for subsequent drug
delivery and intubation of the trachea for artificial ventilation. The animal was then positioned on the Horsley-Clarke stereotaxic apparatus. The electrocardiogram, expired CO2 (3.8-4.2%), and rectal
temperature were monitored continuously. Anesthesia was maintained
throughout the experiment by infusion of sodium thiopental (10 mg/ml;
Abbott, North Chicago, IL) followed by pentobarbital (10 mg/ml;
Abbott). Muscle paralysis was induced with a bolus of gallamine
triethiodide (1.5 mg/kg; Sigma, St. Louis, MO) and maintained by
continuous infusion of the same drug (1 mg · kg 1 · h1 in
2.5% dextrose/lactate Ringer's solution). Throughout the experiment, the level of anesthesia was assessed by continuously monitoring the
heart rate. Additional thiopental was given to maintain the heart rate
at or below its level during the preparatory phase of the experiment,
when the animal was intubated and positioned in the stereotaxic
apparatus but was not paralyzed and could therefore react to noxious stimuli.
Details of the optical imaging protocols have been published previously
(Crair et al., 1997). Briefly, a bone flap of approximately 10 mm × 10 mm was removed above area 17, around anteroposterior 0 of the
stereotaxic coordinates. The dura was carefully removed, and the
opening was filled with 3% agarose and sealed with a clear glass
coverslip to ensure a flat surface. The cortical surface was
illuminated with a green light, and the slow-scan CCD camera (Princeton
Instruments, Trenton, NJ) was initially focused on the pial surface to
obtain a clear image of the blood vessels. For acquiring intrinsic
signals related to cortical activity, the surface of the cortex was
illuminated with 610 nm light, and the camera was focused 250-500 µm
below the pial surface. The animal was visually stimulated with
computer-generated square-wave gratings (0.10 or 0.15 cycles/degree)
moving in both directions at four different orientations (0, 45, 90, and 135°). The stimuli were presented on a monitor placed 40 cm in
front of the animal. For each run, the four oriented stimuli and a
blank screen isoluminant with average grating luminance were presented
to each eye individually; these presentations were repeated 16 times in
random order. For each stimulus orientation, the acquired raw images
were averaged and then normalized against the blank gray stimulus.
Images were processed with 3-pixel low-pass and 70-pixel high-pass
filters (each pixel in the final images occupied ~17 µm on the
cortex). Angle maps were constructed by determining, for each pixel,
the orientation that gave the best signal, and assigning a color to each orientation. An overall optical Contralateral Bias Index [optical
CBI; Crair et al. (1998)] was calculated for each map by assigning to
each pixel an eye dominance value based on the relative response
strength through each eye and then averaging all pixels within the
regions of the maps that were free of artifact. CBI values of 1.00 and
0.00 represent complete dominance of the contralateral eye and the
ipsilateral eye, respectively.
Once the optical imaging was completed, the coverslip and the top layer
of the agarose were removed, and the activity of single units was
recorded extracellularly with tungsten electrodes that were advanced
vertically through the medial bank of the lateral gyrus, at ~0 of the
anterior-posterior stereotaxic coordinates. Visual stimuli consisted
of oriented light bars moved by hand in different directions. Neurons
were classified in the seven traditional ocular dominance groups
according to Hubel and Wiesel (1962).
Two indices were used to evaluate the ocular preference. The
"reversal index" (RI), which simply represents the proportion of
neurons dominated by the OD eye, has been used in previous works
(Blakemore and van Sluyters, 1974; Movshon, 1976) to estimate the
extent of the ocular dominance shift reversal and is used here for a
comparison between our data and those published previously. In our
experiments the OD eye was the right eye, and we have recorded in all
cases from the right hemisphere. Therefore, the reversal index is given
by the sum of neurons in classes 5, 6, and 7 divided by the total
number of neurons. The CBI is a weighted average toward one or the
other eye and is calculated by the formula: CBI = [(n1  n7) + 2/3(n2 n6) + 1/3(n3 n5) + N]/2N, where N is the total
number of cells and nx is the number of cells in a ocular
dominance group x. CBI values of 1.00 and 0.00 represent complete dominance by the contralateral or the ipsilateral eye, respectively. This index is analogous to the optical CBI.
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PHA-L experiments |
Single geniculocortical arbors, anterogradely labeled with the
Phaseolus lectin PHA-L (Vector, Burlingame, CA) (Gerfen and Sawchenko, 1984) injected into the LGN, were serially reconstructed in
one control and four reverse-sutured animals. Table 2 lists the entire
sample of geniculocortical arbors reconstructed in the two groups of animals.
PHA-L injections
The goal of the experiment was to inject PHA-L into lamina A of
the right and left LGN, allowing the analysis, in the same animal, of
geniculocortical arbors serving the OD and OND eyes. Thus, special care
was taken to clearly identify electrophysiologically the main laminae
of the LGN before the PHA-L injection. Electrophysiological recordings
and PHA-L injections into the LGN were performed according to the
protocol described in detail in previous papers (Antonini and Stryker,
1993b, 1996). Briefly, the animal was initially anesthetized with a
mixture of ketamine hydrochloride (0.2 mg/kg; Ketalar, Parke-Davis,
Morris Plains, NJ) and acepromazine (0.02 mg/kg; PromAce, Ayerst,
Rouses Point, NY). Anesthesia was maintained with halothane (1-2%) in
N2O/O2 (1:1) throughout the experiment. Tungsten microelectrode penetrations were made between the
Horsley-Clarke stereotaxic coordinates anteroposterior 4.0-6.0
and mediolateral 7.0-8.5. Once a clear response from lamina A was
obtained, the metal microelectrode was withdrawn and substituted with a
PHA-L-filled glass pipette 10-15 µm in diameter. The 2.5% solution
of PHA-L (Vector) in 0.1 M sodium PBS, pH 8, was
iontophoretically injected using a high-voltage current source device
(Midgard Electronics; Stoelting, Wood Dale, IL) with a positive
current (8 µAmp) delivered in 7 sec pulses for 4 min. Usually,
two to four lectin injections were made in each LGN. After completion
of the experiment the skin of the skull was sutured closed, and
antibiotic was administered systemically. PHA-L was injected at the end
of the first period of MD; the deprived eye was reopened to allow
electrophysiological recordings from both LGNs. At the end of the
procedure the OND eye was then sutured closed.
Perfusion and immunohistochemistry
Ten days after the PHA-L injections, equivalent to 10 d of
reverse suture, the animals were killed with an overdose of
Nembutal (60 mg/kg) and perfused transcardially with, in succession,
ice-cold 0.1 M phosphate buffer; 4% paraformaldehyde,
0.5% glutaraldehyde in 0.1 M phosphate buffer; 4%
paraformaldehyde, 3.42 gm/l L-lysine (Sigma), 0.55 gm/l
sodium meta-periodate (Sigma) in 0.1 M phosphate buffer.
All solutions had a pH of 7.4. The brain was removed and post-fixed
overnight. Blocks containing the LGN and the entire caudal pole of each
hemisphere where the visual cortex is located were embedded in
gelatin-albumin and cut (80 µm) with a vibratome in the frontal
plane. All sections were collected in ice-cold potassium buffered
saline (KPBS), pH 7.4, and processed for standard indirect
immunohistochemistry. The immunohistochemical procedure has been
described in detail in previous papers (Antonini and Stryker, 1993a,
1996). Briefly, sections were incubated overnight at 4°C in a
blocking solution composed of 2.5% bovine serum albumin (BSA), 2%
normal rabbit serum (NRS), and 0.7% Triton X-100. They were then
transferred into a solution of 2.5% BSA and 2% NRS containing the
primary antibody (goat anti-PHA-L, Vector) at a dilution of 1:1000 and
kept at 4°C for 48-72 hr. Sections were subsequently incubated
overnight at 4°C in a solution containing rabbit anti-goat biotinylated secondary antibody (Vector) in 2.5% BSA, 2% NRS, and
0.3% Triton X-100, then transferred for 3-4 hr in an avidin-HRP complex, and finally reacted with a solution of 0.05% diaminobenzidine hydrochloride (DAB) (Sigma), 0.7% nitroammonium sulfate, and 0.3% hydrogen peroxide in Tris buffer, pH 7.4. All of the washes between the
incubation in the primary and secondary antibody and between the
secondary antibody and the avidin-HRP complex solution were performed
in KPBS; the final washes before and after the DAB reaction were made
in Tris buffer.
Axonal reconstructions
We considered for analysis only those experiments in which PHA-L
injection sites were limited to the binocular zone of the LGN and
confined to layer A. We limited our analysis to axons with well filled
terminal arborizations that could be followed up to their thinnest terminals.
PHA-L-filled arbors were three-dimensionally reconstructed at 1000×
from serial sections with the aid of a computer graphic system, the
Neurotrace system (InterAction, Boston, MA), which has been described
previously (Passera et al., 1988; Antonini and Stryker, 1993b, 1996).
In Figures 3-5, the axonal reconstructions are shown in two views: in
the coronal plane (as reconstructed) and after rotation about the
ventrodorsal axis, providing in this case a view tangential to the pial surface.
Several measurements were used to quantify the features of the terminal
arborization of the reconstructed afferents [also see Antonini and
Stryker (1993b, 1996)].
Measurements related to the size of the geniculocortical arbors:
the total linear length of the arborization. This value was obtained by the addition of the lengths of all the branches
constituting the terminal field of an arbor. Only the portion of
the arbor located in layers III and IV was considered for this
measure. For this reason, the main axonal trunk was clipped just
below layer IV, as is clearly visible in arbors shown in Figures 3-5. Terminal branches <5 µm were not considered for the analysis.
Measurements related to the size of the geniculocortical arbors:
the coverage area of the arborization in layer IV. The terminal arborization was considered to be compressed along an axis
perpendicular to the pial surface and to lie in a single plane. From
this view, the coverage area of the arbor was calculated as the area
over which arbor density (see below) was higher than 2 µm/1000
µm2.
Measurements related to the complexity and density of the
geniculocortical arbors: the number of branch points of the terminal arborization in layer IV. Again, branch points giving rise to terminals <5 µm in length were not considered.
Measurements related to the complexity and density of the
geniculocortical arbors: the density of the terminal arborization in
layer IV. For comparison with earlier findings (Antonini and Stryker, 1993b), we measured the density of axonal branches per unit
area within layers III/IV rather than the density of synaptic boutons.
The arbor density measure used here is not directly related to synaptic
density, because some thick axonal branches may bear only a small
number of boutons. Density was evaluated from the two-dimensional pial
view of the arbor, after compression along an axis perpendicular to the
pial surface. The density at each 5 × 5 µm square within the
territory covered by the arbor was calculated by summing the total
lengths of the portions of all branches that lay within the area
enclosed by a circle of 100 µm diameter. The maximal density of the
terminal arborization (expressed in micrometers per 1000 µm2) was then evaluated.
Measurements related to the complexity and density of the
geniculocortical arbors: high-density areas of the terminal
arborization. With the aim of better understanding the internal
organization of the terminal arborization, we used this measure to
reveal the presence of areas of dense clustering of collateral
branches. In a previous paper (Antonini and Stryker, 1993b) we defined
the standard characteristics of zones of high density of innervation, called "patches," from the analysis of arbors reconstructed in normal animals at postnatal day (P) 30/31 and P40, which is the same
population used here as control. For each arbor, the high-density patches were defined as regions of the terminal arborization exceeding a threshold density of half the maximal density. The average threshold density across animals was 38 µm of arbor length per 1000 µm2 of area and was used to define the threshold
density for a standard cluster. For each arbor, we summed the areas of
the individual patches to obtain the total area of the high-density clusters.
For all features measured, evaluation of the differences among groups
has been obtained by comparing groups two at a time, using the
Mann-Whitney U test for nonparametric statistical analyses.
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RESULTS |
The results are presented in three sections. First, we describe
the physiological characteristics of the visual cortex in reverse-sutured animals, based on the analysis of both optical imaging
of intrinsic signals in area 17 and single-unit recordings. Next, we
describe and compare serially reconstructed geniculocortical arbors
serving the OD and OND eyes in reverse-sutured animals, along with
arbors reconstructed in an age-matched control. Finally, we present
measurements of the size, complexity, and distribution of the
reconstructed arbors and compare the effects of reverse suture with
those of an initial period of monocular deprivation.
Ocular dominance and response characteristics in area 17 of
reverse-sutured animals
In three animals (K2, K12, and K28) (Table
1), optical imaging of intrinsic
signals was acquired from a 2.4 × 3.2 mm area centered on the
lateral gyrus over the intra-aural line. In all three animals, the
originally deprived eye was on the right, and the recordings, after the
end of the reverse-suture period, were obtained from the right
hemisphere. Figure 1A
shows for the reverse-sutured kitten K12 the distribution of cortical
activity in response to the four oriented stimuli (see Materials and
Methods) presented to the OD (a-d) and OND
(e-h) eye. The cortical activity elicited through the OD
eye was strong and selective for each stimulus orientation, indicating
that the pathway driven by this eye had fully recovered within the
10 d of reverse suture. The activity map driven by the OND eye
showed a much weaker signal, but the responses through this eye
remained clearly orientation selective. Figure 1B
shows the effect of the initial period of deprivation, before the
reverse suture, in a P38 animal monocularly deprived for 7 d
before the recording session; animals monocularly deprived for shorter
periods show the same effect (Crair et al., 1997). The effect on
orientation selectivity of the second period of deprivation was quite
different from that after the initial deprivation, in which the strong
responses through the deprived eye were largely not orientation
selective (Fig. 1B,a-d). After the reverse suture, optical CBIs were 0.376, 0.387, and 0.369 for kittens K2, K12, and K28,
respectively, indicating in all cases a predominant response to the eye
ipsilateral to the cortex under study; that is, the OD (right) eye
prevailed over the OND eye in its ability to elicit visual responses.
The optical CBI in normal animals between P22 and P40 is 0.55, and in
animals deprived for 7 d starting around P28 it is 0.74 (Crair et
al., 1997).
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Figure 1.
Optical imaging of intrinsic signals obtained from
the lateral gyrus in a reverse-suture kitten (A)
and in a P38 kitten monocularly deprived for 7 d
(B). In both A and
B, a-h are cortical activity maps in
response to each of the four oriented stimuli indicated in the
left corner of each image; j is the image
of the vascular pattern, and i and k are
color-coded angle maps of each hemisphere, combining the responses
obtained from all orientations (see Materials and Methods).
A, Distribution of cortical activity presented to the OD
(a-d) and the OND eye (e-h). Note that
the activity maps from the OND eye are orientation selective. i,
k, Angle maps obtained from OD and OND eye, respectively.
B, Distribution of cortical activity in response to
oriented stimuli presented to the deprived eye (a-d)
and the nondeprived eye (e-h). i, k,
Angle maps obtained from deprived and nondeprived eye, respectively.
Note in both the activity and angle maps that the responses through the
deprived eye are nonoriented and limited to small cortical regions.
Scale bar (shown in Aj for Aa-k, Ba-k):
500 µm.
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After completion of optical imaging, the activity of single units was
recorded extracellularly in one or two vertical penetrations originating within the area that was mapped optically and directed down
the medial bank of the lateral gyrus. Receptive fields of the neurons
encountered were well within the binocular visual field. In Figure
2A, a sketch of
electrode tracks along with the ocular dominance of the single units
encountered is shown for each animal. Most of the neurons were
dominated by the OD eye; only a few groups of neurons that were driven
well or dominated by the OND eye were encountered along the electrode
penetration.
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Figure 2.
Single units recorded in vertical penetrations
along the medial bank of the lateral gyrus in three reverse-sutured
animals. A, Sketch of electrode tracks with the single
units sequentially encountered is shown for each animal. The dominance
of the OD or OND eye in activating each cell is indicated by different
shading. Most neurons were dominated by the OD eye;
units dominated by the OND eye, or equally driven by both eyes, were
encountered in clusters. B, Ocular dominance
distribution for neurons recorded in each animal. C,
Ocular dominance distribution for the entire sample of cells recorded
in the three reverse-sutured animals (left) and for 260 cells recorded in seven MD kittens [from Reiter and Stryker (1988)].
The contralateral bias index (CBI) is indicated
above each plot.
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Figure 2B illustrates the ocular dominance
distribution of the recorded neurons for each animal. In all cases
after reverse suture, the OD eye has came to dominate the cortical
response. The greatest and the smallest effects occurred in K2 and K12, respectively (K2: CBI = 0.16, RI = 0.84; K12: CBI = 0.32, RI = 0.75). However, in every case the OND eye still drove
and dominated a small contingent of cortical neurons, in contrast with
the almost complete absence of strong selective responses through the
deprived eye in animals submitted to a single monocular deprivation
(Fig. 2C) (Wiesel and Hubel, 1963; Movshon, 1976; Crair et
al., 1997).
In summary, both optical and single-unit measures of cortical activity
reveal a very substantial recovery of strong and selective responses to
the OD eye and an accompanying reduction in response to the OND eye
that is less severe and preserves greater selectivity than the deficit
after the original deprivation.
Organization of geniculocortical afferents
PHA-L injections into the LGN and cortical labeling
In reverse-sutured animals, PHA-L injection sites were intended to
be restricted to lamina A of both LGNs, to label selectively geniculocortical arbors in each hemisphere serving either the OD or the
OND eye. Moreover, the injection sites had to be located in the
binocular portion of the LGNs to ensure that the labeled afferents had
been influenced by the binocular competitive interactions that are
thought to underlie plastic remodeling (Hubel et al., 1977; LeVay
et al., 1980). We obtained successful bilateral labeling of the
geniculocortical connections in both hemispheres in only one animal
(MUC 927, Table 2). In the other cases,
only one hemisphere could be used, either because the quality of the
label was not adequate to allow single axon reconstruction or because
the injection site also involved lamina A1. In the normal P49 animal,
PHA-L injection sites were also restricted to lamina A of the LGN.
Therefore, all of the reconstructed arbors were in the pathway serving
the contralateral eye. In kitten K28, one hemisphere was used for single arbor reconstructions, and the other was used for optical imaging and single-unit recordings.
The quality of labeling between the arbors reconstructed in
reverse-sutured animals was similar to the normal animal, indicating that deprivation per se does not interfere with the transport of the
lectin (Antonini and Stryker, 1996).
We refer to our reconstructions as arbors in layer IV and not as
complete geniculocortical axons, because, as reported and discussed
previously (Antonini and Stryker, 1996), PHA-L staining is very
consistent in layer IV but becomes faint in the deeper portion of layer
VI and the white matter, thus raising the possibility that
collateralization of the main axonal trunk, had it occurred at this
level, would have been missed. For these reasons, we have also
disregarded the ramifications in layer VI.
Although labeled axons were found in both areas 17 and 18, we have
exclusively analyzed geniculocortical afferents to area 17. All of the
reconstructed arbors were located in the top third of the medial bank
of the lateral gyrus, in an area corresponding to the binocular zone of
the visual cortex. This zone corresponds to that mapped by the
electrode penetrations during single-unit recordings. Table 2 gives the
experimental protocol and the list of arbors reconstructed in each animal.
Geniculocortical arbors in a normal P49 kitten
Five arbors were reconstructed from the medial bank of the lateral
gyrus (area 17) in one P49 animal (Table 2). In Figure 3, three arbors (N1, N3,
N6) are shown in coronal view and from the pial surface
after a 90° rotation along the ventrodorsal axis. The terminal
arborizations of these arbors were characterized by a considerable
extension along the ventrodorsal axis (reaching more than 2 mm in N3)
and by the presence of zones of high concentration of collaterals.
Overall, the P49 arbors were longer and more complex than those studied
previously at P40, indicating that growth continues during this period.
All arbors except N6 ramified mainly in the top portion of layer IV,
with a few branches straddling the layer III/IV border. The terminal
field of arbor N6 also covered deeper regions of layer IV.
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Figure 3.
Computer reconstructions of PHA-L-immunostained
axonal arbors in area 17 in a normal P49 animal. All geniculocortical
arbors in normal, OND (Fig. 4), and OD (Fig. 5) animals were obtained
from the dorsal-most portion of the medial bank of the lateral gyrus.
A shows the arbors as originally reconstructed in the
coronal plane, and B shows the arbors as seen from the
pial surface, after a 90° rotation along the dorsoventral axis of the
lateral gyrus. The arrowheads indicate the boundaries of
layer IV. V D = ventrodorsal axis indicated in
A; AP = anteroposterior axis
indicated in B. Inset, Drawing of coronal
section showing arbor N3 and rectangle in the medial bank of the
lateral gyrus containing all arbors reconstructed.
Inset: D, Dorsal direction;
V, ventral direction.
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Geniculocortical arbors serving the OD eye
Thirteen geniculocortical arbors serving the OD eye were
reconstructed from area 17 in kittens MUC 927 and K28 perfused at P48
and P49, respectively. These animals began 7 d of MD at age P31/32
and were reverse-sutured at P38/39 for 10 d (Table 2). This group
of arbors varied greatly with respect to the complexity of their
terminal arborization, as exemplified in Figure
4. The majority of arbors (arbors RS3,
RS5, RS6, RS8, RS10, RS12, RS28, and RS31) appeared scantily ramified
and generally occupied a restricted portion of layer IV, as is typical
of arbors serving a deprived pathway (Antonini and Stryker, 1996). In
contrast, five remaining arbors were large, like those in normal
animals. Their terminal arborizations were extensively ramified and
formed one or more clusters of densely packed collaterals, best
appreciated in coronal view. Nine arbors ramified mainly in the top
tier of layer IV, whereas the remaining four arbors spanned the entire width of layer IV. No relation was found between the complexity of the
terminal arborization and its location within layer IV.
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Figure 4.
Computer reconstructions of PHA-L-immunostained
geniculocortical arbors reconstructed in animals monocularly deprived
for 1 week and reverse-sutured for 10 d. These arbors serve the OD
eye. Arbors are shown in coronal view (A) and in
surface view (B). Abbreviations and symbols are
the same as in Figure 3.
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Geniculocortical arbors serving the OND eye
Fourteen arbors serving the OND eye were reconstructed
from the medial bank of the lateral gyrus in three kittens (Table 2). Figure 5 illustrates four examples from
this group of arbors. All but one of the arbors displayed the poorly
ramified terminal arborization characteristic of deprived arbors. The
exception was arbor RS14, which had a relatively elaborated terminal
field that was also organized into two distinct clusters of collaterals separated by a collateral-free zone. All arbors except RS19 and RS31
ramified mainly in the top tier of layer IV.
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Figure 5.
Computer reconstructions of PHA-L-immunostained
geniculocortical arbors serving the OND eye reconstructed in
reverse-sutured animals. Arbors are shown in coronal view
(A) and in surface view
(B). Abbreviations and symbols are the same as in
Figure 3.
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Quantitative aspects of geniculocortical arbors
Previous experiments (Antonini and Stryker, 1993a, 1996)
measured the remodeling of single geniculocortical arbors serving the
deprived and nondeprived eye after 6-7 d of MD terminating at P40. The
remodeling involved several aspects of the organization of the terminal
arborization, including total length, complexity, maximal density, and
characteristics of the areas of high density of collaterals. Reverse
deprivation in the present experiment was planned to begin after 7 d of MD ending at P40, so that the data from previous experiments
(Antonini and Stryker, 1996, 1998) would provide a baseline from which
the further changes produced by reverse suture could be measured. In
particular, for arbors serving the OD eye, the changes produced by
reverse suture can be measured by comparison with the deprived arbors
studied after 6-7 d MD (6/7d-D arbors). Similarly, the effects of
reverse suture on OND arbors are evaluated by comparison with the
nondeprived arbors after 6-7 d MD (6/7d-ND arbors). Finally, the
deprived arbors are compared with those in normal animals.
The scattergrams in Figures 6 and
7 illustrate the values for the
individual arbors in each experimental group. Table
3 lists for each parameter the median
value for arbors in each experimental group, and Table
4 gives the significance of the
statistical comparisons between groups (Mann-Whitney U
test).
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Figure 6.
Scattergram of the total length
(A) and coverage area (B)
of the terminal arborization in layer IV (see Materials and Methods)
for arbors reconstructed in reverse-sutured animals (OD and OND arbors)
and in the P49 normal control. For comparison, data from arbors serving
the deprived and nondeprived eye in animals monocularly deprived for
6-7 d (6/7d-D and 6/7d-ND arbors) and in
normal animals at P30 and P40 are also plotted.
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Figure 7.
Scattergrams of number of branch points
(A), maximal-density (B),
and (C) high-density areas (see Materials and
Methods) of the terminal arborization in layer IV in arbors
reconstructed in reverse-sutured animals (OD and OND arbors), in
animals monocularly deprived for 6-7 d (6/7d-D and
6/7d-ND arbors), and in normal animals at P30, P40, and
P49. The density is expressed in µm/1000 µm2.
Note that the high-density areas in four 6/7d-D arbors are equal to 0, because these arbors did not reach the threshold density of 38 µm/1000 µm2.
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Total length and coverage area
Measures of total length and coverage area reflect the
size of geniculocortical arbors. The scattergrams in Figure
6A,B show the distribution of these two parameters
for arbors serving the OD and OND eye in reverse-sutured animals, for
arbors serving the ND and D eye in animals monocularly deprived for 1 week (6/7d-ND and 6/7d-D), and finally, for
arbors reconstructed in normal animals at P30, P40, and P49.
Arbors serving the OD and the OND eye were significantly
different from each other in size. For both parameters, the reverse opening of the eye caused a significant expansion of the arbors serving
the OD eye compared with their state at the end of the first
deprivation (p < 0.01; OD vs 6/7d-D) (Table 4).
The reverse MD caused an even greater reduction in the total length of
arbors serving the OND eye as compared with their previous state after the initial week of monocular vision (p < 0.001; OND vs 6/7d-ND), although in this case the change in coverage
area was not significant. The sizes of the deprived arbors at the end
of the first and second period of deprivation were similar (not
significant; OND vs 6/7d-D).
Comparisons with normal animals indicate that the reverse suture
procedure interfered with normal development, rendering
geniculocortical arbors smaller than arbors reconstructed in the
age-matched control at P49. The opening of one eye during the second MD
allowed OD arbors to only partially recover the total length, enough to
make them similar to normal arbors at a younger age, P40 (OD vs Normal P40).
Number of branch points and density measurements
These parameters are an index of the complexity of the terminal
arborization. The number of branch points and the maximal density of
individual arbors in the different experimental groups are shown in
Figure 7A,B; statistical comparisons are indicated in Table
4. After the reverse suture, OD arbors showed a significant increase in
both measures relative to their state at the end of the first
deprivation (OD vs 6/7d-D). Concurrently, after the second deprivation,
OND arbors suffered a great reduction in the number of branch points
(p < 0.001) and, to a lesser extent, in the
maximal density (p < 0.04) compared with after
the first deprivation (OND vs 6/7d-ND).
At the end of the reverse suture, arbors serving both the OD and OND
eye had many fewer branch points than arbors in the P49 age-matched
control (OD vs P49, OND vs P49), although their maximal density was not
different. Note, however, that the maximal density values of the
population of normal arbors are very widespread.
Another approach for characterizing the internal structure of
geniculocortical arbors is the assessment of regions of dense clustering of collateral branches within the terminal arborization. As
discussed in Materials and Methods, the standard threshold density
value was used to evaluate the zones of high-density areas in arbors of
all groups of animals.
The scattergram of Figure 7C indicates the total area of
high-density clusters for each arbor. Arbors reconstructed in normal animals at P40 and P49 show a great variability in the extent of the
total area of high density. This measure is meaningful where dramatic
changes occur but is not sensitive for detecting subtle modifications
in the structure of the terminal arborization.
The terminal arborization of arbors serving the OND eye suffered a
significant reduction in the total area of high density compared with
their previous state at the end of the first deprivation (OND vs
6/7d-ND). Concomitantly, but to a lesser extent, the high-density areas
in arbors serving the OD eye expanded after 10 d of monocular vision (OD vs 6/7d-D).
Note that the first deprivation was much more deleterious than the
second in that many 6/7d-D arbors did not reach the defined threshold
density of 38 µm/1000 µm2 and thus did not form
high-density areas (OND vs 6/7d-D). In contrast, reverse monocular
vision generally appeared to be sufficient to cause a re-expansion of
the patches to the size they supposedly were 10 d before (OD vs
6/7d-ND). However, for a few arbors serving the OD eye, the area of the
patches remained relatively small.
Comparison of effects of the first versus the
reverse deprivation
With the aim of comparing the efficacy of the first MD versus the
reverse MD in inducing plastic changes in geniculocortical arbors, we
have measured the changes in each of the arbor parameters between the
beginning and the end of each period of deprivation. Thus, for the
first MD, we have measured the proportional changes of the arbors'
parameters after 6-7 d of deprivation relative to values obtained in
normal animals at an age corresponding to the beginning of the
deprivation, i.e., between P30 and P40. Because the age at the
beginning of the initial 7 d of deprivation was P33, we have
interpolated a P33 value of each parameter from the normal values
measured at P30 and P40 (2 × value at P30 + value at P40)/3. For
the reverse MD, we have measured the changes of OD and OND arbors
relative to arbors reconstructed in animals after the first
deprivation, i.e., relative to arbors reconstructed after the 6/7 d MD.
These results are plotted in Figure 8.
For clarity, the percentage decrements or increments relative to the initial condition have been plotted as negative and positive values, respectively.
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Figure 8.
Percentage changes in total length, coverage area,
number of branch points, maximal-density, and high-density areas after
an initial period of 6-7 d of monocular deprivation (stipple
bars) and after 10 d of reverse suture (white
bars) in arbors serving the closed (A)
and the open (B) eye. The percentage changes are
referred to the state of the arbors before each deprivation. For the
initial deprivation, comparisons were obtained relative to the values
obtained in normal animals at P33 [(P33-6/7d-D) × 100/P33 and
(P33-6/7d- ND) × 100/P33, for arbors serving the closed and open eye,
respectively (see Results)]. For the reverse deprivation, we have
measured the changes of OD and OND arbors relative to arbors
reconstructed in animals deprived for 6-7 d [(6/7dND-OND × 100/6/7d-ND and (6/7d-D-OD) × 100/6/7d-D for arbors serving the closed
and open eye, respectively]. Note that reverse suture has a greater
effect than the initial deprivation on arbors serving the open eye,
whereas arbors serving the closed eye appear to be equally affected by
both the initial and reverse deprivation.
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For deprived arbors, the first MD appears to be more deleterious than
the reverse MD in inducing a reduction in the number of maximal density
and high-density areas (Fig. 8A). The proportional changes in total length, branch points, and coverage area are similar
in the two conditions.
In contrast, the open eye's arbors appear to benefit more from the
reverse than from the first MD, in that the increments of all
parameters relative to the initial condition are higher after the
reverse MD than after the first MD.
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DISCUSSION |
The aim of this work was to analyze the extent to which the
physiological recovery observed in the visual cortex after reverse MD
is matched by changes in the anatomical characteristics of geniculocortical arbors serving the two eyes. This study was motivated by previous work on the effects of brief periods of MD on
geniculocortical afferents (Antonini and Stryker, 1996). In that study
we demonstrated that a few days of MD are sufficient to cause striking
morphological changes in the geniculocortical connections serving the
deprived eye, whereas arbors serving the nondeprived eye are little
affected (Antonini and Stryker, 1996). These earlier findings suggested two conclusions. First, removal of axonal branches occurs faster than
addition of new collaterals, at least during the first week of
deprivation. Second, if the open eye's rapid ascent to dominance of
cortical responses is predominantly the expression of geniculocortical innervation, then such dominance must be attributed to the loss of
connections serving the deprived eye rather than to the expansion of
connections serving the nondeprived eye.
To allow comparisons between data from the present reverse-suture study
and those from previous anatomical studies of the effects of brief MD,
the reverse-suture protocol was designed to incorporate an initial
period of deprivation identical to that studied previously (Antonini
and Stryker, 1993a, 1996). Therefore, we were able to take the previous
data as the baseline for changes produced by the reverse deprivation.
The 10 d duration of the reverse MD was chosen to be consistent
with protocols in the literature (Blakemore and van Sluyters, 1974;
Movshon and Blakemore, 1974). According to these studies, 10 d of
reverse suture in 6 week old kittens previously deprived for 10 d
(van Sluyters, 1978) or since eye opening (Movshon, 1976) was
sufficient to induce a reversal of the ocular dominance shift.
Because the shrinkage of deprived afferents is more rapid and more
extensive than the expansion of those serving the open eye, we
predicted that reverse suture from P40 to P50 near the end of the
critical period might yield a cortex in which the pathways of both eyes
were impaired. This prediction was confirmed. Indeed, we found that the
OND arbors, whose baseline size at the end of the initial MD was
similar to that of afferents in normal animals, did shrink rapidly and
dramatically after the reverse suture, and the majority of the OD
arbors did not greatly expand. Nonetheless, physiological responses to
the OD eye recovered strength and selectivity, and responses to the OND
eye, although diminished in strength, retained selectivity.
Physiological and anatomical effects of reverse suture
Cortical activity after reverse suture
Binocular interactions in area 17 were studied by both
optical imaging of intrinsic signals and single-unit recordings.
Although the portions of the visual cortex examined by these two
different techniques were different, one confined to the crown of the
lateral gyrus and the other including its medial bank, both
physiological measures were made within the central 10° of the visual
field, well within the most binocular zone of area 17. Ocular dominance is not reported to differ over this range of eccentricities. In agreement with previous studies (Movshon and Blakemore, 1974; Movshon,
1976), we have shown that after reverse suture, single-unit responses
exhibit a shift in favor of the open, OD eye, implying that
functionally the thalamocortical and/or intracortical circuits serving
that eye have recovered substantially. In our experiments, the mean
reversal index (see Materials and Methods) is 0.78, very close to that
found by Movshon (1976) after 9-12 d of reverse deprivation at the age
of 5-6 weeks (>0.70). Furthermore, the orientation specificity of the
OD eye in the activity map of the cortex acquired during optical
imaging is consistent with the recovery of function demonstrated by Kim
and Bonhoeffer (1994), using the same experimental paradigm, and with
the earlier single-unit findings of Van Sluyters (1978). The nearly
complete functional recovery evident in neurophysiological experiments
suggests that the reinnervation by the OD pathway ought to form in a
manner mimicking the pattern of connectivity present before the first deprivation.
The OND eye is typically considerably less potent than the newly opened
eye in driving cortical neurons. However, this eye in reverse-sutured
animals is still able to evoke strong cortical activity in clusters of
neurons, in which it may even be dominant over the open eye. This
observation is in contrast to that after the initial MD in which the
majority of neurons become monocularly activated by the open eye.
Single-unit recordings show that the reverse ocular dominance shift in
our kittens is not as great as the shift at the end of the initial MD
[contralateral bias index: 0.11 for the initial MD vs 0.25 for the
reverse MD (Fig. 2C)]. The analysis of visual cortical
activity by optical imaging also shows a substantial difference between
the initial MD and reverse-sutured animals. In the initial MD, all of
the residual strong activity elicited by the deprived eye is
concentrated in cortical patches (centered on the pinwheel
singularities of the orientation map) in which responses after MD are
not orientation selective (Crair et al., 1997) (Fig. 1). These
"deprived eye patches" of strong responses do not appear in the OND
eye's map after reverse suture. Instead, the strongest cortical
activity through the OND eye shows a clear selectivity for oriented stimuli.
Two factors may contribute to the stability of the orientation
selectivity in the newly deprived pathway. First, the reverse deprivation occurs between P40 and P50, after the peak of the critical
period, and therefore the visual cortical circuits serving the OND eye
may inherently be less apt to collapse into patches of unselective
responses. Second, the OND eye's pathway may not be pushed into such a
collapse by competition from a strong pathway serving the other eye,
because the other (OD) eye's pathway is itself largely collapsed at
the outset of the reverse suture.
Geniculocortical afferents after reverse suture
Geniculocortical afferents were reconstructed from the medial bank
of the lateral gyrus, in approximately the same portion of area 17 from
which single-unit recordings were made. After reverse suture, we found
a significant restructuring of single afferents of OD and OND arbors
relative to their condition after the first MD. Specifically, the OND
arbors suffer a reduction of almost all the parameters studied, with
the result that they are actually smaller than normal arbors at P50,
their age-matched controls. Thus, as with an initial MD, reverse
deprivation is effective in inducing a loss of terminals in the
deprived arbors. However, the morphological condition of arbors serving
the OND eye after the reverse MD is not as deficient as after the first MD; indeed, OND arbors appear on average larger and more complex than
the 6/7d-D group. These findings are consistent with our observations
from the physiological results discussed above. Again, this may be
attributable to the slight advantage that the OND arbors acquired
during the first deprivation (Antonini and Stryker, 1996), or it may be
purely age-dependent, reflecting the decreased efficacy of plastic
processes toward the end of the critical period.
The group of OD arbors shows an increase in all parameters studied.
However, this group of arbors is quite heterogeneous. Ten days of
monocular usage of the OD eye has clearly promoted regrowth of some
arbors, whereas others still maintain characteristics of deprived
arbors. Thus, regrowth of terminals can occur within a short period of
reverse suture, but it is not a widespread phenomenon. We can only
speculate which population of geniculocortical arbors is more
predisposed to regrowth of terminals. For example, terminals located in
the periphery of ocular dominance columns might be more susceptible to
the influences of competitive interactions between the two eyes. After
reverse suture, OD arbors are still smaller than normal age-matched
controls. It is possible that a longer period of reverse suture would
allow the OD arbors to recover fully.
Earlier works have suggested anatomical reorganizations after reverse
suture. For example, Dursteler et al. (1976) compared neuronal somata
sizes in the OD and OND laminae of the lateral geniculate nucleus. They
inferred a partial regrowth by cells in the OD lamina and a concomitant
shrinkage of cells in the OND lamina after only a few days of reverse
suture. In the monkey, transneuronal labeling after reverse suture
during the critical period shows a recovery of the OD eye's lost
territory in layer IV (LeVay et al., 1980; Swindale et al., 1981), also
consistent with the present findings. These earlier findings are
informative about the relative sizes and territories occupied by the
two eyes' pathways, but they do not allow the absolute comparisons
with geniculocortical arbors in age-matched normal control animals.
Comparison of anatomy and physiology with behavior
The present findings show only a partial correlation between
physiological and morphological changes after reverse suture, with the
morphology of both eyes' pathways more impaired than one would expect
from the physiology. Strong physiological responses through the OD eye
are not fully matched by the morphological characteristics of the OD
afferents, because only a few appear to have regrown. The OND afferents
are also less well developed morphologically than the physiological
responses would suggest, because these afferents appear to be nearly as
affected as deprived-eye afferents after the initial MD, but the
cortical activity elicited by this eye is stronger and very much more
selective than that after an initial MD.
These findings indicate that the substrate for the reacquisition of
apparently normal responses through the OD eye is not, as one might
have predicted, the reestablishment of the pattern of connectivity that
was present before the onset of any deprivation (Kim and Bonhoeffer,
1994). Reconstituted responses that mimic the original ones can be
generated by afferent input that is different in detail and
considerably impoverished. This finding would suggest that
intracortical circuitry may be more stable than the thalamocortical input and can organize and maintain strong and selective responses when
this input is impoverished. Strong responses to weak afferent input may
be generated by intracortical circuitry through several mechanisms. For
example, an imbalance of reciprocal inhibitory influences among
cortical neurons located in different ocular dominance columns (Ramoa
et al., 1988; Mower and Christen, 1989; Sengpiel et al., 1994) might
enhance the small advantage of the OD pathway and increase its cortical
representation. In addition, feed-forward excitation or amplification
within a cortical column could also enhance weak input signals (Douglas
et al., 1995).
This view of stable intracortical connectivity appears to contradict
the idea that the rapid plasticity of upper layer cortical responses
after brief MD depends on rapid changes in corticocortical rather than
thalamocortical circuitry (Crair et al., 1997). One may reconcile this
apparent contradiction by assuming that it is the pattern of
corticocortical connections that is responsible for the selective
responses that we have measured and that this pattern is stable, but
that the activation of these intracortical circuits depends on the
relative strengths of inputs from the two eyes. Thus, when inputs from
both eyes are reduced, the selective cortical circuits can respond to both.
Behaviorally, the recovery from the effects of deprivation after
reverse occlusion is not stable (Murphy and Mitchell, 1986, 1987).
Animals initially deprived from eye-opening to 4 or 5 weeks, followed
by a period of reverse suture and then binocular vision, develop a
severe bilateral amblyopia. In these animals, the acuity of the OD eye
drops dramatically to very low levels, independent of the length of the
reverse MD. Vision in the OND eye recovers somewhat but never reaches
normal acuity (Mitchell, 1991). Such binocular amblyopia does not occur
after binocular recovery from an initial MD. These findings suggest
that the impaired morphology of both eyes' pathways after reverse
suture may have behavioral consequences that could not be predicted
from the present physiological changes.
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FOOTNOTES |
Received July 7, 1998; revised Sept. 14, 1998; accepted Sept. 15, 1998.
This work was supported by National Institutes of Health Grant
EY02874 to M.P.S.
Correspondence should be addressed to Dr. Michael P. Stryker,
Department of Physiology, Room S-762, Box 0444, 513 Parnassus Avenue,
University of California, San Francisco, CA 94143-0444.
Dr. Gillespie's present address: Department of Neurobiology,
Northwestern University, Evanston, IL 60208.
Dr. Crair's present address: Department of Neuroscience, Baylor
College of Medicine, Houston, TX 77030.
| |
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Top
Abstract
Introduction
