Download Pioneers of cortical plasticity: six classic papers by Wiesel and Hubel

J Neurophysiol 99: 2741–2744, 2008;
doi:10.1152/jn.00061.2008.
Editorial Focus
ESSAYS ON APS CLASSIC PAPERS
Pioneers of cortical plasticity: six classic papers by Wiesel and Hubel
Martha Constantine-Paton
McGovern Institute for Brain Research, Department of Brain and Cognitive Science, Massachusetts Institute of Technology,
Cambridge, Massachusetts
opens Torsten Wiesel’s 1981 Nobel
Lecture: “In the early sixties, having begun to describe the
physiology of cells in the adult cat visual cortex, David Hubel
and I decided to investigate how the highly specific response
properties of cortical cells emerged during postnatal development” (http://nobelprize.org/nobel_prizes/medicine/laureates/1981/
wiesel-lecture.html). This modest statement belies the tidal
wave of experiments on developmental brain plasticity that
was initiated by their publications in 1963, continues to this
day, and extends well beyond the occipital lobe to virtually all
sensory areas, motor areas, and to “higher centers” involved in
learning, memory, and decision making. To be sure, many
great experimentalists and philosophers dealt with the issue of
nature versus nurture in brain development before them (see
Lehrman 1970), but Wiesel and Hubel were the first to recognize that their high-resolution, single-neuron analyses of visual
response properties in cat cortex (Hubel and Wiesel 1962,
1963a) provided a powerful approach to deciphering how
much of sensory feature extraction was fixed at birth and how
much depended for its appearance on environment-introduced
visual activity.
THE FOLLOWING SENTENCE
Address for reprint requests and other correspondence: M. ConstantinePaton, McGovern Institute for Brain Research, Dept. of Brain and Cognitive
Science, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139 (e-mail: [email protected]).
http://www.the-aps.org/publications/classics
The six papers published in the Journal of Neurophysiology
between 1963 and 1965 constitute the seminal contributions of
David Hubel and Torsten Wiesel to developmental plasticity in
the central nervous system. The work grew out of Stephen
Kuffler’s successful effort to bring the two together to work on
the central visual pathway of the cat in his laboratory in the
Wilmer Institute of Ophthalmology at the Johns Hopkins
Hospital. Kuffler had already distinguished himself in visual
neurophysiology by characterizing the “on” and “off” centersurround receptive field properties of ganglion cells in the cat
retina (Kuffler 1953). In Kuffler’s laboratory, quite by accident, according to David Hubel (http://nobelprize.org/nobel_
prizes/medicine/laureates/1981/hubel-lecture.html), he and
Torsten discovered that cat striate cortical neurons responded
dramatically to the oriented edge of a clear microscope slide,
ignoring the small black dot they had pasted on the slide
hoping that it would drive the cortical neurons as effectively as
dots drove the ganglion cells in Kuffler’s original study.
Moreover, not any edge would do. The edge had to be presented at a particular position in the visual field (expected) and
at an angle specific to that cell (unexpected). The paper
describing the visual cortical simple cells (Hubel and Wiesel
1959) was the beginning of a series of publications that
described cortical neuron responsiveness in terms of binocularity, edge, bar, and slit detection, and orientation selectivity
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This essay looks at six APS classic papers published by D. H. Hubel and T. N.
Wiesel that first identified a developmental critical period for environment influenced receptive field plasticity in the visual pathway. These classic papers are freely
available online. These are listed here, in chronological order.
Wiesel TN, Hubel DH. Effects of visual deprivation on morphology and
physiology of cells in the cat’s lateral geniculate body. J Neurophysiol 26:
978 –993, 1963 (http://jn.physiology.org/cgi/reprint/26/6/978).
Hubel DH, Wiesel TN. Receptive fields of cells in striate cortex of very young,
visually inexperienced kittens. J Neurophysiol 26: 994 –1002, 1963 (http://jn.
physiology.org/cgi/reprint/26/6/994).
Wiesel TN, Hubel DH. Single-cell responses in striate cortex of kittens deprived
of vision in one eye. J Neurophysiol 26: 1003–1017, 1963 (http://jn.physiology.org/
cgi/reprint/26/6/1003).
Wiesel TN, Hubel DH. Comparison of the effects of unilateral and bilateral eye
closure on cortical unit responses in kittens. J Neurophysiol 28: 1029 –1040, 1965
(http://jn.physiology.org/cgi/reprint/28/6/1029).
Hubel DH, Wiesel TN. Binocular interaction in striate cortex of kittens reared
with artificial squint. J Neurophysiol 28: 1041–1059, 1965 (http://jn.physiology.
org/cgi/reprint/28/6/1041).
Wiesel TN, Hubel DH. Extent of recovery from the effects of visual deprivation
in kittens. J Neurophysiol 28: 1060 –1072, 1965 (http://jn.physiology.org/cgi/
reprint/28/6/1060).
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ESSAYS ON APS CLASSIC PAPERS
(Hubel and Wiesel, 1962, 1963a). From this work and subsequent combined anatomical and physiological studies on cats
and monkeys (Hubel and Wiesel, 1977; LeVay et al., 1975;
Livingstone and Hubel, 1984) the notion of a cortical hypercolumn would eventually arise as a representation of one locus
in visual space encompassing cells with color sensitivity, all
orientation sensitivities, and receiving input of varying degrees
through both eyes. In the interim, and shortly after a move to
Harvard University, Hubel and Wiesel began their developmental work.
Studies in visually naive kittens
Disruptive effects of prolonged abnormal visual experience
The third paper in the 1963 series (Wiesel and Hubel, 1963b)
grew from these initial developmental observations observations.
Earlier, Hubel and Wiesel (1962) published a description of
binocular interaction in the mature cat visual cortex. In the third
1963 paper, they introduced the now famous monocular deprivation paradigm and explored the behavior and physiology of the
visual cortex of kittens with long-term monocular occlusion.
Kittens deprived from 1– 4 months of age, when forced to use
only the deprived eye, behaved as if they were blind. When the
same kittens were allowed to use the non-deprived eye, visual
behavior was normal. An adult cat studied with the same paradigm showed no effect of the deprivation. Electrophysiological
analyses rapidly revealed the cause of the behavioral blindness: of
84 cells recorded in the cortex contralateral to the deprived eye,
J Neurophysiol • VOL
Competition in cortical plasticity
In the first of a second series of papers in 1965 Wiesel and
Hubel (1965a) directly addressed the question of whether a
visually deprived eye’s response to deprivation is dependent on
the activity of the other eye. They answered it in the affirmative.
Both eyes of young kittens were sutured shut, and their striate
cortices were recorded from 2.5– 4.5 months later. In these animals, most active cells could be driven through both eyes, and
some with simple and complex receptive field properties were
found. However, many cells lacked a defined orientation preference, and roughly one-quarter of the active cells were unresponsive to visual stimulation. There were no obvious differences
between left and right eye layers in the LGN, but comparisons
with normal animals revealed some cell size shrinkage in all
layers. Furthermore, kittens with this long-term binocular deprivation proved to be behaviorally blind, similar to the dark-reared
animals of earlier investigators and to those kittens forced to use
a deprived eye after shorter monocular occlusion. Kittens with
long-term monocular deprivation were similarly blind in the
closed eye, but, in contrast to the binocularly deprived animals,
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In the first paper of the 1963 triple back-to-back series
(Wiesel and Hubel 1963a), one eyelid of kittens was sutured
closed just before eye opening. The kittens were reared in this
monocularly deprived condition until they were 3 months old,
at which time electrophysiological analyses of afferent retinal
axons and neurons in the lateral geniculate nucleus (LGN)
contralateral to the deprived eye were undertaken. In general,
the visual receptive field properties of the LGN neurons were
similar to those of adult cats in size and center-surround
organization, although, in the visually deprived layers, background activity was low and few single-cell responses could be
isolated. Histological analyses of the LGNs revealed pronounced shrinkage in cells receiving input from the deprived
eye (Wiesel and Hubel 1963a). The second paper in this series
(Hubel and Wiesel 1963b) asked whether the distinct cortical
response types of the adult cat were present in young kittens
deprived of visual experience. In the cortex of visual pattern
naive animals (postnatal day P8 before eye opening and P16
with translucent occluders), active cells were hard to find.
Stimuli that produced robust responses in adults were either
nonexistent or sluggish and fatigued rapidly. Nevertheless, the
responding cells were selective for edges, bars, and slits with
distinct, though not precisely tuned orientation preferences.
Normal binocularity also seemed to have developed in these
kittens. Comparison with a P20 normal kitten and a P19 kitten
with only one eye covered with a translucent occluder revealed
more spontaneous activity, brisker responses to patterned visual stimuli, and stricter orientation preferences than seen in
the younger animals. Indeed, these were the responses expected if the cortical circuit was preformed and needed pattern
vision only to strengthen young connections.
only 1 neuron responded to that eye. Normally, an eye dominates
responses in the contralateral cortex. However, in an additional
experiment where cortical neuron recordings were made contralateral to an eye that had only the thin nictitating membrane
sewn across it for 5 months, LGN histology showed no pronounced atrophy in the deprived eye LGN layers. Nevertheless,
the ocular dominance histogram showed pronounced non-deprived eye domination. The result was the first indication that the
primary locus for the LGN neuron atrophy was in the cortex and
not the LGN. Guillery (1972) would later eliminate binocular
competition from the nondeprived eye in a small region of cortex
and experimentally support the hypothesis that the atrophy in the
LGN arose from competition between the eye-specific inputs in
the cortex.
On the basis of long-term dark rearing from birth in a variety
of mammals, a number of early investigators had argued that in
order to develop in the first place, visual connections require
visual stimulation (Berger 1900; Goodman 1932). The third
1963 Wiesel and Hubel report (Wiesel and Hubel 1963b) broke
with this earlier work by showing abnormal experience at an
early developmental stage could permanently disrupt initially
formed circuits. This idea was new. Although Konrad Lorenz
had introduced the concept of developmental critical periods
with his studies of imprinting in young precocial birds (Lorenz
1937), experiments in which normal experience was prevented
for short periods in early development did not invariably have
long-term effects (Marler and Hamilton 1966). Hubel and
Wiesel introduced into the electrophysiological literature an
extension of an idea articulated first by Hebb in 1949. They
imply in their conclusion to this third report that competition
between the two eyes may be occurring, i.e., . . . “if one eye is
not stimulated, the fate of its projections in the central visual
pathway may partly depend on whether or not the other eye is
stimulated”. Three decades later Antonini and Stryker (1993)
finally provided single neuron anatomical evidence of this
competition by reconstructing individual LGN axon terminals
and demonstrating a highly significant difference between
sparse deprived eye terminals and robustly arborized terminals
from the nondeprived eye.
Editorial Focus
ESSAYS ON APS CLASSIC PAPERS
J Neurophysiol • VOL
possibilities was impossible, but cell and molecular biology when
combined with the appropriate whole animal paradigms promise
to reveal what a “matter of age” involves: specifically, which
signaling pathways can, and which cannot, change upon vision
later in life after early deprivation. Visual developmental plasticity
has come a long way since 1963, and most progress has been built
upon the experimental procedures first laid out in these six
seminal papers. However, we now understand that spontaneous
activity in the retina and many brain areas contributes significantly
to the refinement of neural circuits frequently long before stimuli
from the outside world impact upon the developing brain. We also
understand that the critical period for ocular dominance plasticity
can be very short, that it depends on inhibitory development, and
that there is a latent plasticity even in the mature brain. The latter
makes efforts to understand exactly what factors limit this plasticity as the brain grows older ever more important to pursue. The
hope is that our new era of genomes, proteomics, and genetic
engineering will ultimately return the full visual world to those
suffering from complete or partial blindness as a result of disrupted vision early in their life.
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100/1/46).
Guillery RW. Binocular competition in the control of geniculate cell growth.
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Hebb DO. Organization of Behavior. New York: Wiley, 1949.
Hubel DH, Wiesel TN. Receptive fields of single neurones in the cat’s striate
cortex. J Physiol 148: 574 –591, 1959.
Hubel DH, Wiesel TN. Receptive fields, binocular interaction and functional
architecture in the cat’s visual cortex. J Physiol 160: 106 –154, 1962.
Hubel DH, Wiesel TN. Shape and arrangement of columns in cat’s striate
cortex. J Physiol 165: 559 –568, 1963a.
Hubel DH, Wiesel TN. Receptive fields of cells in striate cortex of very
young, visually inexperienced kittens. J Neurophysiol 26: 994 –1002, 1963b
(http://jn.physiology.org/cgi/reprint/26/6/994).
Hubel DH, Wiesel TN. Binocular interaction in striate cortex of kittens reared
with artificial squint. J Neurophysiol 28: 1041–1059, 1965 (http://jn.
physiology.org/cgi/reprint/28/6/1041).
Hubel DH, Wiesel TN. The period of susceptibility to the physiological
effects of unilateral eye closure in kittens. J Physiol 206: 419 – 436, 1970.
Hubel DH, Wiesel TN. Ferrier Lecture: Functional architecture of macaque
monkey visual cortex. Proc R Soc Lond B Biol Sci 198: 1–59, 1977.
Kuffler SW. Discharge patterns and functional organization of the mammalian retina.
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Tobach E, Lehrman DS, Rosenblatt JS. San Francisco: Freeman, 1970, p.
17–52.
LeVay S, Hubel DH, Wiesel TN. The pattern of ocular dominance columns
in macaque visual cortex revealed by a reduced silver stain. J Comp Neurol
159: 559 –576, 1975.
Livingstone MS, Hubel DH. Specificity of intrinsic connections in primate
primary visual cortex. J Neurosci 4: 2830 –2835, 1984.
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they showed a consistent shift toward dominance by the nondeprived eye, many cells lacked orientation sensitivity, and, as in
the binocularly deprived animals, many cells were unresponsive.
The second paper of this second series asked if the activity
arriving at the cortex through the two eyes had to be coincident
in order to produce cells equally driven by the two eyes. Once
again Hubel and Wiesel (1965) answered the question in the
affirmative. Kittens raised with surgically induced divergent
strabismus for 3 months or 1 year, though behaviorally competent and showing robust normal field properties through
either eye, had exceptionally few cells driven by both eyes, and
an electrode passing through cortex encountered large areas of
cells responding only to inputs from one or the other eye.
Similar studies were conducted in animals with alternating
monocular occlusion, and the effects on ocular dominance in
these animals were more extreme than in the kittens with
squint: 91% of the all cortical neurons encountered were driven
only by one eye and, as in the squint kittens, there was a
pronounced spatial segregation of cells driven by each eye. In
fact, this paper gives one of the first indications of ocular
dominance columns. Prompted by the eye-dependent segregation seen in the squint and alternating monocular deprivation
animals, Hubel and Wiesel went back to examine data in a
previous publication focused on orientation columns in normal
adult cats (Hubel and Wiesel 1963a). They tabulated the first
few units encountered in each penetration to show surface
maps of where each eye dominated the cellular responses. Thus
this 1965 paper presents the first tangential image of cortical
ocular dominance.
In the final publication of the 1965 series, Wiesel and Hubel
(1965b) tackled a question that has recently, with the advent of
congenital cataract removal and lens replacement in older
patients, become highly relevant: namely, the extent of recovery from early visual deprivation (Fine et al. 2003; Ostrovsky
et al. 2006). With long-term monocular deprivation, despite
subsequent periods where the non-deprived was closed forcing
use of the deprived eye, the animals showed little behavioral
recovery of vision through the deprived eye, and the cortical
neuron response properties remained abnormal. Somewhat
different results were found when kittens binocularly deprived
for 3 months were kept for over a year with only one eye open.
Compared with kittens with only 3 months of binocular deprivation, these cats had many fewer unresponsive cells but also
fewer normal cells, and almost twice as many abnormal cells
were driven predominantly from the reopened eye. Significantly, most of these cells were abnormal because they lacked
orientation sensitivity through the open eye. This result is
interesting, in light of recent work, because it suggests that
orientation selectivity is significantly more labile to early
deprivation than is ocular dominance. Though it may be
coincidence, this discordance between ocular dominance and
orientation sensitivity is reminiscent of studies indicating that
orientation tuning in mammalian visual cortex is sensitive to
disruption of NMDA receptor function whereas ocular dominance is not (Fagiolini et al. 2003; Ramoa et al. 2001).
Wiesel and Hubel (1965b) close their discussion of this last
paper by listing two possibilities to explain their results: “Either
connections once lost are incapable of properly re-establishing
themselves, or the failure of recovery may simply be a matter of
age”, reflecting something “that happens between the third month
and the first year”. In 1965, distinguishing between these two
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Marler P, Hamilton WJ. Mechanisms of Animal Behavior. New York: Wiley,
1966, p. 660 – 668.
Ramoa AS, Mower AF, Liao D, Jafri SI. Suppression of cortical NMDA
receptor function prevents development of orientation selectivity in the
primary visual cortex. J Neurosci 21: 4299 –309, 2001.
Ostrovsky Y, Andalman A, Sinha P. Vision following extended congenital
blindness. Psychol Sci 17: 1009 –14, 2006.
Wiesel TN, Hubel DH. Effects of visual deprivation on morphology and
physiology of cells in the cats lateral geniculate body. J Neurophysiol 26:
978 –993, 1963a (http://jn.physiology.org/cgi/reprint/26/6/978).
Wiesel TN, Hubel DH. Single-cell responses in striate cortex of kittens
deprived of vision in one eye. J Neurophysiol 26: 1003–1017, 1963b
(http://jn.physiology.org/cgi/reprint/26/6/1003).
Wiesel TN, Hubel DH. Comparison of the effects of unilateral and
bilateral eye closure on cortical unit responses in kittens. J Neurophysiol 28: 1029 –1040, 1965a (http://jn.physiology.org/cgi/reprint/28/6/
1029).
Wiesel TN, Hubel DH. Extent of recovery from the effects of visual deprivation
in kittens. J Neurophysiol 28: 1060 –1072, 1965b (http://jn.physiology.org/cgi/
reprint/28/6/1060).
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