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Learning in the oculomotor system: from molecules to behavior
Jennifer L Raymond
A combination of system-level and cellular–molecular
approaches is moving studies of oculomotor learning rapidly
toward the goal of linking synaptic plasticity at specific sites in
oculomotor circuits with changes in the signal-processing
functions of those circuits, and, ultimately, with changes in eye
movement behavior. Recent studies of saccadic adaptation
illustrate how careful behavioral analysis can provide constraints
on the neural loci of plasticity. Studies of vestibulo-ocular
adaptation are beginning to examine the molecular pathways
contributing to this form of cerebellum-dependent learning.
Addresses
Department of Neurobiology, Stanford University School of Medicine,
Sherman Fairchild Building, Room 251, Stanford, California 94305, USA;
e-mail: [email protected]
Current Opinion in Neurobiology 1998, 8:770–776
http://biomednet.com/elecref/0959438800800770
© Current Biology Ltd ISSN 0959-4388
Abbreviations
LTD
long-term depression
VOR
vestibulo-ocular reflex
From an experimental standpoint, oculomotor learning
offers many advantages. Eye movements are easily quantified, and oculomotor learning can be induced within a
single experimental session. The anatomy and physiology
of the oculomotor system are conserved across a wide
range of species. The topography of the oculomotor circuitry allows electrical stimulation at several different sites
to be used to elicit eye movements. Moreover, detailed
studies of identified neurons of the oculomotor system can
be performed in vivo during learning and in reduced preparations. By capitalizing on these advantages, previous
research has described the neural circuits mediating the
different types of eye movement behavior in considerable
detail and has analyzed the computational or signal-processing functions of different loci in those circuits [1•,2•].
These detailed anatomical and physiological studies pave
the way for efforts to identify the synaptic sites of plasticity and the cellular–molecular changes associated with
learning, and to determine how those cellular–molecular
changes are induced, how they alter neural signal processing in oculomotor circuits, and how the altered signal
processing ultimately results in a learned change in eye
movement behavior.
Introduction
Studies of the neural mechanisms of learning generally
have proceeded on two separate and parallel levels. At
one level, neuroanatomical structures involved in particular types of learning have been identified. At another
level, molecular pathways involved in synaptic plasticity
have been identified at a number of sites in the brain. A
major challenge in neuroscience over the coming years
will be to bridge these levels of analysis to create a comprehensive understanding of the interrelationship
between cellular–molecular and circuit properties in the
regulation of behavior by learning. The oculomotor system is an experimental system particularly well suited to
this challenge.
Eye movements can be categorized into several types
of reflexive and voluntary movements — the vestibuloocular reflex (VOR), the optokinetic reflex, ocular
following, smooth pursuit, vergence, saccades, and gaze
holding [1•,2 •]. These eye movements function to
acquire visual targets and to stabilize images on the retina for improved visual acuity. The accuracy required for
these functions is maintained by motor learning throughout development, aging, and injury. Some form of
learning has been demonstrated in each type of eye
movement. (The various forms of learning in the oculomotor system have been collectively referred to as
oculomotor plasticity. For clarity, I use an alternate term,
oculomotor learning, to refer to behavioral changes in
eye movements, and I reserve the term plasticity to refer
to changes in the nervous system.)
The present review highlights recent advances in studies of
two forms of oculomotor learning — saccadic adaptation and
VOR adaptation. The studies of saccadic adaptation illustrate
how behavioral analysis can constrain sites of plasticity by
establishing the functional relationship between plasticity and
the signal-processing functions of the oculomotor pathways.
For VOR adaptation, anatomical sites of plasticity have been
localized, and initial attempts have been made to identify the
synaptic loci and cellular–molecular pathways involved in this
form of learning. In addition, three new experimental preparations are described that should provide powerful tools for
future attempts to link systems-level and cellular–molecular
analyses of oculomotor learning. Finally, general issues in
learning that can be explored using the integrated approaches
available in the oculomotor system are discussed.
Learned changes in saccade gain
A saccade is a rapid change in the position of the eye that
functions to bring visual targets onto the fovea. The gain of a
saccade is defined as the ratio of saccade amplitude to target
displacement. Adaptive changes in saccade gain can be
induced by experimental manipulations that cause saccades
to consistently miss their targets. For example, weakening
the eye muscles causes saccades to consistently fall short of
visual targets. If the muscles of one eye are weakened,
monocular viewing with the weak eye results in a gradual
increase in the gain of saccades in both eyes, and monocular
viewing with the normal eye reverses the increase in gain [3].
A second paradigm for inducing an increase (or decrease) in
saccade gain is to train with a visual target that consistently
Learning in the oculomotor system: from molecules to behavior Raymond
jumps forward (or backward) during saccades toward the target [4]. With either saccadic adaptation paradigm, changes in
gain can take place within a few hundred saccades [5••] and,
therefore, are easily induced within a single experimental
session. In the absence of training to reverse adaptation, the
changes can last at least 20 h in the dark [6••].
Recent studies of saccadic adaptation illustrate how careful behavioral analysis can provide constraints on the
neural loci of plasticity. For example, saccadic adaptation
is specific for the amplitude and direction in three-dimensional space of the saccades elicited during training (see
e.g. [6••,7•,8–11]). This specificity indicates that plasticity
must take place at a site in the brain in which saccades
with different amplitudes or directions are encoded in
separate, or at least partially separate, neural pathways. On
the other hand, saccadic adaptation induced using visual
targets generalizes to saccades made to auditory targets,
indicating that plasticity must take place at a site where
commands for saccades elicited by auditory and visual targets are carried by the same neural pathways [10]. In at
least some cases, the patterns of generalization versus
specificity depend on the particular training paradigm.
For example, saccadic adaptation can generalize across
orbital position, or it can exhibit orbital position specificity, depending on the training paradigm [5••,10,11].
Patterns of specificity and generalization are, on the
whole, similar in human and monkey, although a few differences have been reported. For example, in monkeys,
changes in the gain of saccadic eye movements induced
with the head fixed transfer to both the eye- and headmovement components of head-free gaze saccades [12••],
whereas in humans, no generalization to the head-movement component has been reported [13].
This type of behavioral analysis constrains the site(s) of
plasticity to loci in which the neural responses exhibit
patterns of specificity and generalization that match
those of the learned changes in behavior. One locus in the
circuit for saccades that seems to meet the constraints
defined by the behavioral experiments is the superior colliculus. However, recordings from the superior colliculus
during saccadic adaptation revealed no change in the
responses of saccade-related burst neurons to visual targets [14,15••], suggesting that saccadic adaptation does
not take place upstream of the colliculus. Moreover,
adaptation does not generalize to eye movements produced by electrical stimulation of the superior colliculus
[16,17], suggesting that saccadic adaptation does not
occur downstream of the colliculus. Together, these
results suggest that saccadic adaptation occurs in a pathway parallel to the one through the superior colliculus.
A likely candidate for the site of plasticity mediating saccadic adaptation is the cerebellum. Neurons in the
cerebellar vermis and caudal fastigial nucleus burst during
saccades, and electrical stimulation of these mid-line
cerebellar structures elicits saccades. Moreover, mid-line
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cerebellar lesions produce saccadic dysmetria and abolish
saccadic adaptation (reviewed in [18]). These results are
consistent with a contribution of the cerebellum to both
the induction and storage of saccadic adaptation.
Recordings of saccade-related signals in the cerebellum
before, during, and after saccadic adaptation should help
elucidate its role.
Learned changes in vestibulo-ocular reflex gain
Learned changes in the gain of another type of eye movement, the VOR, have been reported in a broad range of
species. Studies of this form of motor learning, called VOR
adaptation, are beginning to combine systems-level analyses with more cellular–molecular approaches.
The VOR is an eye movement driven by vestibular signals. The VOR functions to stabilize images on the
retina by producing eye movements in the opposite
direction from head movements. The gain of the VOR is
defined as the ratio of eye speed to head speed. As with
saccadic adaptation, experimentally manipulated optical
conditions can induce learned changes in the gain of the
VOR [19]: for example, if head movements are paired
with movements of the visual surround in the same
direction as the head movements, a gradual reduction in
the gain of the VOR is induced; whereas, if head movements are paired with movements of the visual surround
in the opposite direction from the head movements, a
gradual increase in the gain of the VOR is induced.
The circuit for the VOR contains several parallel pathways
from the vestibular afferents that encode head movements
to the motor neurons that move the eye. After years of controversy, it is now widely accepted that VOR adaptation is
associated with plasticity at two sites — in the vestibular
nuclei and in a pathway through the cerebellar cortex
[20,21•,22]. Why does an apparently simple change in
reflex gain require more than one site of plasticity? One
hypothesis suggests that plasticity in the vestibular nuclei
may be primarily responsible for the gain changes per se,
whereas plasticity in the cerebellar cortex may function to
regulate eye movement dynamics [20,23]. A second
hypothesis, suggested by recent lesion studies, is that the
cerebellar cortex may be more important for changes in the
low-frequency components of the VOR, whereas the
vestibular nuclei may be more important for changes in the
high-frequency components of the VOR [24,25•]. These
hypotheses need not be mutually exclusive.
The region of the cerebellar cortex that has been implicated in VOR adaptation is the floccular complex, which
comprises the flocculus and adjacent ventral paraflocculus. Physiological studies have not demonstrated any
qualitative differences between the responses of Purkinje
cells in the ventral paraflocculus and the responses of
Purkinje cells in the flocculus during the VOR before or
after adaptation (for a discussion, see [26]). However,
anatomical studies have reported some differences in the
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Motor systems
afferent and efferent projections of the flocculus and ventral paraflocculus, which raise the possibility that the two
structures may make somewhat different contributions to
the VOR [27,28•,29•].
To understand VOR adaptation, it will be important to
specify more precisely which synapses in the vestibular
pathways through the cerebellar cortex and vestibular
nuclei are modified during learning and to identify the
cellular–molecular mechanisms that produce those
changes. Some clues are provided by in vitro studies,
which have begun to identify forms of synaptic plasticity
in the circuit for the VOR. One particular form of plasticity in the cerebellar cortex has received the most
attention, long-term depression of synapses from parallel
fibers to Purkinje cells, known as cerebellar LTD [30]. To
evaluate the potential contribution of this form of synaptic plasticity to learning, several studies have compared
the behavioral sensitivity of VOR adaptation to various
pharmacological manipulations with the sensitivity of
cerebellar LTD to similar pharmacological manipulations
in vitro. A number of parallels have been found. Systemic
administration of (6R)-5,6,7,8-tetrahydro-L-biopterin
(R-THBP) produces an increase in VOR gain and
occludes induction of further gain increases with behavioral training [31•]. R-THBP facilitates activation of
guanylate cyclase in the cerebellum, which, in turn, has
been implicated in the induction of cerebellar LTD in
vitro. Likewise, inhibition of protein kinase C (PKC) in
Purkinje cells blocks both cerebellar LTD in vitro and
VOR adaptation in vivo [32••].
These pharmacological similarities are consistent with a
contribution of cerebellar LTD to VOR adaptation.
However, in vivo recording results are difficult to reconcile with traditional hypotheses [22,30] about the role of
cerebellar LTD in VOR adaptation. Measured changes
in the vestibular sensitivity of Purkinje cells accompanying VOR adaptation are in the opposite direction from
that predicted by LTD [26,33,34]. In addition, the patterns of neural activity present in vivo during VOR
adaptation would, in some cases, fail to trigger cerebellar
LTD in the appropriate synapses to account for the
changes in behavior [35••,36••]. Further experiments
that combine in vivo recordings with pharmacological or
molecular manipulations are needed to evaluate whether
and how cerebellar LTD might contribute to VOR adaptation [37••,38••].
Future studies must also evaluate whether VOR adaptation involves plasticity in the cerebellar cortex at
synapses other than those from parallel fibers to Purkinje
cells. Synaptic plasticity has been observed between
cerebellar inhibitory interneurons and Purkinje cells,
and could contribute to learning in the VOR [39,40].
Finally, future research needs to characterize the plasticity mechanisms in the vestibular nucleus that
contribute to VOR adaptation [20,21 •,35 ••,41 •,42 •].
These studies will be facilitated by new experimental
preparations that have been introduced recently.
Promising new experimental preparations
Several new experimental preparations for studying the
oculomotor system have been introduced recently and
should prove extremely useful for linking the different
forms of oculomotor learning with their underlying cellular–molecular mechanisms.
First amongst the new experimental preparations is the study
of oculomotor learning in the rodent [32••,43••,44•,45•].
The mouse VOR undergoes a 50% increase in gain after
one hour of behavioral training [32••,43••]. Use of a mouse
model system makes it possible to apply the powerful
molecular–genetic manipulations that are becoming
increasingly available to the study of the molecular pathways involved in VOR adaptation. For example, transgenic
mice have been used to demonstrate the dependence of
VOR adaptation on intact PKC signaling pathways in
Purkinje cells [32••]. The mouse also exhibits a robust
optokinetic reflex [32••,43••,46], although learning has not
yet been examined in the optokinetic reflex of this species
(see Note added in proof).
A second new experimental preparation is the zebrafish,
another species that is amenable both to molecular–genetic approaches and to studying oculomotor learning. The
VOR, the optokinetic reflex and saccadic eye movements
of zebrafish are mature by 5 days post-fertilization
[47,48••]. Oculomotor learning has not yet been examined
in zebrafish, but it has been described in other species of
fish. Zebrafish have a rapid life cycle, and can be easily
raised in large numbers, making them well suited for mutagenesis screens. Because eye movements are readily
measured in zebrafish with video analysis, a screen for
mutants with a loss of oculomotor learning seems quite
feasible. In addition, the rapid development of the
zebrafish suggests that it could be used to relate gene
expression in a tissue- and stage-specific manner to the
development of oculomotor learning.
Finally, a guinea pig isolated whole brain in vitro preparation that may serve to bridge in vitro and in vivo studies has
recently been described [49,50•,51•]. This preparation
offers stable intracellular recordings while keeping neural
circuits intact, so that neurons with well-defined intrinsic
membrane properties can be placed in a functional context. An in vitro analog of the VOR can be elicited in this
preparation by electrically stimulating the vestibular nerve
and recording the neural responses in the abducens nerve.
Likewise, an in vitro analog of visually driven eye movements, such as the optokinetic reflex, can be elicited by
stimulating the optic tract and recording from the
abducens nerve. If an in vitro analog of learning could be
induced in these in vitro eye movement ‘behaviors’, it
could provide a powerful tool for linking systems-level and
cellular analyses of plasticity.
Learning in the oculomotor system: from molecules to behavior Raymond
General issues in learning can be studied in
the oculomotor system
Eye movements exhibit an extensive repertoire of learning. Saccades and the VOR exhibit learned changes in
direction and dynamics as well as learned changes in gain
(e.g. [3,8,52–54]), and both types of eye movement exhibit non-associative changes in gain (e.g. habituation or
central fatigue) in addition to the associative changes
described above [55–58]. Other types of eye movement —
such as smooth pursuit, ocular following, the optokinetic
reflex, and vergence — also exhibit learning (e.g. [59–62];
for more recent results, see [63–68]). Thus, different forms
of learning can be compared within a single type of eye
movement, and similar forms of learning can be compared
across different types of eye movement. Many of the fundamental issues in motor learning are experimentally
accessible in one or more eye movement systems. Below, I
discuss just a few such issues.
Are there multiple mechanisms for accomplishing the
same behavioral change?
A decrease in the gain of saccades or the VOR can be
induced through habituation/central fatigue, through associative training to decrease gain, or during the recovery
from increase gain training induced by a return to normal
viewing [6••,55,56,69]. Are these three forms of gain
decrease mediated by the same synaptic modifications? A
recent study of saccadic adaptation shows the time course
of decrease gain adaptation and recovery from increase
gain to be similar, consistent with the idea of a common
mechanism [6••]. In the VOR, lesion studies suggest that
habituation and adaptive decreases in gain are mediated by
different regions of the cerebellum and are therefore distinct processes (see e.g. [70]).
Similarly, increases in VOR gain induced with optical
manipulations can be compared with increases in VOR
gain during recovery from unilateral vestibular lesions, a
process known as vestibular compensation [71,72]. There
is evidence that these two forms of VOR gain increase
have different mechanisms [73], and comparison of the two
could provide insight into how the plasticity mechanism
used to achieve a particular behavioral change is selected
from a number of potentially available mechanisms.
What are the mechanisms for modification of behavior
on different time scales?
Several types of oculomotor learning can be induced either
within hours (using ‘short-term’ training paradigms within
a single experimental session) or over several days (using
‘long-term’ training paradigms in the home cage). To what
extent are the mechanisms of the short- and long-term
forms of learning similar? If they are different, what happens at the molecular level during the transition from
short-term to long-term learning?
Eye movements can also undergo immediate, on-line
modifications of gain. A recent study demonstrates that,
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under appropriate conditions, monkeys can simultaneously store in long-term memory two motor sets that use
different oculomotor ranges, and they can rapidly switch
between them [74••]. On-line modifications also can be
produced by factors such as fixation distance, strategy, or
alertness (see e.g. [6••,75]). Do these on-line modifications
share sites of action or cellular–molecular effector systems
with short- and long-term learning?
What are the neural signals that drive learning?
Sensory stimuli that drive learning must be encoded in
patterns of neural activity at the site(s) of plasticity.
Recent studies of VOR adaptation have begun to evaluate
the features of these patterns that are necessary and sufficient to trigger plasticity by comparing the patterns
present during a broad range of stimuli that induce VOR
adaptation. This type of analysis can map the protocols
used to induce synaptic plasticity in vitro onto the induction of learning in vivo [35••,36••].
An important consideration in addressing this issue is the
timing of neural signals that trigger plasticity. For most
movements, error signals about the accuracy of a movement are delayed relative to the neural activity that drives
the movement. How is this delayed feedback used to modify the synapses responsible for the error? Biologically
constrained computational models of saccadic adaptation,
VOR adaptation, and predictive pursuit suggest that in the
cerebellum, error signals carried by climbing fibers may
interact with a delayed ‘eligibility trace’ related to previous
parallel fiber activity that contributed to the erroneous
movement [35••,76,77•].
Conclusions
The oculomotor system offers an excellent opportunity to
study neural plasticity in the context of a wide range of
well-defined learning paradigms. Studies of VOR adaptation have begun to combine molecular–genetic approaches
with more traditional, systems-level approaches, with the
goal of establishing causal links between synaptic plasticity and changes in behavior. Progress in identifying sites of
plasticity for saccadic adaptation and other forms of oculomotor learning will soon make it possible to apply similar
approaches to a wide range of eye movement behaviors.
The many experimental advantages of the oculomotor system enumerated in this review make it an outstanding
model for examining fundamental issues in motor learning,
from the level of molecules through to behavior.
Note added in proof
Recently, a form of learning that depends on an intact flocculus was demonstrated in the optokinetic reflex of the
mouse [78].
Acknowledgements
Thanks to A Churchland, M Churchland, M Kahlon, N Priebe, and
H Rambold for critical comments on the manuscript and to S Lisberger for
his support. The author’s work is funded by National Institutes of Health
grants DC03342 and EY03878.
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overlapping but non-identical patterns of afferent and efferent projections of
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Learning in the oculomotor system: from molecules to behavior Raymond
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This pioneering work uses transgenic mice to investigate the molecular pathways in Purkinje cells necessary for VOR adaptation. The pcp-2 (L7) gene
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