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770 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 771 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 772 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, 773 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. 774 Motor systems References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: • of special interest •• of outstanding interest 1. Büttner-Ennever JA, Horn AK: Anatomical substrates of oculomotor • control. Curr Opin Neurobiol 1997, 7:872-879. Review of the neural circuitry of the oculomotor system, with an emphasis on the extent to which circuits for different types of eye movement remain segregated. 2. Ilg UJ: Slow eye movements. Prog Neurobiol 1997, • 53:293-329. Review of the behavioral, anatomical and physiological properties of the different types of slow eye movements. 3. Optican LM, Robinson DA: Cerebellar-dependent adaptive control of primate saccadic system. J Neurophysiol 1980, 44:1058-1076. 4. McLaughlin SC: Parametric adjustment in saccadic eye movements. Percept Psychophys 1967, 2:359-362. 5. •• Scudder CA, Batouria EY, Tunder GS: Comparison of two methods of producing adaptation of saccade size and implications for the site of plasticity. J Neurophysiol 1998, 79:704-715. Demonstrates that saccadic adaptation induced with a muscle-weakening paradigm takes place at a similar rate to adaptation induced with intra-saccadic target steps if the two adaptation paradigms are matched for number of visual targets. The results remove the rationale for hypothesizing that the two paradigms employ different neural mechanisms, which had been proposed on the basis of the longer time course of adaptation that was generally observed with the muscle-weakening paradigm. 6. •• Straube A, Fuchs AF, Usher S, Robinson FR: Characteristic of saccadic gain adaptation in rhesus macaques. J Neurophysiol 1997, 77:874-895. A thorough characterization of several features of saccadic adaptation, including time course, spatial specificity, and effects on the duration, velocity and latency of saccades. These features constrain the neural loci of plasticity. 7. Chaturvedi V, van Gisbergen JA: Specificity of saccadic adaptation • in three-dimensional space. Vision Res 1997, 37:1367-1382. Demonstrates the ability of the saccadic system to adopt different gains for saccades to different depth planes. 8. Mack A, Fendrich R, Pleune J: Adaptation to an altered relation between retinal image displacements and saccadic eye movements. Vision Res 1978, 18:1321-1327. 9. Miller JM, Anstis T, Templeton WB: Saccadic plasticity: parametric adaptive control by retinal feedback. J Exp Psychol [Hum Percept Perform] 1981, 7:356-366. 10. Frens MA, van Opstal AJ: Transfer of short-term adaptation in human saccadic eye movements. Exp Brain Res 1994, 100:293-306. 11. Albano JE: Adaptive changes in saccade amplitude: oculocentric or orbitocentric mapping? Vision Res 1996, 36:2087-2098. 12. Phillips JO, Fuchs AF, Ling L, Iwamoto Y, Votaw S: Gain adaptation •• of eye and head movement components of simian gaze shifts. J Neurophysiol 1997, 78:2817-2821. Reports generalization of saccadic adaptation induced with the head fixed to both the head- and eye-movement components of head-free gaze shifts. The authors found that saccadic adaptation did not alter the way gaze saccades of a given size were parsed into separate eye- and head-movement components. These results are consistent with the hypothesis that in monkeys, saccadic adaptation occurs upstream of the parsing of the commands for gaze shifts into separate head- and eye-movement components. 13. Kröller J, Péllison D, Prablanc C: On the short-term adaptation of eye saccades and its transfer to head movements. Exp Brain Res 1996, 111:477-482. 14. 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Studies of the horizontal and vertical VOR have independently suggested that VOR adaptation involves plasticity both in the vestibular nuclei and in a pathway through the cerebellar cortex. 22. Ito M: Cerebellar control of the vestibulo-ocular reflex — around the flocculus hypothesis. Annu Rev Neurosci 1982, 5:275-298. 23. Lisberger SG, Sejnowski TJ: Motor learning in a recurrent network model based on the vestibulo-ocular reflex. Nature 1992, 360:159-161. 24. Pastor AM, de la Cruz RR, Baker R: Cerebellar role in adaptation of the goldfish vestibuloocular reflex. J Neurophysiol 1994, 72:1383-1394. 25. McElligott JG, Beeton P, Polk J: Effect of cerebellar inactivation by • lidocaine microdialysis on the vestibuloocular reflex in goldfish. J Neurophysiol 1998, 79:1286-1294. Inactivation of the cerebellum with lidocaine blocked the induction and retention of VOR adaptation during vestibular stimulation at 0.125 Hz. This study confirms the dependence of adaptation of the low-frequency components of the VOR on an intact cerebellum, which was previously reported using surgical lesions [24]. 26. Lisberger SG, Pavelko TA, Bronte-Stewart HM, Stone LS: Neural basis for motor learning in the vestibulo-ocular reflex of primates: II. Changes in the responses of horizontal gaze velocity Purkinje cells in the cerebellar flocculus and ventral paraflocculus. J Neurophysiol 1994, 72:954-973. 27. Gerrits NM, Voogd J: The topographical organization of climbing and mossy fiber afferents in the flocculus and ventral paraflocculus in the rabbit, cat, and monkey. Exp Brain Res 1989, 17(suppl):26-29. 28. Nagao S, Kitamura T, Nakamura N, Hiramatsu T, Yamada J: Location • of efferent terminals of the primate flocculus and ventral paraflocculus revealed by anterograde axonal transport methods. Neurosci Res 1997, 27:257-269. See annotation [29•]. 29. Nagao S, Kitamura T, Nakamura N, Hiramatsu T, Yamada J: • Differences in the primate flocculus and ventral paraflocculus in the mossy and climbing fiber input organization. J Comp Neurol 1997, 382:480-498. This paper (see also [27,28•]) is part of a current controversy about the relative roles of the flocculus and ventral paraflocculus in the VOR. The authors report overlapping but non-identical patterns of afferent and efferent projections of these two cerebellar regions. They interpret the differences as support for the hypothesis that the flocculus is mainly involved in the VOR whereas the ventral paraflocculus is mainly involved in smooth pursuit eye movements. However, other interpretations are possible. For example, the flocculus and ventral paraflocculus could make identical contributions to the VOR that depend on the anatomical connections they have in common, but they could have additional, different functions that require different anatomical connections. 30. Ito M: Long-term depression. Annu Rev Neurosci 1989, 12:85-102. 31. Nagao S, Kitazawa H, Osanai R, Hiramatsu T: Acute effects of • tetrahydrobiopterin on the dynamic characteristics and adaptability of vestibulo-ocular reflex in normal and flocculus lesioned rabbits. Neurosci Lett 1997, 231:41-44. Tetrahydrobiopterin produces an increase in VOR gain, which the authors suggest might be mediated by effects on guanylate cyclase or on monoamines in the cerebellum. Learning in the oculomotor system: from molecules to behavior Raymond 32. De Zeeuw CI, Hansel C, Bian F, Koekkoek SK, van Alphen AM, •• Linden DJ, Oberdick J: Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex. Neuron 1998, 20:495-508. This pioneering work uses transgenic mice to investigate the molecular pathways in Purkinje cells necessary for VOR adaptation. The pcp-2 (L7) gene promoter was used to selectively express a pseudosubstrate PKC inhibitor in Purkinje cells. Mice expressing the transgene exhibited no adaptation of the VOR, and cerebellar slice cultures from these animals exhibited no LTD. This work demonstrates the power and potential of applying molecular–genetic approaches to the oculomotor system. In addition, it has generated discussion about how molecular–genetic approaches might best be combined with systems-level approaches to study the neural mechanisms of learning [37••,38••]. 33. Miles FA, Braitman DJ, Dow BM: Long-term adaptive changes in primate vestibulo-ocular reflex. IV. Electrophysiological observations in the flocculus of adapted monkeys. J Neurophysiol 1980, 43:1477-1493. 34. Arikan R, Highstein SM: Modulation changes of individual Purkinje cells in the flocculus vertical zone during adaptation of the vestibulo ocular reflex. Soc Neurosci Abstr 1997, 23:749. 35. Raymond JL, Lisberger SG: Neural learning rules for the •• vestibulo-ocular reflex. J Neurosci 1998, 18:9112-9129. This work compares the induction of learning in vivo to the requirements for induction of synaptic plasticity in vitro. It examines the patterns of neural activity present in the cerebellar cortex and vestibular nuclei during a range of stimuli that induce VOR adaptation. Patterns of neural activity that are consistently present during learning are identified as candidates for the in vivo trigger of synaptic plasticity. 36. Raymond JL, Lisberger SG: Multiple subclasses of Purkinje cells in •• the primate floccular complex provide similar signals to guide learning in the vestibulo-ocular reflex. Learn Mem 1997, 3:503-518. This study demonstrates that different subclasses of Purkinje cells in the floccular complex all receive similar information about the change in VOR gain required to improve image stability on the retina. 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