Vestibulo-Ocular Reflex (VOR) Plasticity
VESTIBULO-OCULAR REFLEX (VOR) PLASTICITY
The vestibulo-ocular reflex (VOR) is driven by head movement and moves the eyes in the direction opposite to the head movement, automatically stabilizing vision relative to space. The VOR is mediated by a trineuronal arc composed of the primary vestibular neurons, relay neurons in vestibular nuclei, and motoneurons for the extraocular muscles. The optokinetic eye-movement response (OKR) is another ocular reflex induced by optokinetic stimuli generated by movements of the visual field relative to the head. VOR and OKR share the same vestibular nuclear neurons and oculomotor neurons, and synergistically stabilize vision. The VOR/OKR pathways are attached with commissural connections between the bilateral vestibular nuclei, internuclear connections between motor nuclei, and other connections with the tegmentum and the cerebellum.
Two types of plasticity have been recognized in the VOR/OKR. The first is gradual recovery of the heavy nystagmus induced by unilateral labyrinthectomy (vestibular compensation) (Magnus, 1924; Vidal et al., 1998). A lesion to the cerebellum retards the onset of recovery, and, when made after recovery, it transiently removes the compensation. Hence, the cerebellum may play a role in initiating this type of plasticity (Courjon et al., 1982). The second is gradual changes of the VOR and OKR gain (amplitude ratio of eye rotation versus head or visual-field rotation) in altered visuovestibular environments (VOR/PKR adaptation) (Gonshor and Melvill-Jones, 1974; Ito et al., 1974; Robinson, 1976). Since the flocculus, an evolutionarily old part of the cerebellum, sends inhibitory axons of Purkinje cells directly to the VOR relay neurons (Fukuda et al., 1972), the flocculus may be the center for the adaptation of VOR/OKR (Ito, 1982). The compensation and adaptation in the VOR/OKR provide simple model systems representing learning capabilities of neuronal circuits (Ito, 1984, 1998; Raymond et al., 1996).
Neuronal Circuit for the VOR and OKR
The VOR contains a number of component reflexes. They arise from the three semicircular canals (horizontal, anterior, and posterior) and two otolith organs (utricle and saccule) in each labyrinth and act on six extraocular muscles (medial and lateral rectus, superior and inferior rectus, superior and inferior oblique) in each eye. In experiments, the VOR is usually divisible into horizontal, vertical, or torsional components through the application of yaw, pitch, roll, linear motion or static tilt to the head. When moving freely, the VOR is mediated via the concerted operation of numerous parallel pathways linking the ten sensors in two labyrinths with the twelve muscles in two eyes (Ezure and Graf, 1984).
In the horizontal VOR, horizontal semicircular canals are stimulated by ipsilateral head rotations that result in transmission of neural signals via the primary vestibular nerve fibers to relay cells of the VOR in the vestibular nuclei. The VOR relay cells, in turn, transmit either excitatory or inhibitory signals to motoneurons in the abducens and oculomotor nuclei. Rotation of the head to one side induces contraction of the ipsilateral medial rectus and contralateral lateral rectus muscles, and relaxation of the ipsilateral lateral rectus and contralateral medial rectus muscles, so that both eyes move in a direction opposite to that of the head rotation. Optokinetic signals arising from the retina are sent to VOR relay neurons, inducing the OKR.
Cerebellar Connections to VOR/OKR Pathways
The flocculus in rabbits and cats has five to six major folia and in rats only one. The classic anatomy of the monkey cerebellum shows ten folia in the flocculus, but recent studies on neuronal connectivity have revealed that the rostrally located five folia belong to the ventral paraflocculus and not to the flocculus (Gerrits and Voogd, 1989). Purkinje cells, which are localized to a narrow zone (H zone, about one mm across) extending across the folia of the flocculus, supply inhibitory synapses to the horizontal VOR-relay neurons. Other zones related to the vertical or torsional VOR flank the H zone (Nagao et al., 1985; Sato and Kawasaki, 1991; Van der Steen et al., 1994). Physiological experiments detect these zones by local electrical stimulation, which induces distinct horizontal, vertical, or rotatory eye movements. The flocculus receives vestibular, optokinetic, and neck afferent signals via mossy fibers, and optokinetic and vestibular signals via climbing fibers (Ito, 1984).
The nodulus and uvula, other phylogenically old parts of the cerebellum, receive vestibular mossy fiber inputs through certain vestibular nuclear neurons, which receive Purkinje cell axons from the nodulus and uvula (Xiong and Matushita, 2000). The nodulus and uvula receive optokinetic signals via climbing fibers.
Velocity Storage and Neural Integrator
Head rotation in darkness at a constant velocity induces nystagmus, which consists of alternating slow phases representing the VOR and quick phases resetting the eye position. Under this condition impulses evoked in the first-order vestibular afferents decline rapidly, within five seconds. Yet the slow-phase velocity of the nystagmus decays slowly, with a time constant of about twenty seconds. There must be a brain-stem mechanism, a velocity storage that stores the initial head velocity as transduced by the canals and maintains it despite the decay in the firing rate of the canal afferents (Raphan et al., 1979). Since electrical stimulation of the nodulus and uvula induces a rapid decline in the horizontal slow-phase velocity, these cerebellar regions may control the velocity storage (Solomon and Cohen, 1994). The same system is responsible for optokinetic after-nystagmus (OKAN).
In the VOR, the head velocity signals generated by the labyrinth are converted to eye position signals for the extraocular muscles. In the OKR, the retinal slip velocity signals are also integrated to eye position signals. Hence, the VOR/OKR pathways must contain a neural integrator mechanism (Robinson, 1975). The integrator for the horizontal VOR/OKR may involve the nucleus prepositus hypoglossi and/or the commissural inhibitory projections between bilateral vestibular nuclei (Arnold and Robinson, 1997). The integrator for the vertical VOR is provided by the interstitial nucleus of Cajal in the midbrain (Fukushima et al., 1992). The velocity storage and neural integrator may represent functions of the same neuronal circuit, but their identity remains unclear.
Compensation for Unilateral Labyrinthectomy
The behavioral recovery from unilateral labyrinthectomy in rats was accompanied by asymmetric expression of isoforms of protein kinase C (PKC α, γ, and δ in the flocculonodular lobe, with a regionally selective increase in the number of PKC-immunopositive Purkinje cells contralateral to the lesion (Goto et al., 1997). This asymmetry occurred within six hours after the labyrinthectomy and was resolved to the control, symmetric pattern within twenty-four hours. The compensation was retarded in rats after intracerebroventricular application of PKC inhibitors (Balaban et al., 1999). Since PKC is required for induction of long-term depression (LTD) in Purkinje cells, these observations suggests that LTD plays a role in vestibular compensation. But because slow recovery of compensation still occurs after lesioning the cerebellum, plastic changes should occur also outside the cerebellum. Reserachers have found an increase in GABAergic neurons in cat vestibular nuclei after unilateral labyrinthectomy (Tighilet and Lacour, 2001); a neuronal network simulation suggests a change in the commissural inhibitory connections (Graham and Dutia, 2001).
In laboratory experiments, sinusoidal or velocity-step, whole-body rotation in darkness induces the horizontal VOR; the VOR gain is the ratio of the attained eye velocity vs. the applied head velocity. The sinusoidal rotation is convenient for measuring the gain and phase of the VOR separately, whereas velocity steps enable us to separate components of VOR responses, which arise with different latencies.
The VOR exhibits marked adaptive changes in gain under sustained mismatching between movement of the head in space and movement of the visual surroundings. Long-term visuovestibular mismatching of days or months can be generated using prism or lens goggles (Gonshor and Melvill-Jones, 1974; Robinson, 1976). However, for short-term mismatching of one to four hours, it is convenient to use the combined rotation of the turntable on which the animal is mounted and a screen representing the visual surroundings (Ito et al., 1974; Nagao, 1989). Both the wearing of Dove prism goggles, which reverse the right-left axis of the visual field, and the in-phase rotation of the turntable and screen in the same direction cause adaptive reduction of horizontal VOR gain. Both the wearing of magnifying lenses (2x) and the out-of-phase rotation of the turntable and screen in opposite directions cause an adaptive increase in horizontal VOR gain. The OKR gain adaptively increases during sustained rotation of the visual field around a stationary animal.
The view that the flocculus is the center for the VOR/OKR adaptation gains support from the observation that the adaptation no longer occurs after lesioning the flocculus, interruption of the climbing fiber input to the interruption of the climbing fiber input to the flocculus, or deprivation of NO that is required for induction of LTD, as tested in various animals. Subdural application of a NO scavenger to the rabbit and monkey flocculus blocked VOR adaptation (Nagao and Ito, 1991). Injection of a NO scavenger or a NOS inhibitor into the goldfish cerebellum (Li et al., 1995) inhibited adaptive increase in VOR gain. NO synthase (NOS)-deficient mutant mice lacked OKR adaptation (Katoh et al., 2000). Induction of LTD also requires activation of PKC; accordingly, transgenic mice that selectively express the pseudosubstrate PKC inhibitor, PKC [19-31], in Purkinje cells lacked VOR adaptation (De Zeeuw et al., 1998).
Researchers have studied the effects of the acute removal of flocculus functions after the development of the VOR adaptation to determine whether or not the once-established VOR adaptation is retained in the flocculus. Microdialysis of lidocaine into the goldfish cerebellum abolished both induction and retention of the VOR adaptation (McElligot et al., 1998), suggesting that the memory for the VOR adaptation is retained, probably entirely, in the cerebellum. In another experiment on goldfish, however, no less than 30 percent of the altered VOR gain was retained after ablation of the cerebellum (Pastor et al., 1994), a result that favors the view that the memory is partly stored outside the cerebellum. A system identification study on the monkey vertical VOR (Hirata and Highstein, 2001) suggests that adaptive changes occur in both the flocculus and nonflocculus pathways.
Neuronal Mechanisms of VOR Adaptation
The major signals of Purkinje cells are simple spikes, elicited by mossy-fiber inputs. In rabbits, ipsilateral horizontal head rotation causes either an increase (in-phase type) or decrease (out-of-phase type) in the simple spike discharges from H-zone Purkinje cells. During sustained visuovestibular mismatching, the simple spike modulation of H-zone Purkinje cells becomes predominantly out-of-phase or in-phase, corresponding to the increase or decrease in the VOR gain, respectively (Ito, 1984, 1998). Complex spikes representing climbing fiber signals are evoked by optokinetic stimuli. Researchers have assumed that these complex spikes encode retinal slips, but a study by Frens and colleagues suggests that they encode the eye-movement performance error rather than retinal slip (2001). The changes in simple spike-response patterns are supposed to result from LTD induced by error signals of climbing fibers and to cause the VOR gain changes (Ito 1982, 1998). Nevertheless, studies of the monkey flocculus/paraflocculus suggest that VOR adaptation is the cause, not the consequence, of the simple spike modulation in Purkinje cells that reflect eye velocity changes (Miles and Lisberger, 1981; Hirata and Highstein, 2001).
Although there is a scholarly consensus about the important roles of the cerebellum in the VOR plasticity, its mechanisms remain unclear, partly because of the use of different animal species and different types of VOR. The sampling of Purkinje cells from both the flocculus and ventral paraflocculus also complicate interpretation because these areas have substantially different input and output connections (Gerrits and Voogd, 1989; Nagao et al., 1997a, b). It should be noted that these areas have different functional assignments: The flocculus plays a role in the control of VOR and OKR, whereas the ventral paraflocculus plays roles in ocular following movement (Shidara et al., 1993) and in the smooth pursuit of a moving target (Stone and Lisberger, 1990). These complications pose the need for further research.
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