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Department of Neuroscience, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
Submitted 11 February 2005; accepted in final form 27 July 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Merfeld and Zupan 2002; Mergner et al. 2003; Raphan et al. 1979). Otolith organs provide a specific contribution to this multisensory system. Electrical stimulation of otolith organs (Fluur and Mellstrom 1971) or otolith nerves (Suzuki et al. 1969) demonstrated that otoliths control eye movements. The otolith signals are conveyed by primary otolith afferents (Fernandez and Goldberg 1976a,b) to the vestibular nuclei (Bush et al. 1993). These signals are able to generate an angular maculoocular reflex, which operates as a low-pass–filtered response (rabbits: Barmack 1981; Van der Steen and Collewijn 1984; rats: Brettler et al. 2000; mice: Harrod and Baker 2003; cats: Rude and Baker 1988; Tomko et al. 1988; monkeys: Angelaki and Hess 1996; Paige and Tomko 1991). In addition, information provided by the otolith organs influences the orientation of the eyes with regard to gravity and linear acceleration (Baarsma and Collewijn 1975; Cohen et al. 2001). This information must be combined with input from semicircular canals to obtain proper compensatory eye movements (Angelaki et al. 2004). Moreover, converged otolith-canal neural activity significantly changes its modulation in different behavioral contexts such as active and passive head movements (McCrea and Luan 2003). In some of these situations the otolith information may be used to transform primary semicircular canal signals into space-reference angular motion (Angelaki and Hess 1995). Thus several lines of evidence suggest that the otolith organs control eye movements by vestibular and oculomotor nuclei that are also used by the semicircular canal system.
According to the multisensory integration theory, one expects not only that deficits in the otoliths can cause a variety of problems in the canal-driven system, but also that compensation must take place. Yet, at present it is not clear whether dysfunctional otoliths can be compensated for and, if so, how and under which circumstances such compensations can occur. Eye movement recordings of primates under microgravity in space have not been conclusive because of small sample sizes, limited experimental time, and the fact that the otoliths can still sense accelerations in this situation (Clement et al. 1993; Correia 1998; Dizio and Lackner 1992; Moore et al. 2003). Moreover investigations on this topic have been hampered by the inability to mechanically lesion the otolith organs or nerves without affecting the input from the semicircular canals or without the loss of afferent fibers that will induce a reactive synaptogenesis (Goto et al. 2002).
To investigate potential vestibular compensatory processes, unilateral stimulation experiments on patients with unilateral vestibular nerve dissections (Clarke and Engelhorn 1998) and gravity-aligned/misaligned rotation experiments on patients with vestibular neuritis were performed (Schmid-Priscoveanu et al. 2004). However, these pathological circumstances were not specific enough to elucidate the compensatory mechanism induced by dysfunctional otoliths.
In the present study, we investigated potential mechanisms for compensation using tilted mice, which lack otoconia because of a spontaneous recessive mutation in otopetrin 1 gene (Otop 1) located on chromosome 5 (Hurle et al. 2003). Although their vestibular ganglion does develop relatively slowly (Smith et al. 2003), the projections from the otolith organs to the vestibular nuclei seem to be at least grossly normal in these mutant mice (de Caprona et al. 2004). Furthermore, tilted mice do not show any permanent abnormal phenotype in organ systems other than the otoliths (Ornitz et al. 1998). The linear vestibular evoked potential (linear VsEP) is absent in tilted mice (Jones et al. 2004) as a consequence of the absence of otoconia. Apart from confirming their deficiency in gravitoinertial information by determining their eye position after static roll paradigms, we investigated their angular vestibuloocular reflex in the dark (aVOR) and the light (angular visually enhanced VOR or aVVOR) as well as their optokinetic reflex (OKR) over a wide range of stimulus parameters. The lack of otoconia decreases the gains and increases the phase errors not only during "otolith-mediated" aVOR but also during "canal-mediated" aVOR and increases the vestibular system dependency on frequency, especially at stimulus frequencies <1 Hz. We demonstrate that a frequency-dependent enhancement of the optokinetic system can be used as a compensatory mechanism for a lack of functional otoliths. Furthermore, a simple model structure was explored to interpret the experimental data, to formulate a possible physiological template of how the canal, otolith, and visual signals share central processing and to obtain insight in the consequences of otolithic dysfunction.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). They were housed on a 12 h:12 h light:dark cycle with unrestricted access to food and water. All animal procedures described were in accordance with the guidelines of the ethical committee of Erasmus MC, Rotterdam. Phenotype assessment
The homozygous tilted mice were easily identified by their inability to swim when they were dropped from 
20 cm height into a deep tank of water. Tilted mice cannot find the surface of the water and need rescuing to prevent drowning. Heterozygous control littermates mice can find the surface of the water and swim easily (Ornitz et al. 1998).
Surgical procedures
An acrylic pedestal was formed on the animal's skull under general anesthesia of a mixture of isofluoran (Isofloran 1–1.5%; Rhodia Organique Fine), nitrous oxide, and oxygen. The pedestal construction was made as follows: a midline incision was made to expose the dorsal cranial surface and four stainless steel screws (1 x 1.5 mm) were implanted in the calvarium and then embedded in dental acrylic. A prefabricated piece equipped with two nuts was attached to the pedestal.
Video eye movement recording apparatus
After a recovery period (3 days), each mouse was handled daily for 2 days. During the experiment it was placed in an acrylic tube, with head secured. The tube was inserted into the setup by a carrier that allowed orientation of the mouse (from mouse upright to mouse with its nose up or down; ±90°). The carrier on which the mouse was fixed also permitted translation of the mouse in the left–right direction and near–far direction from the camera. The purpose of these translations was to position the mouse's eyeball on the rotation axis of the video camera, which ran through the center of the table (Stahl et al. 2000).
A cylindrical screen (diameter 63 cm) with a random-dotted pattern (each element 2°) surrounded the turntable (diameter 60 cm). Both the surrounding screen and the turntable were driven independently by an AC servo-motor (Harmonic Drive AG, Eindhoven, The Netherlands). The table and drum position signal were measured by potentiometers, filtered (cutoff frequency 20 Hz), digitized (CED Limited, Cambridge, UK), and stored on a computer.
Three infrared emitters (maximum output 600 mW, dispersion angle 7°, peak wavelength 880 nm) illuminated the eye during the recording. The camera and two infrared emitters were fixed to the turntable. The third infrared emitter was connected to the camera and aligned horizontally with the camera's optical axis. This third emitter produced the tracked corneal reflection (CR).
The eye movements were recorded using the eye-tracking device of Chronos Vision. The images of the eye were captured using an infrared-sensitive CMOS camera (frame rate 50 Hz) and were relayed to a personal computer equipped with acquisition software from Chronos Vision (IRIS).
Behavioral testing
A head-fixed coordinate frame was defined as follows: the yaw (z) axis was the ventrodorsal axis, the roll (x) axis was nasooccipital, and the pitch (y) axis was interaural. Four different approaches were used to test the eye movement performance. First, the eye movement counterroll performances were measured during different static horizontal roll stimuli. Mice in upright stance (nasooccipital axis along an earth-horizontal plane) were positioned at different roll angles between +20 and –20°. The mice were rotated very slowly (5°/s) around their nasooccipital axis from one to another position. All tilt positions of the mouse were held at least for 20 s or until the eye position was stable. Second, the optokinetic eye movements (OKR), the angular vestibuloocular eye movements (aVOR), and the angular visually enhanced vestibuloocular eye movements (aVVOR) were measured during different paradigms. The amplitude was kept at 5°, whereas the frequency of the sinusoidal stimulus ranged from 0.2 to 1 Hz (generating a peak velocity between 6 and 31°/s, and a peak acceleration between 8 and 197°/s2) during the following paradigms.
1) Dynamic horizontal yaw (Yh): mice upright (nasooccipital axis along the earth-horizontal plane), rotation around ventrodorsal axis
2) Dynamic vertical roll (Rv): mice nose up (nasooccipital axis along the earth-vertical plane), rotation around nasooccipital axis
3) Dynamic horizontal roll (Rh): mice upright (nasooccipital axis along the earth-horizontal plane), rotation around nasooccipital axis
Third, aVOR was tested at constant peak velocities (8 and 30°/s), whereas the frequency varied between 0.1 and 1.6 Hz. Fourth, aVOR was tested at constant peak acceleration (18°/s2), whereas the frequency varied between 0.1 and 1.6 Hz. The constant peak velocity and acceleration were tested using the dynamic horizontal yaw paradigm (Yh).
Each paradigm was presented to the mice for at least 3 days, but not all the paradigms were delivered on the same day. Each animal was recorded no more than once a day. Before aVOR recordings, pilocarpine 4% (Laboratories Chauvin, Montpellier, France) was used to limit the pupil dilatation in darkness.
Data analysis
A calibration was made before any of the recordings were started. The camera was rotated several times by ±10° around the earth-vertical axis passing through the center of the table. The positions of the pupil (P) and corneal reflection (CR) recorded at the extreme positions of the camera rotation were used to calculate Rp, the radius of rotation of the pupil (Stahl et al. 2000).
The gain and the phase of the eye movements were calculated by using a custom-made Matlab program (The MathWorks, Natick, MA). The eye position (E) was calculated using the CR and P positions from the recorded file and the Rp value was computed from the calibration (Stahl et al. 2000)
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). Model description and simulation
The model is a feedback model (Fig. 6A) for roll aVORs and OKRs and represents an extension of that proposed by Green and Galiana (1998). The boxes in the model represent dynamic element and circles represent summing junctions. The first-order approximations of semicircular canals C(s) = 1/(Tcs + 1), otolith organs O(s) = 1/(Tos + 1), neural feedback filter F(s) = 1/(Tfs + 1), eye plant P(s) = 1/(Tps + 1), and retinal slip integrator R(s) = 1/s were implemented with Tc = 3 s (Curthoys 1982; Jones and Spells 1963: rat), To = 0.016 s, and Tf = Tp = 0.24 s (Fernández and Goldberg 1976c; Galiana and Outerbridge 1984; Green and Galiana 1998; Robinson 1981). The retinal slip velocity signal was saturated before it entered the model (saturation threshold 2°/s) because of the limited sensitivity of the retinal ganglion cells (Collewijn 1972; Oyster et al. 1972). Model parameters associated with the gains of different pathways (see Fig. 6A, a–d) were chosen to satisfy the following criteria: 1) first, weight a (vestibular nuclei projection) was chosen to reproduce experimentally observed horizontal roll aVOR gains of tilted mice (a = 0.28); 2) then projection weight b (otoliths afferent projection) was chosen to fit the static otolith sensitivity of 26°/g of control mice (b = 0.121); 3) the remaining projection weights c (retina projection) and d (cerebellar projection) were chosen to reproduce the OKR in control mice (c = 0.10 and d = 6.5).
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Statistics
To compute the session average, gain and phase values were combined per trial. Session averages from at least 3 days were used to calculate the final gain and phase values per mouse. Data were presented as means ± SD. For statistical comparisons we used the two-way ANOVA for repeated measures and the standard t-test. Statistical analysis was performed using the commercial software package SPSS 11.0 (SPSS, Chicago, IL).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Tilted mice lack otoconia in both otolith organs (Ornitz et al. 1998). To test the function of the otolith organs, mice were subjected to static horizontal roll. Mice were rotated very slowly (5°/s) toward the endpoint roll angle where they were held at least for 20 s or until the eye position was stable. Head-roll angles around an earth-horizontal axis varied between +20 and –20° generating a projection of the gravity vector along the interaural axis ranging from –0.34 to +0.34 g. Sensitivity and gain of the eye counterroll in tilted mice were 3 ± 3°/g and 0.06 ± 0.005 (n = 7), respectively (Fig. 1, A and B). Both values were significantly lower than those in control mice (n = 7; sensitivity 26 ± 4°/g, P < 0.001, t-test; gain 0.45 ± 0.07, P < 0.001, t-test; Fig. 1, A and B). In control mice, but not in tilted mice, there was a linear relationship (r2 = 0.79) between eye position and linear acceleration along the interaural axis. Tilted mice did not show any relationship between the eye position and the head-roll angle (r2 = 0.002). Together, these data indicate that the static contribution of the otoliths to compensatory eye movements is negligible in otoconia-deficient mice.
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If the static contribution of otoliths to the eye position is affected in the mutants, one expects that the dynamic contribution of otoliths to the VOR is also affected. We therefore subjected control and tilted mice to horizontal roll (Rh), which activates conjunctively the vertical semicircular canals and otolith organs (Fig. 2A). The vertical roll (Rv; Fig. 2B) and horizontal yaw (Yh; Fig. 2C) paradigms were used to dynamically stimulate the vertical semicircular canals or the horizontal semicircular canals, respectively. An eye movement recording from each stimulus paradigm is shown in Fig. 2.
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Because the aVORs over the studied frequency range depend on peak acceleration (van Alphen et al. 2001), we tested the horizontal yaw aVOR not only during constant amplitude (5°) but also during constant peak velocity and constant peak acceleration paradigms. In control mice (n = 8) the gains of the horizontal yaw (Yh) aVOR at constant amplitude stimulation varied from 0.43 ± 0.11 at 0.2 Hz to 0.77 ± 0.11 at 1 Hz, whereas their phase leads decreased from 27.9 ± 10.2° at 0.2 Hz to 6.1 ± 2.6° at 1 Hz (Fig. 4A). Tilted mice (n = 7) had significantly lower gains (varying from 0.15 ± 0.04 at 0.2 Hz to 0.44 ± 0.07 at 1 Hz; P < 0.005, ANOVA) and significantly higher phase leads (varying from 103.6 ± 23.2° at 0.2 Hz to 23.2 ± 4.7° at 1 Hz; P < 0.001, ANOVA). When the performance of the horizontal yaw (Yh) aVOR was tested during constant peak velocity (8 and 30°/s; Fig. 4B) and constant peak acceleration (18°/s2; Fig. 4C), tilted mice (n = 5) again showed significantly lower gains and significantly higher phase leads than those of control mice (for all gain and phase values P < 0.001, ANOVA). The aVOR gains and phases in control mice were dependent not only on frequency but also on acceleration of the stimulus (Fig. 4C), increasing and decreasing, respectively, as the acceleration increased. If in tilted mice the aVOR gains and phases had been also dependent on amplitude and/or acceleration of the stimulus, then separate curves should have emerged in Fig. 4B. In tilted mice aVOR gains do not depend on amplitude and/or acceleration at low frequencies (0.1 and 0.2 Hz), but depend only on the frequency of the stimulus, whereas aVOR phases depend only on stimulus frequency over the studied frequency range.
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OKR compensation
The data described above showed that the otolith organs can improve both by static and dynamic mechanisms the eye movement performance around different axes in space. This contribution is most prominent at lower frequencies. These findings raise the question whether the deficits that occur in otoconia-deficient mice during aVOR can be compensated by a secondary enhanced OKR, which can particularly dominate oculomotor performance at the lower-frequency range (Collewijn and Grootendorst 1979). We therefore tested the OKR under the same set of body orientations and frequencies that were used for the experiments described above. For the vertical eye movement OKR, i.e., that of the horizontal roll and vertical roll, the gain values of the OKR of tilted mice (n = 11) were significantly higher than those of control mice (n = 10) at the two lowest frequencies of 0.2 and 0.4 Hz, which correspond to velocities 6 and 8°/s but not at the higher frequencies (Fig. 5, A and B). In control mice (n = 8) the gains of the horizontal yaw OKR varied from 0.69 ± 0.08 at 0.2 Hz to 0.15 ± 0.04 at 1 Hz, whereas tilted mice (n = 7) had significantly higher gains (varying from 0.80 ± 0.05 at 0.2 Hz to 0.26 ± 0.08 at 1 Hz; data not shown). The significance levels varied from P < 0.05 in vertical roll position to P < 0.001 in yaw position (ANOVA). In contrast, no significant differences were observed in the phase values of the OKR among the mutants and controls (P levels varied from 0.54 in horizontal roll to 0.98 in vertical roll; ANOVA). The subtraction of the OKR gain values of control mice in horizontal roll position from those of tilted mice in the same position did not differ from the same subtraction in vertical roll position (Fig. 5D). Thus the position of the mouse does not influence the gains of the vertical eye movement OKR. Although the optokinetic compensation was significant and robust in all body positions in tilted mice, it was not sufficient to obtain a normal gain of the VVOR (Table 1). For example, the VVOR gains during yaw movements were significantly higher in control mice (n = 9; 0.88 ± 0.06) than in tilted mice (n = 8; 0.80 ± 0.06) (P < 0.01, ANOVA).
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The dynamic behaviors of the horizontal and vertical roll aVOR and OKR of control and tilted mice were simulated by the model shown in Fig. 6A. To simulate the horizontal roll aVOR of control mice, vestibular nuclei projection weight a was set to 0.28, otoliths projection weight b was set to 0.121, and retina projection weight c and cerebellar projection weight d were set to zero. To mimic the vertical roll aVOR of control mice, the otolithic projection weight b was reduced. In tilted mice this projection weight b was set to zero.
Figure 6B shows the experimental and predicted data of the roll aVOR of control and tilted mice. The predicted frequency responses of the horizontal roll aVOR of control and tilted mice are consistent with our experimental data. The vertical roll aVOR of control mice was simulated by reducing the projection weight b by 35%.
Simulations of the model for the optokinetic response of control and tilted mice are illustrated in Fig. 6C. To simulate roll OKR of control mice, vestibular nucleus projection weight a was set to 0.28, otolith projection weight b was set to zero, retina projection weight c was set to 0.1, and cerebellar projection weight d was set to 6.5. An increment of the cerebellar projection weight d from 6.5 to 8.7 mimicked the optokinetic compensation observed in tilted mice. Both the experimental data as well as the predicted data show that this compensatory mechanism is frequency dependent.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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VOR deficits
The lack of otoconia in tilted mice resulted in dysfunctional otolith organs that were virtually unable to evoke correct eye movement responses after static or dynamic displacement of the head. With regard to the static stimuli, we found that the gain and sensitivity of their eye counterrolls were approximately 10% of those in control mice littermates. The residual counterroll eye movements in tilted mice might be driven by inputs from extracervical somatosensory receptors (Krejcova 1971; Yates et al. 2000) or by inputs from giant otoconia that are sometimes present in tilted mice (Ornitz et al. 1998). The sensitivity in control mice (26°/g) was in between that of rabbits (17°/g) (Maruta et al. 2001) and fish (30°/g) (Benjamins 1918; Cohen et al. 2001). With regard to the dynamic stimuli in tilted mice, we found the most prominent aberrations during horizontal roll, indicating that this paradigm evokes a relatively high activity in the otolith organs. Interestingly, comparison between control mice and tilted mice also revealed deficits in eye movement performance after horizontal yaw and vertical roll stimulation even though these paradigms are thought to evoke relatively little dynamic activity in the otolith organs (see also Harrod and Baker 2003). Moreover we showed that subtraction of the eye movement performance during horizontal roll in the mutants from that during horizontal roll in control mice is not equal to the difference between eye movement performance during vertical roll in control mice and that during horizontal roll in control mice (Fig. 3C).
Together, these results suggest the presence of an otolith component during both horizontal yaw and vertical roll stimulations and show that by placing control mice in the vertical position, the contribution of the otolith organs to aVOR is not completely removed. This possibility is confirmed by the model suggested (Fig. 6A), which indicates that in vertical position the otolith organs of control mice still give a functional contribution (Fig. 6B). The most obvious explanation for these unexpected otolith contributions in this situation is that the otolith organs are statically stimulated and that this static otolith signal is partially able to correct the "vertical semicircular canals aVOR" in these control mice (Figs. 3B and 6B). The presence of a static otolith signal during rotation of mice in the plane of the horizontal canals will also explain the eye movement aberration found in tilted mice during horizontal yaw stimulations. An alternative explanation is that otolith organs were not precisely placed in the center of rotation during stimulation. Consequently, a dynamic stimulation of the otolith organs was induced that would be large enough to contribute substantially to the aVOR. This possibility is very unlikely because the tangential and centripetal acceleration are under these circumstances too low (tangential acceleration = 0.002g; centripetal acceleration = 0.0002g) to elicit a response (Clarke and Engelhorn 1998). The tilt angle of the rotation axis with respect to gravity elicits the otolith responses, therefore the facts that the macular surface of the otolith organs is curved, not planar (Flock 1964), and that otolith organs do not lie in the plane of the semicircular canals (Curthoys et al. 1999) are also no plausible explanations for our results. Nevertheless, it remains unclear whether the mechanism suggested is entirely responsible for this large otolith–dependent aVOR component. The possibility that otolithic deprivation in tilted mice altered the neuronal activity of utricular afferents still needs to be elucidated. To unravel this mechanism, electrophysiological measurements of either utricular afferents or vestibular nuclei neurons are necessary.
The similarities in eye-movement responses evoked by horizontal linear acceleration and off-vertical axis rotation in rats led to the conclusion that utricular-driven eye movement in rodents complements the semicircular canal activations to achieve gaze stability during horizontal roll stimulation (Hess and Dieringer 1990, 1991). The horizontal roll aVOR can be explained by the fact that signals derived from otolith organs and semicircular canals converge at the level of vestibular neurons, which send their eye movement commands to the oculomotor nuclei (Dickman and Angelaki 2002; Sato et al. 2000; Zhang et al. 2001, 2002). The missing static otolith correction in the tilted mice and the convergence of the otolith and canal driven signals might also explain our finding that the aberrations in aVOR of tilted mice were frequency dependent not only during horizontal roll, but also during vertical roll and horizontal yaw. This is the first study that shows that in the absence of otolith input, the dependency of the vestibular system on the frequency of the stimulus is increased. Taken together our aVOR data support the multisensory integration theory in that the brain must combine information from semicircular canals and otolith organs to make proper compensatory eye movements (Angelaki et al. 2004; Harrod and Baker 2003).
OKR compensation
We found that OKR gain values of tilted mice were significantly increased. Several findings support the argument that this increase reflects a mechanism that will compensate for deficits in the aVOR. First, the increases in OKR gain occurred in every position at which deficits in the aVOR were detected, i.e., that of the horizontal roll, horizontal yaw, and vertical roll. Second, the increases in OKR gain occurred predominantly at the lower frequencies, which corresponds to the frequency range at which the aVOR gain values were most prominently affected. Furthermore, the VVOR gain values were not increased in tilted mice, suggesting that the OKR increase was not a primary effect but a secondary effect in an attempt to correct the VVOR gain values that were partly reduced.
The mechanism that underlies OKR compensation in tilted mice probably resembles that underlying OKR and VOR adaptation after visuovestibular or visual training paradigms (Collewijn and Grootendorst 1979; Iwashita et al. 2001; Nagao 1983). During these adaptations OKR or VOR gain values change in response to enhanced retinal slip. Whereas a change in VOR gain depends on the direction of retinal slip in relation to the direction of the eye movement, the OKR gain always increases when there is enhanced retinal slip, independent from the direction of the slip (Collewijn and Grootendorst 1979; De Zeeuw et al. 1998). In tilted mice the aVOR gains are reduced as a result of dysfunctional otoliths, which in turn increase the retinal slip triggering a compensatory change in the OKR. Similarly, the low-frequency aVOR can be enhanced as a mechanism to compensate for a decrease in OKR gain; this reversed process occurs in lurcher mice, which suffer from reduced OKR gain values as a result of a lack of floccular Purkinje cells (van Alphen et al. 2002). Even so, it should be noted that a total blockage of the VOR such as occurs in shaker mutants, Usher Syndrome Type 1B patients, or subjects after bilateral labyrinthectomy does not necessarily result in increased OKR gains (Barmack et al. 1980; Cohen et al. 1973; Sun et al. 2001). In these cases the vestibular deficits fall too much in the high-frequency range and/or the increased retinal slip levels fall outside the optimal range that can drive optokinetic signals mediating adaptation in the flocculus of the cerebellum (Simpson et al. 1996). Thus the optokinetic system may be particularly suited to compensate for the lack of otolith-driven information necessary for a proper aVOR because both systems have similar low-pass filter characteristics, whereas it may not be well designed to compensate for deficits in the vestibular-canal system, which dominates the higher frequencies. These observations correspond with the behavior of our model. Alterations in the weight of cerebellar projection d affect the responses in a similar low-pass-filter–characteristic way as described above (Fig. 6C), suggesting that the cerebellar cortex is a suitable site for this OKR compensatory mechanism.
In conclusion, by analyzing mutants with specific deficits in their otoliths we provide evidence that the otolithic input shows central cross talk with the input of the semicircular canals and that the otolith organs provide indispensable information for the angular vestibuloocular reflex. The lack of otolith input increases the dependency of the vestibular system on the stimulus frequency. The optokinetic reflex can compensate for the lack of gravitoinertial perception in the low-frequency range. By using a simple model, in which the vestibular nucleus was embedded as a multisensory integration unit, we were able to simulate all behaviors observed in control and in tilted mice. All these phenomena support the presence of an adaptive multisensory integration system that combines information from otolith organs, semicircular canals, and retina to make proper compensatory eye movements.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. de Jeu, Department of Neuroscience, Erasmus University Medical Center Rotterdam, Dr. Molewaterplein 50, 3000 DR, Rotterdam, The Netherlands (E-mail: m.dejeu{at}erasmusmc.nl)
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), gravity-induced interaural acceleration (
). Output of the model is eye position (E). Boxes are dynamic elements that represent a sensor [C(s), O(s), and R(s)], a motor plant [P(s)], or a neural filter [F(s)]. Circles are summing junctions used to represent particular cell populations including neurons of the vestibular nucleus (VN), neurons of the oculomotor nucleus (OMN), and neurons of the prepositus hypoglossi (PrH). Model parameters a, b, c, and d associate with the projection weight of the different pathways. Detailed description of the model parameters can be found in METHODS. B: comparison of model predictions and experimental horizontal roll aVOR of control (filled circles; b = 0.121) and tilted mice (open circles; b = 0). Vertical roll aVOR of control mice was simulated by changing the projection weight b into 0.079. C: comparison of model predictions and experimental optokinetic responses of control (filled circles; d = 6.5) and tilted mice (open circles; d = 8.7).
