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Gaze stabilization during head/body movements is achieved to a large extent by vestibular-evoked compensatory eye movements. These reflexes derive from semicircular canal and otolith organs and depend on the transformation of the respective sensory signals into extraocular motor commands. To elicit directionally and dynamically appropriate compensatory eye movements, extraocular motoneurons require spatiotemporally specific inputs from semicircular canals and regions of the utricular epithelium with matching directional sensitivity. The ontogenetic establishment and maturation of the directional tuning of otolith inputs in extraocular motoneurons was studied in Xenopus laevis tadpoles. In young larvae at stage 46-48, superior oblique (SO) extraocular motoneurons receive omnidirectional utricular signals during horizontal translational motion, indicating an absence of spatial tuning. In contrast, in older larvae beyond stage 49 these motoneurons were activated by directionally more restricted otolith inputs with an increasingly enhanced spatial tuning until stage 53. This developmental process limited the origin of otolith signals to a utricular epithelial sector with a hair cell sensitivity that is coaligned with the pulling direction of the SO eye muscle. The maturation of the otolith response vector was abolished by enzymatic prevention of semicircular canal formation in postembryonic tadpoles at stage 44, suggesting that functionally intact semicircular canals are causally responsible for the observed directional tuning of utricular responses. A likely mechanism by which semicircular canals might influence the tuning of the otolith responses includes stabilization of coactivated and centrally converging sensory signals from semicircular canal and spatially aligned epithelial utricular regions during natural head/body motion.
Figure 1 Semiâ€intact preparation of Xenopus laevis tadpoles for characterizing the spatial specificity and developmental maturation of SO motor nerve responses during horizontal linear translation. (A–D) Photograph of a semiâ€intact preparation of a stage 55 tadpole, illustrating the preserved anatomical structures (A), the right otic capsule with macroscopically visible semicircular canal and otolith endorgans (B), the hair cell orientation (arrows) on the amphibian utricle (C) and motor nerve innervation of the extraocular muscles of the lefteye (D); scheme, illustrating utricular hair cell orientation (C) was adapted from Straka and Dieringer (2004). (E and F) Linear sled (E) used for application of horizontal translational acceleration (white arrow); stepwise rotation of an adjustable platform (blue arrow) allows reorienting the recording chamber with the semiâ€intact preparation relative to the translational motion direction (F). (G) Multipleâ€unit activity of the left SO motor nerve in the absence of motion (G1) and during seven cycles of sinusoidal sled oscillations at 0.5 Hz (±5 cm) with the preparation (pictograms) oriented 45° to the left (G2) or to the right (G3) relative to the translation direction; upper traces indicate sled positional oscillations (negative sine wave indicates forward motion) and lower traces the nerve discharge. (H) Instantaneous firing rate of the three recordings shown in G1–3 (same color code as in G). (I) Averaged firing rates of the SO motor nerve discharge shown in G2,3 as PSTH (±SEM; n = 7 oscillations, respectively) for a single cycle; robust modulation occurs when the preparation (pictograms) was oriented 45° to the left (I1), no modulation when the preparation was oriented 45° to the right relative to the translation direction (I2); black sinusoid indicates sled position (negative sine wave indicates forward motion). Calibration bars represent 2.5 mm in A and 0.5 mm in B and D. AC, HC, PC, anterior vertical, horizontal, posterior vertical semicircular canal; LA, lagena; LR, MR, lateral rectus, medial rectus eyemuscle; OC, otic capsule; ON, optic nerve; SA, saccule; SO, SO eyemuscle; UT, utricle.
Figure 2 Developmental tuning of translational motionâ€evoked extraocular motor responses in larval Xenopus. (A) Typical PSTHs of the discharge recorded from the left SO motor nerve during horizontal sinusoidal translation (negative sine wave indicates forward motion) at 0.5 Hz (±5 cm), averaged over a single cycle (from n = 20–30 cycles) in tadpoles at stage 46 (A1), 52 (A2), and 54 (A3); upper and lower plots show responses with the preparation (pictograms) oriented 45° to the left (parallel to the left SO eyemuscle) and 45° to the right relative to the translational direction (perpendicular to the left SO eyemuscle), respectively. (B) Polar plots illustrating directional distributions of SO motor nerve discharge modulation over 360° following stepwise (15°) alterations of the position of the preparation relative to the translational vector in three groups of tadpoles at stages 46–48 (Group 1; B1; n = 9), stages 49–52 (Group 2; B2; n = 12), and stages 53–60 (Group 3; B3; n = 13). (C) Bar plots of normalized SO motor nerve firing rate modulation during translational motion parallel (left bar) and perpendicular (right bar) to the SO eyemuscle (see pictograms) of the same three age groups of tadpoles (C1–3) shown in B; significance of difference between the two orientations is indicated (**p ≤ 0.01, ***p ≤ 0.0001, Wilcoxon signedâ€rank test); n.s., not significant.
Figure 3 Aligned sensoryâ€motor vector components of SO extraocular motor nerve responses during sinusoidal roll motion stimulation. (A) Photograph of the inner ear, illustrating the location and average orientation of the posterior semicircular canal (PC) relative to the body length axis (mean ±SEM; n = 12). (B) Systematic reorientation of the position of the preparation with respect to the plane of horizontal axis roll motion. (C) Multipleâ€unit activity of the left SO motor nerve during seven cycles of sinusoidal roll motion (1 Hz; ±10°) with the preparation oriented 30° (C1), 45° (C2), and 60° (C3) to the left (pictograms); upper trace indicates table position and lower traces the nerve discharge. (D) Averaged firing rates of the SO motor nerve discharge shown in C1–3 as PSTH (±SEM; n = 7 oscillations, respectively) for single cycles, respectively, along the three roll motion planes (C1–3); black sinusoid indicates table positional change (negative sine wave indicates forward motion). (E) Response modulation of SO motor nerve discharge during translational (green curve) and roll (red curve) motion in different planes relative to the body length axis (0°); data for the translational response modulation were obtained from animals at stage 53–55 of Group 3 (n = 6) shown in Figure 2; blue and red shaded areas represent the mean ±SEM of the posterior semicircular canal orientation and the pulling direction of the SO eyemuscle, respectively. Calibration bar in A represents 0.5 mm. AC, PC, HC, anterior vertical, posterior vertical, horizontal semicircular canal; LA, lagena; SA, saccule; UT, utricle.
Figure 4 Morphoâ€physiological correlates of semicircular canal deficient stage 52 Xenopus tadpoles following prior intraotic injections of hyaluronidase at stage 44. (A and B) Horizontal sections through the left and right otic capsules at a ventral (A1,B1) and a more dorsal level (A2,B2) in a stage 52 sham control (A) and an ageâ€matched animal in which semicircular canal formation was prevented (B); note the presence of clear tubular canal structures in A (AC, PC) and the lack thereof in B (red * indicates putative locations in controls). (C) Schematic view of the positional orientation of the preparation for vertical axis rotation that selectively modulates the activity of the left PC—right AC (oriented horizontally), without changing the gravity vector relative to the utricle. (D) Multipleâ€unit discharge modulation of the left SO motor nerve during 7 cycles of vertical axis sinusoidal motion (1 Hz; ±10°) with the preparation in an oblique vertical position (see C) in a sham control (D1) and a semicircular canal deficient tadpole (D2); upper trace indicates table position and lower traces the nerve discharge. (E) Averaged firing rates of the SO motor nerve discharge shown in D1,2 as PSTH (±SEM; n = 7 oscillations, respectively) for a single cycle; robust modulation occurs in the control (E1) but not in the preparation obtained from a semicircular canal deficient tadpole (E2); black sinusoid indicates table motion (negative sine wave indicates forward motion). Calibration bar in A1 represents 0.5 mm and applies to A2 and B1,2. AC, PC, anterior and posterior vertical semicircular canal.
Figure 5 Absence of developmental vectorial tuning of translational motionâ€evoked extraocular motor responses in semicircular canal deficient and sham control Xenopus tadpoles. (A) Typical PSTHs of the discharge recorded from the left SO motor nerve during horizontal sinusoidal translation (negative sine wave indicates forward motion) at 0.5 Hz (±5 cm), averaged over a single cycle (from n = 20–30 cycles) in a stage 52 sham control animal (A1), a stage 52 (A2) and a stage 55 semicircular canal deficient tadpole (A3); upper and lower plots show responses with the preparation (pictograms) oriented 45° to the left (parallel to the left SO eyemuscle) or 45° to the right relative to the translational direction (perpendicular to the left SO eyemuscle), respectively. (B) Polar plots illustrating directional distributions of SO motor nerve discharge modulation magnitudes over 360° of translational motion in stage 52 sham controls (B1; n = 5), stage 52 (B2; n = 5) and stage 55 semicircular canal deficient tadpoles (B3; n = 4). (C) Bar plots of normalized SO motor nerve firing rate modulation during translational motion parallel and perpendicular to the SO eyemuscle (pictograms); data were obtained from the respective polar plots in B of the three groups of tadpoles (C1–3); significance of difference in the normalized response rates during motion in the two directions is indicated (**p ≤ 0.01, Wilcoxon signedâ€rank test); n.s., not significant.
Figure 6 Schematic diagram depicting the hindbrain connectivity of bilateral vestibular endorgans and the SO eyemuscle along with the developmental changes in utricularâ€posterior semicircular canal contributions to the SO motor response vector. At stage 46, SO motor responses derive from the entire utricle (yellow area), whereas at stage 55, SO motor responses derive from a utricular sector that aligns with the PC on the same side. AC, PC, HC, anterior, posterior vertical, horizontal semicircular canal; ACc, inhibitory commissural AC neuron; ACi, inhibitory AC neuron; IO, inferior oblique; IR, inferior rectus; LR, lateral rectus; MR, medial rectus; PCe, excitatory PC neuron; r1–8, rhombomere 1–8; SR, superior rectus eyemuscle; Tro, trochlear motoneurons.
