Functional maturation in abducens motoneurons populations during angular VOR larval development
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eLife Assessment
The study makes a valuable contribution to understanding the development of reflexes responsible for gaze stabilization. Using a combination of behavioural, electrophysiological and imaging approaches and analyses in developing Xenopus tadpoles, the findings provide a convincing demonstration that maturation of the angular vestibulo-ocular reflex in larval tadpoles involved increased modulation of silent but not spontaneously firing abudens motor units during horizontal semicircular canal activation, as well as increased myelination and innervation of the lateral rectus motor nerve. The findings will set the stage for future investigations to uncover the mechanistic underpinnings of the current observation.
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Abstract
Extraocular motoneurons are the final neuronal relay implicated in gaze motor control and are known to be subdivided in functional subgroups, differently implicated in ocular motion dynamics. However, the maturation of these functional populations of extraocular motoneurons, in relation with the development of gaze-stabilizing reflexes remains largely unexplored. In amphibian tadpoles, the angular vestibulo-ocular reflex (VOR) appears later than other visuo-vestibular ocular reflexes and matures until the metamorphosis climax. Two types of Abducens motoneurons have been described to participate to the angular VOR in larval frog: spontaneous motor units, exhibiting a robust resting activity and silent motor units recruited only during head motion. The aim of this study was to investigate the maturation of these two types of Abducens motor units in relation with the development of the angular VOR by evaluating their discharge dynamic in response to head rotation in semi-intact preparations of larval Xenopus laevis. During larval life, the discharge modulation during sinusoidal head rotations increases significantly for silent units only, demonstrating a better sensitivity of this Abducens motoneuron sub-population to horizontal semicircular canal activation. In addition, this functional maturation was accompanied by an increase of the myelination in the lateral rectus motor nerve, promoting a faster conductivity in late larval stages than in early one. These findings showed that the development of the angular VOR is supported by a selective maturation of extraocular motoneurons subpopulations, specifically implicated in the improvement of the ocular kinematic during the reflex.
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eLife Assessment
The study makes a valuable contribution to understanding the development of reflexes responsible for gaze stabilization. Using a combination of behavioural, electrophysiological and imaging approaches and analyses in developing Xenopus tadpoles, the findings provide a convincing demonstration that maturation of the angular vestibulo-ocular reflex in larval tadpoles involved increased modulation of silent but not spontaneously firing abudens motor units during horizontal semicircular canal activation, as well as increased myelination and innervation of the lateral rectus motor nerve. The findings will set the stage for future investigations to uncover the mechanistic underpinnings of the current observation.
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Reviewer #1 (Public review):
Summary:
Movements, including reflexes, can undergo changes during development. This is the case for the angular vestibulo-ocular reflex in many species, including the Xenopus laevis frog. This study aimed to study the underlying mechanisms by which this reflex matures during development of larval Xenopus laevis using electrophysiology and electron microscopy. Their electrophysiological recordings of the motor axons of the abducens motor nerve during evoked angular vestibulo-ocular reflex reveal that a subpopulation of abducens motoneurons, those that are silent rather than spontaneously active, increase their firing rate and modulation during the angular vestibulo-ocular reflex during development. Furthermore, electron microscopy imaging of the developing abducens motor nerve shows increased myelination. …
Reviewer #1 (Public review):
Summary:
Movements, including reflexes, can undergo changes during development. This is the case for the angular vestibulo-ocular reflex in many species, including the Xenopus laevis frog. This study aimed to study the underlying mechanisms by which this reflex matures during development of larval Xenopus laevis using electrophysiology and electron microscopy. Their electrophysiological recordings of the motor axons of the abducens motor nerve during evoked angular vestibulo-ocular reflex reveal that a subpopulation of abducens motoneurons, those that are silent rather than spontaneously active, increase their firing rate and modulation during the angular vestibulo-ocular reflex during development. Furthermore, electron microscopy imaging of the developing abducens motor nerve shows increased myelination. Light microscopy reveals increased innervation of the lateral rectus muscle
Strengths:
Recordings during the evoked angular vestibulo-ocular reflex enable assessment of activity of motoneurons during the movement. Recordings done at specific developmental stages reveal convincing changes in modulation of firing of silent motor units that are distinguished by their high-amplitude spikes in nerve recordings. Microscopy, both electron and light, provide strong evidence for increased myelination of the abducens motor nerve and innervation of the lateral rectus muscle.
Weaknesses:
The authors did not provide data showing why the silent motor units became more responsive with development. Is it related to maturation of the sensory inputs to these neurons or changes in intrinsic properties?
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Reviewer #2 (Public review):
Summary:
The manuscript by Pain et al. explores the functional maturation of key oculomotor populations responsible for gaze stabilization. The work is motivated by our poor understanding of this process in establishing appropriate reflexes during development. The authors focus on two types of abducens motoneurons implicated in the maturation of angular vestibulo-ocular reflexes (VOR) in amphibian tadpoles, namely spontaneous motor units that provide baseline control and silent motor units recruited only during head motion. This is a particularly good choice given the well-defined and evolutionarily conserved functions of these populations and the ease with which they can be tracked during changes in angular VOR as tadpoles develop.
The authors first use semi-intact larval preparations and both step and …
Reviewer #2 (Public review):
Summary:
The manuscript by Pain et al. explores the functional maturation of key oculomotor populations responsible for gaze stabilization. The work is motivated by our poor understanding of this process in establishing appropriate reflexes during development. The authors focus on two types of abducens motoneurons implicated in the maturation of angular vestibulo-ocular reflexes (VOR) in amphibian tadpoles, namely spontaneous motor units that provide baseline control and silent motor units recruited only during head motion. This is a particularly good choice given the well-defined and evolutionarily conserved functions of these populations and the ease with which they can be tracked during changes in angular VOR as tadpoles develop.
The authors first use semi-intact larval preparations and both step and sinusoidal horizontal stimuli to characterize developmental improvements in angular VOR, which include faster, more robust compensation of head rotation and higher frequency tuning. Next, to explore the central versus peripheral origins of maturational changes, the authors use galvanic vestibular stimulation of the vestibular nerve (which should be independent of canal size) and BrdU-pulse chase to track neurogenesis, which strongly link improvements in VOR to changes in existing circuits, rather than the addition of new ones. To provide a more comprehensive assessment of what these functional changes may entail, they then perform recordings of changes in motor neuron discharge patterns during development specific to horizontal motion. By combining with sophisticated spike sorting analysis, these data reveals improvements in head velocity encoding by silent subtypes, while head positioning by spontaneous subtypes is relatively consistent during development. Finally, electron microscopy analysis of the abducens motor nerve is used to demonstrate that improvements in encoding are accompanied by broad changes in peripheral myelination and innervation.
Together, the data argue that silent abducens motor units show the largest changes in recruitment in response to sinusoidal head rotations, which is accompanied by increases in myelination and signal fidelity. Ultimately, the work suggests that improvements in oculomotor reflexes during development are accomplished by non-uniform changes within defined oculomotor populations, which is novel and interesting.
Strengths:
Overall, the data are very convincing, the analysis is thorough, the findings will be of interest to those in the VOR field, and also set the stage for future investigations aimed at uncovering the mechanistic underpinnings of this cool observation. I only have a few comments to consider for improvement.
Weaknesses:
Major.
(1) A bit more clarity is needed.
For non-specialists, it would be helpful in the introduction (e.g., Line 52) to spell out what the functional differences are to begin between spontaneous and silent subtypes. The contribution to head positioning versus head velocity is raised later on, but bringing it up earlier would be helpful to understand the functional implications of differences up front.
(2) Figure call outs.
These should be double-checked. I found one that did not seem appropriate on line 332. In addition, the reference to Figure 3A and the spike rate are not illustrated.
(3) Spelling and grammar.
It would be helpful to proofread more carefully for typographical errors, particularly in terms of using singular versus plural and the appropriate articles. Most are minor (those that I found listed below), but in one case the lack of clarity was particularly problematic. On Line 518: 'Altogether, past studies and our present work suggest the existence'. Consider revising this sentence; it reads now that motoneurons mature 'conjointly'; however, this does not seem to capture the main point here, which is that they are not maturing at the same time. Do the authors mean staggered or conjointly with the behaviours they control?
(4) Interpretation.
In the discussion, it would be good to be clearer that myelination will not explain the changes in firing pattern, but could explain the behavioural changes. Ideally, this would be linked to the different types, but I appreciate it is not easy to decipher that from EM.
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