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Loss of Projections, Functional Compensation, and Residual Deficits in the Mammalian Vestibulospinal System of Hoxb1-Deficient Mice.

Di Bonito M, Boulland JL, Krezel W, Setti E, Studer M, Glover JC - eNeuro (2015)

Bottom Line: Several general motor skills appear unimpaired, but hindlimb vestibulospinal reflexes, which are mediated by the LVST, are greatly reduced.This functional deficit recovers, however, during the second postnatal week, indicating a substantial compensation for the missing LVST.Our results provide a comprehensive account of the developmental role of Hoxb1 in patterning the vestibular system and evidence for a remarkable developmental plasticity in the descending control of reflex limb movements.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Biology Valrose, UMR 7277, University of Nice Sophia Antipolis, 06108 Nice, France; Institute of Biology Valrose, INSERM, U1091, 06108 Nice, France; Institute of Biology Valrose, CNRS, UMR 7277, 06108 Nice, France.

ABSTRACT
The genetic mechanisms underlying the developmental and functional specification of brainstem projection neurons are poorly understood. Here, we use transgenic mouse tools to investigate the role of the gene Hoxb1 in the developmental patterning of vestibular projection neurons, with particular focus on the lateral vestibulospinal tract (LVST). The LVST is the principal pathway that conveys vestibular information to limb-related spinal motor circuits and arose early during vertebrate evolution. We show that the segmental hindbrain expression domain uniquely defined by the rhombomere 4 (r4) Hoxb1 enhancer is the origin of essentially all LVST neurons, but also gives rise to subpopulations of contralateral medial vestibulospinal tract (cMVST) neurons, vestibulo-ocular neurons, and reticulospinal (RS) neurons. In newborn mice homozygous for a Hoxb1- mutation, the r4-derived LVST and cMVST subpopulations fail to form and the r4-derived RS neurons are depleted. Several general motor skills appear unimpaired, but hindlimb vestibulospinal reflexes, which are mediated by the LVST, are greatly reduced. This functional deficit recovers, however, during the second postnatal week, indicating a substantial compensation for the missing LVST. Despite the compensatory plasticity in balance, adult Hoxb1- mice exhibit other behavioral deficits that manifest particularly in proprioception and interlimb coordination during locomotor tasks. Our results provide a comprehensive account of the developmental role of Hoxb1 in patterning the vestibular system and evidence for a remarkable developmental plasticity in the descending control of reflex limb movements. They also suggest an involvement of the lateral vestibulospinal tract in proprioception and in ensuring limb alternation generated by locomotor circuitry.

No MeSH data available.


Related in: MedlinePlus

Behavioral effects of the Hoxb1- mutation in young mice. A–E, Open field swimming test. A, Typical swimming trajectories of wild-type (blue) and Hoxb1- mice (red). B, Comparison of maximum and average swimming speeds. C, Comparison of time spent within the central region (A, light gray) and peripheral region (A, dark gray). D, Comparison of average total swimming distances (trajectory). E, Comparison of average number of turns (rotations). F, G, Hindlimb vestibular reflex test. F, An example of the test. A wild-type mouse pup mounted in the rotation device is shown from the rear. At rest (top), the pup holds its hindlimbs in a flexed position and its tail straight back. Red arrow indicates the right hindlimb. No movement is detected at the midpoint of the rotation (middle), but by full rotation (bottom) a marked extension of the right hindlimb has been elicited, and the tail has deviated to the same side and upward. G, Comparison of the average response rate in the hindlimb vestibular reflex test from P5 to P11. Error bars represent SEM. *p < 0.1, ****p < 0.005, *****p < 0.001.
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Figure 6: Behavioral effects of the Hoxb1- mutation in young mice. A–E, Open field swimming test. A, Typical swimming trajectories of wild-type (blue) and Hoxb1- mice (red). B, Comparison of maximum and average swimming speeds. C, Comparison of time spent within the central region (A, light gray) and peripheral region (A, dark gray). D, Comparison of average total swimming distances (trajectory). E, Comparison of average number of turns (rotations). F, G, Hindlimb vestibular reflex test. F, An example of the test. A wild-type mouse pup mounted in the rotation device is shown from the rear. At rest (top), the pup holds its hindlimbs in a flexed position and its tail straight back. Red arrow indicates the right hindlimb. No movement is detected at the midpoint of the rotation (middle), but by full rotation (bottom) a marked extension of the right hindlimb has been elicited, and the tail has deviated to the same side and upward. G, Comparison of the average response rate in the hindlimb vestibular reflex test from P5 to P11. Error bars represent SEM. *p < 0.1, ****p < 0.005, *****p < 0.001.

Mentions: Testing general motor capability in early postnatal life is challenging because during the first postnatal week rodents are not strong enough to bear their own weight with extended limbs (Muir 2000), and motor function develops gradually thereafter (Geisler et al., 1993; Brocard et al 1999; Clarac et al., 2004; Lelard et al., 2006). Thus, specially designed tests need to be used. Here, we used an open field swimming test to first assess general motor capacity, and a specially designed body rotation device to test specifically the vestibulospinal reflex as it manifests in the hindlimbs (Fig. 6A–G).


Loss of Projections, Functional Compensation, and Residual Deficits in the Mammalian Vestibulospinal System of Hoxb1-Deficient Mice.

Di Bonito M, Boulland JL, Krezel W, Setti E, Studer M, Glover JC - eNeuro (2015)

Behavioral effects of the Hoxb1- mutation in young mice. A–E, Open field swimming test. A, Typical swimming trajectories of wild-type (blue) and Hoxb1- mice (red). B, Comparison of maximum and average swimming speeds. C, Comparison of time spent within the central region (A, light gray) and peripheral region (A, dark gray). D, Comparison of average total swimming distances (trajectory). E, Comparison of average number of turns (rotations). F, G, Hindlimb vestibular reflex test. F, An example of the test. A wild-type mouse pup mounted in the rotation device is shown from the rear. At rest (top), the pup holds its hindlimbs in a flexed position and its tail straight back. Red arrow indicates the right hindlimb. No movement is detected at the midpoint of the rotation (middle), but by full rotation (bottom) a marked extension of the right hindlimb has been elicited, and the tail has deviated to the same side and upward. G, Comparison of the average response rate in the hindlimb vestibular reflex test from P5 to P11. Error bars represent SEM. *p < 0.1, ****p < 0.005, *****p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697082&req=5

Figure 6: Behavioral effects of the Hoxb1- mutation in young mice. A–E, Open field swimming test. A, Typical swimming trajectories of wild-type (blue) and Hoxb1- mice (red). B, Comparison of maximum and average swimming speeds. C, Comparison of time spent within the central region (A, light gray) and peripheral region (A, dark gray). D, Comparison of average total swimming distances (trajectory). E, Comparison of average number of turns (rotations). F, G, Hindlimb vestibular reflex test. F, An example of the test. A wild-type mouse pup mounted in the rotation device is shown from the rear. At rest (top), the pup holds its hindlimbs in a flexed position and its tail straight back. Red arrow indicates the right hindlimb. No movement is detected at the midpoint of the rotation (middle), but by full rotation (bottom) a marked extension of the right hindlimb has been elicited, and the tail has deviated to the same side and upward. G, Comparison of the average response rate in the hindlimb vestibular reflex test from P5 to P11. Error bars represent SEM. *p < 0.1, ****p < 0.005, *****p < 0.001.
Mentions: Testing general motor capability in early postnatal life is challenging because during the first postnatal week rodents are not strong enough to bear their own weight with extended limbs (Muir 2000), and motor function develops gradually thereafter (Geisler et al., 1993; Brocard et al 1999; Clarac et al., 2004; Lelard et al., 2006). Thus, specially designed tests need to be used. Here, we used an open field swimming test to first assess general motor capacity, and a specially designed body rotation device to test specifically the vestibulospinal reflex as it manifests in the hindlimbs (Fig. 6A–G).

Bottom Line: Several general motor skills appear unimpaired, but hindlimb vestibulospinal reflexes, which are mediated by the LVST, are greatly reduced.This functional deficit recovers, however, during the second postnatal week, indicating a substantial compensation for the missing LVST.Our results provide a comprehensive account of the developmental role of Hoxb1 in patterning the vestibular system and evidence for a remarkable developmental plasticity in the descending control of reflex limb movements.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Biology Valrose, UMR 7277, University of Nice Sophia Antipolis, 06108 Nice, France; Institute of Biology Valrose, INSERM, U1091, 06108 Nice, France; Institute of Biology Valrose, CNRS, UMR 7277, 06108 Nice, France.

ABSTRACT
The genetic mechanisms underlying the developmental and functional specification of brainstem projection neurons are poorly understood. Here, we use transgenic mouse tools to investigate the role of the gene Hoxb1 in the developmental patterning of vestibular projection neurons, with particular focus on the lateral vestibulospinal tract (LVST). The LVST is the principal pathway that conveys vestibular information to limb-related spinal motor circuits and arose early during vertebrate evolution. We show that the segmental hindbrain expression domain uniquely defined by the rhombomere 4 (r4) Hoxb1 enhancer is the origin of essentially all LVST neurons, but also gives rise to subpopulations of contralateral medial vestibulospinal tract (cMVST) neurons, vestibulo-ocular neurons, and reticulospinal (RS) neurons. In newborn mice homozygous for a Hoxb1- mutation, the r4-derived LVST and cMVST subpopulations fail to form and the r4-derived RS neurons are depleted. Several general motor skills appear unimpaired, but hindlimb vestibulospinal reflexes, which are mediated by the LVST, are greatly reduced. This functional deficit recovers, however, during the second postnatal week, indicating a substantial compensation for the missing LVST. Despite the compensatory plasticity in balance, adult Hoxb1- mice exhibit other behavioral deficits that manifest particularly in proprioception and interlimb coordination during locomotor tasks. Our results provide a comprehensive account of the developmental role of Hoxb1 in patterning the vestibular system and evidence for a remarkable developmental plasticity in the descending control of reflex limb movements. They also suggest an involvement of the lateral vestibulospinal tract in proprioception and in ensuring limb alternation generated by locomotor circuitry.

No MeSH data available.


Related in: MedlinePlus