Analysis of Proprioceptive Sensory Innervation of the Mouse Soleus: A Whole-Mount Muscle Approach

Sonner, Martha; Walters, Marie C.; Ladle, David R.

doi:10.1371/journal.pone.0170751

Cited by 16 publications

(27 citation statements)

References 39 publications

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“…Second, we showed that the cell bodies of Nxph1 + neurons are smaller than the average PV + neuron cell body size (mean cell body diameter 24.5 ± 0.4 μm for Nxph1 , n= 88 neurons; 27.6 ± 0.4 μm for PV , n= 183 neurons; p<0.001, Student’s t-test), consistent with the notion that type II afferent neurons are smaller in caliber than groups Ia or Ib neurons, (Matthews, 1972; Wu et al, 2019). Third, based on morphological observations that MS are typically innervated by one group Ia and one to two group II afferents, the ratio of cluster 1 (group Ia) to cluster 2-4 (putative group IIs) we observed (1:1.53) aligns with the expected ratio for group Ia:group II afferents (1:1.5) (Banks et al, 1982; data not shown; but see Sonner et al, 2017). To test if class 2-4 neurons represent group II afferents, we examined the expression of the class 4 marker Tachykinin 1 ( Tac1 ) in DRG and muscle.…”

Section: Resultssupporting

confidence: 79%

Molecular development of muscle spindle and Golgi tendon organ sensory afferents revealed by single proprioceptor transcriptome analysis

Oliver

Florez-Paz

Badea

et al. 2020

Preprint

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Anatomical and physiological analyses have long revealed differences between proprioceptive groups Ia, II, and Ib sensory neurons, yet the molecular correlates of these three muscle afferent subtypes remain unknown. We performed single cell RNA sequencing of genetically identified adult proprioceptors and, using unbiased bioinformatics approaches, detected five molecularly distinct neuronal clusters. Validation of cluster-specific transcripts in dorsal root ganglia (DRG) and skeletal muscle provides evidence these clusters correspond to functionally distinct muscle spindle (MS) or Golgi tendon organ (GTO) afferent proprioceptors. Remarkably, while we uncovered just one type of GTO afferents, four of the five clusters represent MS afferents, thus demonstrating a previously unappreciated diversity among these muscle proprioceptors. In vitro electrophysiological recordings reveal just two broadly distinct proprioceptor types, and suggest that the refinement of functional subtype diversity may occur along multiple axes of maturation. Lineage analysis between proprioceptor transcriptomes at different developmental stages show little or no correlation for transcripts that define adult MS or GTO afferents, supporting the idea that proprioceptor subtype identity emerges late in development. Together, our data provide the first comprehensive molecular signature for groups Ia and II MS afferents and group Ib GTO afferents, and offer new strategies for genetic interrogation of the role of these individual proprioceptor subtypes in regulating voluntary motor behavior.

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Section: Resultssupporting

confidence: 79%

Molecular development of muscle spindle and Golgi tendon organ sensory afferents revealed by single proprioceptor transcriptome analysis

Oliver

Florez-Paz

Badea

et al. 2020

Preprint

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“…2013; Sonner et al . 2017). To analyse the number of spindles per muscle, entire soleus muscles were cryosectioned and each section was stained with anti‐vGluT1 antibodies.…”

Section: Resultsmentioning

confidence: 99%

“…1989; Sonner et al . 2017). Type II afferents have so far not been detected in mice by immunohistochemical and electrophysiological methods (Wilkinson et al .…”

Section: Introductionmentioning

confidence: 99%

Impaired muscle spindle function in murine models of muscular dystrophy

Gerwin

Rossmanith

Haupt

et al. 2020

The Journal of Physiology

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Key points Muscular dystrophy patients suffer from progressive degeneration of skeletal muscle fibres, sudden spontaneous falls, balance problems, as well as gait and posture abnormalities. Dystrophin‐ and dysferlin‐deficient mice, models for different types of muscular dystrophy with different aetiology and molecular basis, were characterized to investigate if muscle spindle structure and function are impaired. The number and morphology of muscle spindles were unaltered in both dystrophic mouse lines but muscle spindle resting discharge and their responses to stretch were altered. In dystrophin‐deficient muscle spindles, the expression of the paralogue utrophin was substantially upregulated, potentially compensating for the dystrophin deficiency. The results suggest that muscle spindles might contribute to the motor problems observed in patients with muscular dystrophy. Abstract Muscular dystrophies comprise a heterogeneous group of hereditary diseases characterized by progressive degeneration of extrafusal muscle fibres as well as unstable gait and frequent falls. To investigate if muscle spindle function is impaired, we analysed their number, morphology and function in wildtype mice and in murine model systems for two distinct types of muscular dystrophy with very different disease aetiology, i.e. dystrophin‐ and dysferlin‐deficient mice. The total number and the overall structure of muscle spindles in soleus muscles of both dystrophic mouse mutants appeared unchanged. Immunohistochemical analyses of wildtype muscle spindles revealed a concentration of dystrophin and β‐dystroglycan in intrafusal fibres outside the region of contact with the sensory neuron. While utrophin was absent from the central part of intrafusal fibres of wildtype mice, it was substantially upregulated in dystrophin‐deficient mice. Single‐unit extracellular recordings of sensory afferents from muscle spindles of the extensor digitorum longus muscle revealed that muscle spindles from both dystrophic mouse strains have an increased resting discharge and a higher action potential firing rate during sinusoidal vibrations, particularly at low frequencies. The response to ramp‐and‐hold stretches appeared unaltered compared to the respective wildtype mice. We observed no exacerbated functional changes in dystrophin and dysferlin double mutant mice compared to the single mutant animals. These results show alterations in muscle spindle afferent responses in both dystrophic mouse lines, which might cause an increased muscle tone, and might contribute to the unstable gait and frequent falls observed in patients with muscular dystrophy.

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“…; Sonner et al . ). Afferent neurons generate action potentials with frequencies that are proportional to the size of the stretch and to the rate of stretching (De‐Doncker et al .…”

Section: Introductionmentioning

confidence: 97%

“…The central (equatorial) part of intrafusal muscle fibres is innervated by two types of afferent proprioceptive sensory neurons (termed 'type Ia afferents' and 'type II afferents' according to their axonal conduction velocity; Banks, 2015). Type Ia afferents form so called annulospiral sensory nerve endings whereas type II afferents flank the Ia afferents (Schroder et al 1989;Sonner et al 2017). Afferent neurons generate action potentials with frequencies that are proportional to the size of the stretch and to the rate of stretching (De-Doncker et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Acetylcholine receptors in the equatorial region of intrafusal muscle fibres modulate mouse muscle spindle sensitivity

Gerwin

Haupt

Wilkinson

et al. 2019

The Journal of Physiology

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Key points Acetylcholine receptors are aggregated in the central regions of intrafusal muscle fibres. Single unit muscle spindle afferent responses from isolated mouse extensor digitorum longus muscle were recorded in the absence of fusimotor input to ramp and hold stretches as well as to sinusoidal vibrations in the presence and absence of the acetylcholine receptor blockers d‐tubocurarine and α‐bungarotoxin. Proprioceptive afferent responses to both types of stretch were enhanced in the presence of either blocker. Blocking acetylcholine uptake and vesicular acetylcholine release by hemicholinium‐3 also enhanced stretch‐evoked responses. These results represent the first evidence that acetylcholine receptors negatively modulate muscle spindle responses to stretch. The data support the hypothesis that the sensory nerve terminal is able to release vesicles to fine‐tune proprioceptive afferent sensitivity. Abstract Muscle spindles are complex stretch‐sensitive mechanoreceptors. They consist of specialized skeletal muscle fibres, called intrafusal fibres, which are innervated in the central (equatorial) region by afferent sensory axons and in both polar regions by efferent γ‐motoneurons. Previously it was shown that acetylcholine receptors (AChR) are concentrated in the equatorial region at the contact site between the sensory neuron and the intrafusal muscle fibre. To address the function of these AChRs, single unit sensory afferents were recorded from an isolated mouse extensor digitorum longus muscle in the absence of γ‐motoneuron activity. Specifically, we investigated the responses of individual sensory neurons to ramp‐and‐hold stretches and sinusoidal vibrations before and after the addition of the competitive and non‐competitive AChR blockers d‐tubocurarine and α‐bungarotoxin, respectively. The presence of either drug did not affect the resting action potential discharge frequency. However, the action potential frequencies in response to stretch were increased. In particular, frequencies of the dynamic peak and dynamic index to ramp‐and‐hold stretches were significantly higher in the presence of either drug. Treatment of muscle spindle afferents with the high‐affinity choline transporter antagonist hemicholinium‐3 similarly increased muscle spindle afferent firing frequencies during stretch. Moreover, the firing rate during sinusoidal vibration stimuli at low amplitudes was higher in the presence of α‐bungarotoxin compared to control spindles also indicating an increased sensitivity to stretch. Collectively these data suggest a modulation of the muscle spindle afferent response to stretch by AChRs in the central region of intrafusal fibres possibly fine‐tuning muscle spindle sensitivity.

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Analysis of Proprioceptive Sensory Innervation of the Mouse Soleus: A Whole-Mount Muscle Approach

Cited by 16 publications

References 39 publications

Molecular development of muscle spindle and Golgi tendon organ sensory afferents revealed by single proprioceptor transcriptome analysis

Molecular development of muscle spindle and Golgi tendon organ sensory afferents revealed by single proprioceptor transcriptome analysis

Impaired muscle spindle function in murine models of muscular dystrophy

Acetylcholine receptors in the equatorial region of intrafusal muscle fibres modulate mouse muscle spindle sensitivity

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