Sciatic nerve injury in adult rats causes distinct changes in the central projections of sensory neurons expressing different glial cell line‐derived neurotrophic factor family receptors

Keast, Janet R.; Forrest, Shelley L.; Osborne, Peregrine B.

doi:10.1002/cne.22378

Cited by 31 publications

(47 citation statements)

References 81 publications

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“…Several earlier studies reported an increase in the number of cells expressing GFRα3 after injury (3,8,14,26). In contrast, we found decreased GFRα3 levels in DRG neurons shortly after DR crush that persisted for at least 12 d (Fig.…”

Section: Discussioncontrasting

confidence: 39%

“…Some previous studies have suggested that GFRα3, the high-affinity binding partner of ARTN, is expressed predominantly in small, unmyelinated sensory neurons, with limited to no expression in large, myelinated neurons (8,9,13,14). Nevertheless, myelinated fibers regenerate after ARTN treatment, suggesting that GFRα3 may be more widely expressed than previously reported.…”

Section: Gfrα3 Is Present In Both Myelinated and Unmyelinated Sensorymentioning

confidence: 80%

“…Previous studies have suggested that GFRα3 is expressed only rarely on myelinated sensory neurons (8,9,14), yet ARTN promotes robust regeneration of myelinated sensory axons (3,6,25). Given this inconsistency, we devised a method to quantify GFRα3 in specific populations of cells, and found similar expression in myelinated neurons and unmyelinated neurons.…”

Section: Discussionmentioning

confidence: 94%

“…Previous studies indicated that GFRα3 is up-regulated after axonal injury (3,8,14). We assessed the effects of DR crush on GFRα3 gene expression using qPCR.…”

Section: Gfrα3 Is Present In Both Myelinated and Unmyelinated Sensorymentioning

confidence: 99%

“…Earlier studies suggested that GFRα3 is expressed primarily in small sensory neurons, with limited expression in large neurons (8,9); thus, how ARTN promotes robust regeneration of large sensory axons is unclear.…”

mentioning

confidence: 99%

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Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush

Wong

Gibson

Arnold

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Recovery after a spinal cord injury often requires that axons restore synaptic connectivity with denervated targets several centimeters from the site of injury. Here we report that systemic artemin (ARTN) treatment promotes the regeneration of sensory axons to the brainstem after brachial dorsal root crush in adult rats. ARTN not only stimulates robust regeneration of large, myelinated sensory axons to the brainstem, but also promotes functional reinnervation of the appropriate target region, the cuneate nucleus. ARTN signals primarily through the RET tyrosine kinase, an interaction that requires the nonsignaling coreceptor GDNF family receptor (GFRα3). Previous studies reported limited GFRα3 expression on large sensory neurons, but our findings demonstrate that ARTN promotes robust regeneration of large, myelinated sensory afferents. Using a cell sorting technique, we demonstrate that GFRα3 expression is similar in myelinated and unmyelinated adult sensory neurons, suggesting that ARTN likely induces long-distance regeneration by binding GFRα3 and RET. Although ARTN is delivered for just 2 wk, regeneration to the brainstem requires more than 3 mo, suggesting that brief trophic support may initiate intrinsic growth programs that remain active until targets are reached. Given its ability to promote targeted functional regeneration to the brainstem, ARTN may represent a promising therapy for restoring sensory function after spinal cord injury.artemin | GFRα3 | regeneration | dorsal root crush | cuneate nucleus S pinal cord (SC) injury results in permanent paresis and paralysis, owing in large part to the failure of axons to regenerate. In the adult SC, axons do not regenerate because of myelin-and injury-associated inhibitory barriers and a limited intrinsic regenerative ability (1). Although there has been some success in removing extrinsic barriers and providing neurotrophic factors to promote functional regeneration over short distances (2-4), meaningful functional recovery requires that damaged axons regenerate and reconnect with their original targets, often centimeters away from the lesion. Studies in which damaged sensory axons were induced to regenerate to the brainstem have failed to show reestablishment of synapses (5). These findings cast doubt on whether sensory axons can regenerate functionally to the brainstem. Dorsal root (DR) crush provides a useful model for studying long-distance axon regeneration without affecting the architecture of the SC. Fine touch and proprioceptive neurons with cell bodies in the DR ganglion (DRG) provide monosynaptic input to neurons in the dorsal column nuclei. These neurons can be traced using transganglionic labeling methods and are easily studied electrophysiologically, making this an ideal injury model for investigating functional regeneration from the brachial SC to the brainstem.Previous studies demonstrated that a 2-wk systemic treatment with the neurotrophic factor artemin (ARTN) promotes topographically specific regeneration of both myelinated and unmyelinated s...

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Section: Discussioncontrasting

confidence: 39%

Section: Gfrα3 Is Present In Both Myelinated and Unmyelinated Sensorymentioning

confidence: 80%

Section: Discussionmentioning

confidence: 94%

“…Previous studies indicated that GFRα3 is up-regulated after axonal injury (3,8,14). We assessed the effects of DR crush on GFRα3 gene expression using qPCR.…”

Section: Gfrα3 Is Present In Both Myelinated and Unmyelinated Sensorymentioning

confidence: 99%

mentioning

confidence: 99%

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Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush

Wong

Gibson

Arnold

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Decellularized Biohybrid Nerve Promotes Motor Axon Projections

Mehta,

Zhang,

Xie

et al. 2024

Adv Healthcare Materials

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Developing nerve grafts with intact mesostructures, superior conductivity, minimal immunogenicity, and improved tissue integration is essential for the treatment and restoration of neurological dysfunctions. A key factor is promoting directed axon growth into the grafts. To achieve this, biohybrid nerves are developed using decellularized rat sciatic nerve modified by in situ polymerization of poly(3,4‐ethylenedioxythiophene) (PEDOT). Nine biohybrid nerves are compared with varying polymerization conditions and cycles, selecting the best candidate through material characterization. These results show that a 1:1 ratio of FeCl3 oxidant to ethylenedioxythiophene (EDOT) monomer, cycled twice, provides superior conductivity (>0.2 mS cm−1), mechanical alignment, intact mesostructures, and high compatibility with cells and blood. To test the biohybrid nerve's effectiveness in promoting motor axon growth, human Spinal Cord Spheroids (hSCSs) derived from HUES 3 Hb9:GFP cells are used, with motor axons labeled with green fluorescent protein (GFP). Seeding hSCS onto one end of the conduit allows motor axon outgrowth into the biohybrid nerve. The construct effectively promotes directed motor axon growth, which improves significantly after seeding the grafts with Schwann cells. This study presents a promising approach for reconstructing axonal tracts in humans.

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Morphological and functional characterization of cholinergic interneurons in the dorsal horn of the mouse spinal cord

Mesnage

Gaillard

Godin

et al. 2011

J of Comparative Neurology

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Endogenous acetylcholine is an important modulator of sensory processing, especially at the spinal level, where nociceptive (pain-related) stimuli enter the central nervous system and are integrated before being relayed to the brain. To decipher the organization of the local cholinergic circuitry in the spinal dorsal horn, we used transgenic mice expressing enchanced green fluorescent protein specifically in cholinergic neurons (ChAT::EGFP) and characterized the morphology, neurochemistry, and firing properties of the sparse population of cholinergic interneurons in this area. Three-dimensional reconstruction of lamina III ChAT::EGFP neurons based either on their intrinsic fluorescence or on intracellular labeling in live tissue demonstrated that these neurons have long and thin processes that grow preferentially in the dorsal direction. Their dendrites and axon are highly elongated in the rostrocaudal direction, beyond the limits of a single spinal segment. These unique morphological features suggest that dorsal horn cholinergic interneurons are the main contributors to the plexus of cholinergic processes located in lamina IIi, just dorsal to their cell bodies. In addition, immunostainings demonstrated that dorsal horn cholinergic interneurons in the mouse are γ-aminobutyric acidergic and express nitric oxide synthase, as in rats. Finally, electrophysiological recordings from these neurons in spinal cord slices demonstrate that two-thirds of them have a repetitive spiking pattern with frequent rebound spikes following hyperpolarization. Altogether our results indicate that, although they are rare, the morphological and functional features of cholinergic neurons enable them to collect segmental information in superficial layers of the dorsal horn and to modulate it over several segments.

show abstract

Sciatic nerve injury in adult rats causes distinct changes in the central projections of sensory neurons expressing different glial cell line‐derived neurotrophic factor family receptors

Cited by 31 publications

References 81 publications

Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush

Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush

Decellularized Biohybrid Nerve Promotes Motor Axon Projections

Morphological and functional characterization of cholinergic interneurons in the dorsal horn of the mouse spinal cord

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