The impact of motor axon misdirection and attrition on behavioral deficit following experimental nerve injuries.

Peripheral nerve transection and neuroma-in-continuity injuries are associated with permanent functional deficits, often despite successful end-organ reinnervation. Axonal misdirection with non-specific reinnervation, frustrated regeneration and axonal attrition are believed to be among the anatomic...

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Main Authors: Jacob Daniel de Villiers Alant, Ferry Senjaya, Aleksandra Ivanovic, Joanne Forden, Antos Shakhbazau, Rajiv Midha
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2013-01-01
Series:PLoS ONE
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24282624/pdf/?tool=EBI
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spelling doaj-56a7a5bad1364580a67b977a7c4b3c622021-03-03T20:18:37ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e8254610.1371/journal.pone.0082546The impact of motor axon misdirection and attrition on behavioral deficit following experimental nerve injuries.Jacob Daniel de Villiers AlantFerry SenjayaAleksandra IvanovicJoanne FordenAntos ShakhbazauRajiv MidhaPeripheral nerve transection and neuroma-in-continuity injuries are associated with permanent functional deficits, often despite successful end-organ reinnervation. Axonal misdirection with non-specific reinnervation, frustrated regeneration and axonal attrition are believed to be among the anatomical substrates that underlie the poor functional recovery associated with these devastating injuries. Yet, functional deficits associated with axonal misdirection in experimental neuroma-in-continuity injuries have not yet been studied. We hypothesized that experimental neuroma-in-continuity injuries would result in motor axon misdirection and attrition with proportional persistent functional deficits. The femoral nerve misdirection model was exploited to assess major motor pathway misdirection and axonal attrition over a spectrum of experimental nerve injuries, with neuroma-in-continuity injuries simulated by the combination of compression and traction forces in 42 male rats. Sciatic nerve injuries were employed in an additional 42 rats, to evaluate the contribution of axonal misdirection to locomotor deficits by a ladder rung task up to 12 weeks. Retrograde motor neuron labeling techniques were utilized to determine the degree of axonal misdirection and attrition. Characteristic histological neuroma-in-continuity features were demonstrated in the neuroma-in-continuity groups and poor functional recovery was seen despite successful nerve regeneration and muscle reinnervation. Good positive and negative correlations were observed respectively between axonal misdirection (p<.0001, r(2)=.67), motor neuron counts (attrition) (p<.0001, r(2)=.69) and final functional deficits. We demonstrate prominent motor axon misdirection and attrition in neuroma-in-continuity and transection injuries of mixed motor nerves that contribute to the long-term functional deficits. Although widely accepted in theory, to our knowledge, this is the first experimental evidence to convincingly demonstrate these correlations with data inclusive of the neuroma-in-continuity spectrum. This work emphasizes the need to focus on strategies that promote both robust and accurate nerve regeneration to optimize functional recovery. It also demonstrates that clinically relevant neuroma-in-continuity injuries can now also be subjected to experimental investigation.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24282624/pdf/?tool=EBI
collection DOAJ
language English
format Article
sources DOAJ
author Jacob Daniel de Villiers Alant
Ferry Senjaya
Aleksandra Ivanovic
Joanne Forden
Antos Shakhbazau
Rajiv Midha
spellingShingle Jacob Daniel de Villiers Alant
Ferry Senjaya
Aleksandra Ivanovic
Joanne Forden
Antos Shakhbazau
Rajiv Midha
The impact of motor axon misdirection and attrition on behavioral deficit following experimental nerve injuries.
PLoS ONE
author_facet Jacob Daniel de Villiers Alant
Ferry Senjaya
Aleksandra Ivanovic
Joanne Forden
Antos Shakhbazau
Rajiv Midha
author_sort Jacob Daniel de Villiers Alant
title The impact of motor axon misdirection and attrition on behavioral deficit following experimental nerve injuries.
title_short The impact of motor axon misdirection and attrition on behavioral deficit following experimental nerve injuries.
title_full The impact of motor axon misdirection and attrition on behavioral deficit following experimental nerve injuries.
title_fullStr The impact of motor axon misdirection and attrition on behavioral deficit following experimental nerve injuries.
title_full_unstemmed The impact of motor axon misdirection and attrition on behavioral deficit following experimental nerve injuries.
title_sort impact of motor axon misdirection and attrition on behavioral deficit following experimental nerve injuries.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2013-01-01
description Peripheral nerve transection and neuroma-in-continuity injuries are associated with permanent functional deficits, often despite successful end-organ reinnervation. Axonal misdirection with non-specific reinnervation, frustrated regeneration and axonal attrition are believed to be among the anatomical substrates that underlie the poor functional recovery associated with these devastating injuries. Yet, functional deficits associated with axonal misdirection in experimental neuroma-in-continuity injuries have not yet been studied. We hypothesized that experimental neuroma-in-continuity injuries would result in motor axon misdirection and attrition with proportional persistent functional deficits. The femoral nerve misdirection model was exploited to assess major motor pathway misdirection and axonal attrition over a spectrum of experimental nerve injuries, with neuroma-in-continuity injuries simulated by the combination of compression and traction forces in 42 male rats. Sciatic nerve injuries were employed in an additional 42 rats, to evaluate the contribution of axonal misdirection to locomotor deficits by a ladder rung task up to 12 weeks. Retrograde motor neuron labeling techniques were utilized to determine the degree of axonal misdirection and attrition. Characteristic histological neuroma-in-continuity features were demonstrated in the neuroma-in-continuity groups and poor functional recovery was seen despite successful nerve regeneration and muscle reinnervation. Good positive and negative correlations were observed respectively between axonal misdirection (p<.0001, r(2)=.67), motor neuron counts (attrition) (p<.0001, r(2)=.69) and final functional deficits. We demonstrate prominent motor axon misdirection and attrition in neuroma-in-continuity and transection injuries of mixed motor nerves that contribute to the long-term functional deficits. Although widely accepted in theory, to our knowledge, this is the first experimental evidence to convincingly demonstrate these correlations with data inclusive of the neuroma-in-continuity spectrum. This work emphasizes the need to focus on strategies that promote both robust and accurate nerve regeneration to optimize functional recovery. It also demonstrates that clinically relevant neuroma-in-continuity injuries can now also be subjected to experimental investigation.
url https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24282624/pdf/?tool=EBI
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