Neumann, Simona; (1997) A-fibre plasticity: Phenotype switch and regenerative capacity. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Primary sensory neurones are a heterogeneous group of cells, highly specialised to transduce environmental stimuli and transmit the resulting information centrally. This information is carried by two types of fibres: C-fibres which are associated with small cell bodies in the dorsal root ganglia and possess unmyelinated axons; and A-fibres, which are associated with medium and large sized dorsal root ganglion cells and possess myelinated fibres. The present study has concentrated on the changes in phenotype and growth capacity of A-fibres following inflammation and central nervous system injury, respectively. The effect of peripheral inflammation in changing the phenotype of A-fibre primary sensory neurones was first assessed. The tachykinin substance-P is significantly increased following the induction of inflammation. However, the phenotype of cells that become positively labelled has not been previously characterised. A retrograde labelling technique that identifies cells with myelinated axons, combined with immunohistochemistry for substance-P, was used to assess whether substance-P is expressed in cells with myelinated axons following the induction of inflammation. It was found that there is a shift in the phenotype of myelinated fibres innervating the inflamed tissue to one resembling C-fibres. The peripheral branch of sensory neurones is capable of regeneration and can reinnervate peripheral targets after injury. However, the central branch of sensory neurones in the central nervous system shows very limited regenerative capacity. In this part of the study the regenerative capacity of injured dorsal column axons was assessed using different manipulations. These included: conditioning the dorsal column fibres into a growth state by a peripheral transection; neutralising an myelin-associated inhibitory protein using the IN-1 antibody; and a combination of the two techniques. A retrograde labelling technique, with a tracer specific for A-fibres, was employed. It was found that while IN-1 antibodies improve the microenvironment in which the injured fibres regenerate, enabling them to grow into the lesion site and beyond, a conditioning peripheral lesion by enhancing the intrinsic growth capacity of the neurones, enabled the injured axons to grow extensively in the lesion site, on the surface of the cord and into the glial scar. In some animals fibres regrew all the way back into the dorsal column nuclei, demonstrating that successful regeneration of a long ascending spinal cord tract can be achieved in the adult rat. These findings indicate that the phenotype of A-fibres is not fixed but can alter. Inflammation alters the transmitter/neuromodulator content of these fibres in an NGF- dependent fashion while peripheral nerve lesion enhances the growth capacity of central A-fibre axons. An understanding of the signal mechanisms that initiate and control these transcription-dependent changes offers the possibility of understanding the pathophysiology of inflammatory pain and spinal cord injury.

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