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Göteborgs universitets publikationer

Large-scale reconstitution of a retina-to-brain pathway in adult rats using gene therapy and bridging grafts: An anatomical and behavioral analysis

Författare och institution:
S. W. You (-); Mats Hellström (Institutionen för kliniska vetenskaper, sektionen för kvinnors och barns hälsa, Avdelningen för obstetrik och gynekologi); M. A. Pollett (-); C. LeVaillant (-); C. Moses (-); P. J. Rigby (-); M. Penrose (-); J. Rodger (-); A. R. Harvey (-)
Publicerad i:
Experimental Neurology, 279 s. 197-211
ISSN:
0014-4886
Publikationstyp:
Artikel, refereegranskad vetenskaplig
Publiceringsår:
2016
Språk:
engelska
Fulltextlänk:
Sammanfattning (abstract):
Peripheral nerve (PN) grafts can be used to bridge tissue defects in the CNS. Using a PN-to-optic nerve (ON) graft model, we combined gene therapy with pharmacotherapy to promote the long-distance regeneration of injured adult retinal ganglion cells (RGCs). Autologous sciatic nerve was sutured onto the transected ON and the distal end immediately inserted into contralateral superior colliculus (SC). Control rats received intraocular injections of saline or adeno-associated virus (AAV) encoding GFP. In experimental groups, three bi-cistronic AAV vectors encoding ciliary neurotrophic factor (CNTF) were injected into different regions of the grafted eye. Each vector encoded a different fluorescent reporter to assess retinotopic order in the regenerate projection. To encourage sprouting/synaptogenesis, after 6 weeks some AAV-CNTF injected rats received an intravitreal injection of recombinant brain-derived neurotrophic factor (rBDNF) or AAV-BDNF. Four months after surgery, cholera toxin B was used to visualize regenerate RGC axons. RGC viability and axonal regrowth into SC were significantly greater in AAV-CNTF groups. In some cases, near the insertion site, regenerate axonal density resembled retinal terminal densities seen in normal SC. Complex arbors were seen in superficial but not deep SC layers and many terminals were immunopositive for presynaptic proteins vGlut2 and SV2. There was improvement in visual function via the grafted eye with significantly greater pupillary constriction in both AAV-CNTF + BDNF groups. In both control and AAV-CNTF + rBDNF groups the extent of light avoidance correlated with the maximal distance of axonal penetration into superficial SC. Despite the robust regrowth of RGC axons back into the SC, axons originating from different parts of the retina were intermixed at the PN graft/host SC interface, indicating that there remained a lack of order in this extensive regenerate projection. (C) 2016 Elsevier Inc. All rights reserved.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
MEDICIN OCH HÄLSOVETENSKAP ->
Medicinska grundvetenskaper ->
Neurovetenskaper
MEDICIN OCH HÄLSOVETENSKAP ->
Klinisk medicin ->
Neurologi
Nyckelord:
Gene therapy, Peripheral nerve transplantation, Adult rat visual system, Axonal regeneration, ganglion-cell axons, optic-nerve regeneration, superior colliculus, visual-system, neurotrophic factor, synapse formation, guidance cues, cntf promotes, cyclic-amp, hamsters, Neurosciences & Neurology
Postens nummer:
236886
Posten skapad:
2016-05-25 08:55
Posten ändrad:
2016-05-25 08:56

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