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Long-term neurogenesis after stroke in the adult rat brain

Thored, Pär LU (2007)
Abstract (Swedish)
Popular Abstract in Swedish

Stroke är en av de ledande dödsorsakerna i västvärlden och det finns idag ingen behandling för funktionell återställning. Efter stroke ökar den striatala neurogenesen och de nybildade neuroblasterna vandrar mot det skadade området. Denna respons har ansetts vara av akut och övergående art. I denna avhandling har en modell av experimentell stroke använts (2 h of middle cerebral artery occlusion, MCAO) för att studera tre aspekter av den stroke-inducerade neurogenesen: 1) de långtida effekterna som stroke har på den striatala neurogenesen, 2) relationen mellan angiogenes och neurogenes, samt vaskulaturens inbladning neuroblasternas migration, och 3) de effekter som nervväxtfaktorn GDNF har på... (More)
Popular Abstract in Swedish

Stroke är en av de ledande dödsorsakerna i västvärlden och det finns idag ingen behandling för funktionell återställning. Efter stroke ökar den striatala neurogenesen och de nybildade neuroblasterna vandrar mot det skadade området. Denna respons har ansetts vara av akut och övergående art. I denna avhandling har en modell av experimentell stroke använts (2 h of middle cerebral artery occlusion, MCAO) för att studera tre aspekter av den stroke-inducerade neurogenesen: 1) de långtida effekterna som stroke har på den striatala neurogenesen, 2) relationen mellan angiogenes och neurogenes, samt vaskulaturens inbladning neuroblasternas migration, och 3) de effekter som nervväxtfaktorn GDNF har på striatal neurogenes.



Efter 2 h av MCAO ökade den striatala neurogenesen inom en vecka efter stroke, och fortsatte att vara uppreglerad under flera månader. Genom att märka in de nybildade cellerna med tymidin-analogen BrdU upptäcktes det att neuroblaster som fötts både tidigt och sent efter stroke var kapabla att bilda mogna nervceller, och att vissa av de celler som fötts tidigt efter stroke överlevde i 4 månader efter insulten. Dessa fynd visar på en mycket långtida neurogenes efter stroke.



Celldelning i subventrikulära zone (SVZ) upptäcktes 4 dagar efter MCAO, och volymen av SVZ ökade, och fortsatte att vara expanderad under flera månader efter stroke. Den ipsilaterala SVZ bildade fler och större s.k. neurosfärer än den contralaterala sidan flera veckor efter skadan. Således inducerar stroke långtida förändringar i stamcellsnichen i SVZ.



Densiteten av blodkärl uppskattades efter MCAO i både SVZ och i striatum strax utanför. Kärldensiteten i SVZ förändrades inte på lång sikt, men ökade i den mest dorsala delen av striatum flera månader efter stroke. Låggradig angiogenes upptäcktes också i detta område tidigt efter MCAO. De nybildade nervcellerna i detta område återfanns mycket nära blodkärlen. Efter att ha blockerat cellsignaleringen genom SDF-1?/CXCR4, en signalering som visats vara involverad i cellmigration, vandrade de nybildade nervcellerna i mindre utsträckning. Dessa fynd visar att de neuroblaster som bildats efter stroke vandrar, i nära association med blodkärlen, genom ett område med ökad kärldensitet och övergående angiogenes.



När GDNF sprutades in i striatum direkt efter MCAO ökade mRNA-nivåerna av GDNF receptorn GFR?1 i SVZ, liksom celldelningen. När GDNF sprutades in senare överlevde de nervceller som bildats efter stroke längre.



Resultaten i denna avhandling visar på en fortgående, långtida nervcellsnybildning efter stroke. Stamcellsnichen i SVZ förändras på lång sikt, liksom den striatala vaskulariseringen. De nybildade nervcellerna vandrar genom ett område med ökad kärldensitet, i nära association med blodkärlen. GDNF ökar den striatala neurogenesen efter stroke och ökar den överlevnaden av de nybildade cellerna. Genom att hitta nya sätt att öka vaskulariseringen, samt förbättra överlevnaden och mognaden av de nya nervcellerna skulle man kunna hitta nya behandlingar för patienter som drabbats av stroke. (Less)
Abstract
Stroke is a leading cause of death and disability for which there is no treatment for functional recovery. Following stroke, striatal neurogenesis is increased, with newly formed neuroblasts migrating towards the damage. This response has so far been considered acute and transient.



In this thesis, a model of experimental stroke (2 h of middle cerebral artery occlusion, MCAO) used to study three aspects of stroke-induced neurogenesis: 1) the long-term effects of stroke on striatal neurogenesis, 2) the relation between angiogenesis and neurogenesis and the vasculature's involvement in neuroblast migration, and 3) the effects of GDNF on striatal neurogenesis. After 2 h of MCAO, striatal neurogenesis was induced within a... (More)
Stroke is a leading cause of death and disability for which there is no treatment for functional recovery. Following stroke, striatal neurogenesis is increased, with newly formed neuroblasts migrating towards the damage. This response has so far been considered acute and transient.



In this thesis, a model of experimental stroke (2 h of middle cerebral artery occlusion, MCAO) used to study three aspects of stroke-induced neurogenesis: 1) the long-term effects of stroke on striatal neurogenesis, 2) the relation between angiogenesis and neurogenesis and the vasculature's involvement in neuroblast migration, and 3) the effects of GDNF on striatal neurogenesis. After 2 h of MCAO, striatal neurogenesis was induced within a week after stroke, and remained elevated for several months. Labeling of newly formed cells with the thymidine analogue BrdU, showed that neuroblasts born early and late after MCAO were able to generate mature neurons, and that some of the neurons born early after MCAO were able to survive for 4 months. These findings demonstrate a long-term striatal neurogenesis after stroke.



Proliferation in the subventicular zone (SVZ) was detected 4 days after MCAO, and the volume was increased, and remained expanded for several months after stroke. The ipsilateral SVZ generated more and larger neurospheres than contralateral sevaral weeks after stroke. Thus, stroke induces long-term changes in the SVZ stem cell niche.



The blood vessel density was estimated after MCAO in the SVZ and the striatum adjacent to the SVZ. Vessel density in the SVZ was not altered long-term, but was increased in the most dorsal part of the striatum several months after stroke. Low-grade angiogenesis was also detected within this area early after MCAO. The neuroblasts in this area were found very close to the vessels. After blocking signaling through the SDF-1?/CXCR4 pathway, involved in migration, the neuroblasts migrated less. These findings show that the stroke-generated neuroblasts migrate through an area with increased vessel density and transient angiogenesis, closely associated with vessels.



When GDNF was infused into the striatum after MCAO, the mRNA levels of the GDNF receptor GFR?1 were increased, as well as SVZ cell proliferation. GDNF infused late after MCAO increased neuronal survival.



The results in this thesis show persistent, long-term neurogenesis after stroke. The SVZ is altered long-term after stroke, as is the striatal vasculature. The new neurons migrate through an area of increased vessel density long-term, closely associated with the vessels. GDNF increases neurogenesis after stroke, and promotes neuronal survival. Increasing the vascularization and improving the maturation of the neurons could lead to new treatments for stroke-patients. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Kuhn, Hans-Georg, Sahlgrenska University Hospital, Gothenburg
organization
publishing date
type
Thesis
publication status
published
subject
keywords
embryologi (människa), Neurology, neuropsychology, neurophysiology, Utvecklingsbiologi, teratologi, embryology (human), ontogeny, Development biology, teratology, Stroke, Stem Cells, Neurogenesis, neurofysiologi, Clinical biology, Klinisk biologi, Neurologi, neuropsykologi
pages
112 pages
publisher
Lund University Medical Faculty
defense location
Segerfalkssalen, BMC A-10 Sölvegatan 17 Lund
defense date
2007-06-15 09:15
ISSN
1652-8220
ISBN
978-91-85559-76-3
language
English
LU publication?
yes
id
8c5e2c47-107f-4f1d-8785-60aaa56b4290 (old id 548840)
date added to LUP
2007-09-12 09:58:13
date last changed
2016-09-19 08:44:58
@phdthesis{8c5e2c47-107f-4f1d-8785-60aaa56b4290,
  abstract     = {Stroke is a leading cause of death and disability for which there is no treatment for functional recovery. Following stroke, striatal neurogenesis is increased, with newly formed neuroblasts migrating towards the damage. This response has so far been considered acute and transient.<br/><br>
<br/><br>
In this thesis, a model of experimental stroke (2 h of middle cerebral artery occlusion, MCAO) used to study three aspects of stroke-induced neurogenesis: 1) the long-term effects of stroke on striatal neurogenesis, 2) the relation between angiogenesis and neurogenesis and the vasculature's involvement in neuroblast migration, and 3) the effects of GDNF on striatal neurogenesis. After 2 h of MCAO, striatal neurogenesis was induced within a week after stroke, and remained elevated for several months. Labeling of newly formed cells with the thymidine analogue BrdU, showed that neuroblasts born early and late after MCAO were able to generate mature neurons, and that some of the neurons born early after MCAO were able to survive for 4 months. These findings demonstrate a long-term striatal neurogenesis after stroke.<br/><br>
<br/><br>
Proliferation in the subventicular zone (SVZ) was detected 4 days after MCAO, and the volume was increased, and remained expanded for several months after stroke. The ipsilateral SVZ generated more and larger neurospheres than contralateral sevaral weeks after stroke. Thus, stroke induces long-term changes in the SVZ stem cell niche.<br/><br>
<br/><br>
The blood vessel density was estimated after MCAO in the SVZ and the striatum adjacent to the SVZ. Vessel density in the SVZ was not altered long-term, but was increased in the most dorsal part of the striatum several months after stroke. Low-grade angiogenesis was also detected within this area early after MCAO. The neuroblasts in this area were found very close to the vessels. After blocking signaling through the SDF-1?/CXCR4 pathway, involved in migration, the neuroblasts migrated less. These findings show that the stroke-generated neuroblasts migrate through an area with increased vessel density and transient angiogenesis, closely associated with vessels.<br/><br>
<br/><br>
When GDNF was infused into the striatum after MCAO, the mRNA levels of the GDNF receptor GFR?1 were increased, as well as SVZ cell proliferation. GDNF infused late after MCAO increased neuronal survival.<br/><br>
<br/><br>
The results in this thesis show persistent, long-term neurogenesis after stroke. The SVZ is altered long-term after stroke, as is the striatal vasculature. The new neurons migrate through an area of increased vessel density long-term, closely associated with the vessels. GDNF increases neurogenesis after stroke, and promotes neuronal survival. Increasing the vascularization and improving the maturation of the neurons could lead to new treatments for stroke-patients.},
  author       = {Thored, Pär},
  isbn         = {978-91-85559-76-3},
  issn         = {1652-8220},
  keyword      = {embryologi (människa),Neurology,neuropsychology,neurophysiology,Utvecklingsbiologi,teratologi,embryology (human),ontogeny,Development biology,teratology,Stroke,Stem Cells,Neurogenesis,neurofysiologi,Clinical biology,Klinisk biologi,Neurologi,neuropsykologi},
  language     = {eng},
  pages        = {112},
  publisher    = {Lund University Medical Faculty},
  school       = {Lund University},
  title        = {Long-term neurogenesis after stroke in the adult rat brain},
  year         = {2007},
}