Long-term neurogenesis after stroke in the adult rat brain

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 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.