| Content: | The ability of the adult brain to produce new neurons raises exciting possibilities for the development of new therapies to cure brain damage and neurodegenerative diseases. The success of such treatments will depend upon a full understanding of the molecular and cellular mechanisms that regulate not only production, maturation, integration and survival of neuronal precursors, but also their migration in the adult tissue. The adult subventricular zone (SVZ) – olfactory bulb (OB) pathway offers an ideal model to investigate the mechanisms of neuronal recruitment in the adult brain since massive neuronal migration occurs. Knowledge about the cellular and molecular cues that govern this neuronal migration can be used to try to direct the new cells to the site of lesion. Interestingly, following stroke the massive migration of endogenous neuronal precursors from their generation site (SVZ) to the damaged brain region has been observed. These observations suggest that strategy of re-routing of the migration of neuronal precursors might be already used by the injured/diseased brain as a repair/compensation mechanism. If so, then it also suggests that intervening in this process could be an effective therapy for degenerative diseases and brain injuries. Our laboratory recently uncovered that neuronal precursors in adult SVZ-OB pathway migrate along blood vessels. We also demonstrated that BDNF is an important signal in the regulation of this mechanism. The endothelial cells of blood vessels constitutively synthesize BDNF, which is released within the extracellular space and fosters neuronal migration via p75NTR expressed by migrating neuroblasts. Interestingly, astrocytes that contact blood vessels and ensheat migrating neuroblasts provide an important regulatory role in the BDNF-mediated neuronal migration, since they trap extracellular BDNF via TrkB receptors and therefore lead to the entry of migrating cells to the stationary phase. The aim of this study is to evaluate if BDNF is also a key player in the regulation of neuroblasts migrating in the ischemic striatum. We use transient (1 hour) middle cerebral artery occlusion (MCAO) model of ischemia. Immunofluorescent analysis for doublecortin, a marker of migrating cells, revealed a massive migration of neuronal precursors into the post-stroke striatum. Interestingly, about 82% of these migrating cells were found in close proximity to the blood vessels. Moreover, MCAO induces expression of BDNF in the post-stroke striatum where BDNF was immunodetected on the astrocyte’s processes and along the blood vessels on witch neuroblast migrates, in the pattern that resemble to the expression of this trophic factor in the SVZ-OB pathway. Our data suggests that molecular mechanisms used for the normal neuronal migration in the adult SVZ-OB pathway might be also re-activated in the ischemic striatum to re-route neuronal precursors to the damaged brain areas. The understanding of the signalling mechanisms that regulate neuronal migration in the normal and pathological adult brain is an essential prerequisite for the use of neural stem cells in future therapeutic approaches. |
