Dynamic imaging reveals that brain-derived neurotrophic factor can independently regulate motility and direction of neuroblasts within the rostral migratory stream

Abstract

Neuronal precursors generated in the subventricular zone (SVZ) migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB). Although, the mechanisms regulating this migration remain largely unknown, studies have suggested that molecular factors, such as Brain-Derived Neurotrophic Factor (BDNF) emanating from the OB, may function as chemoattractants drawing neuroblasts toward their target. To better understand the role of BDNF in RMS migration, we used an acute slice preparation from early postnatal mice to track the tangential migration of GAD65-GFP labeled RMS neuroblasts with confocal time-lapse imaging. By quantifying the cell dynamics using specific directional and motility criteria, our results showed that removal of the OB did not alter the overall directional trajectory of neuroblasts, but did reduce their motility. This suggested that additional guidance factors may be present locally within the RMS. Thus, we next demonstrated that BDNF and its high affinity receptor, TrkB, are indeed heterogeneously expressed within the RMS at postnatal day 7, and by altering BDNF levels within the entire pathway, showed that reduced BDNF signaling changes both neuroblast motility and direction, while increased BDNF levels changes only motility. Together these data reveal that during this early postnatal period BDNF plays a complex role in regulating both the motility and direction of RMS flow, and that it arises from within the RMS itself, as well as from the olfactory bulb.

Abnormal Neuronal Migration Changes the Fate of Developing Neurons in the Postnatal Olfactory Bulb

“…In this context, DCX is required directly in migrating cells for the appropriate cytoskeletal dynamic and could also regulate the intracellular signaling and trafficking required to sense external signals that direct tangential migration. Among others, BDNF is a recent candidate that has been demonstrated to regulate bidirectional RMS flow via different receptors such as TrkB (Bagley and Belluscio, 2010) and p75NTR (Snapyan et al, 2009). …”

Improving neurorepair in stroke brain through endogenous neurogenesis-enhancing drugs

“…Noteworthy, among these drugs tested in preclinical stroke models that may confer protection of the cerebrovasculature include endogenous neurogenesis-enhancing drugs, including those discussed above. [9][10][11][12][18][19][20]23,25,34 Other drugs examined as potentially exerting anti-HT features include those that preserve the BBB and those directly enhancing the brain vasculatures. However, despite encouraging laboratory evidence demonstrating amelioration of HT in stroke animals, optimization of the drug regimen, including the dose, timing, and route of administration, remains to be determined in order to translate these findings into clinical applications.…”

“…In nonstroke animals, BDNF has been shown to enhance migration of NPCs from the SVZ toward the olfactory bulbs. [18][19][20] In stroke animals, systemic administration of BDNF enhanced the recruitment of NPCs into the lesioned site. 21 Atorvastatin, a chemical that activates the expression of BDNF, enhanced migration of SVZ cells.…”

An update on stem cell therapy for neurological disorders: cell death pathways as therapeutic targets

“…For example, the article refers to a key study in which post-treatment with BMP7 enhanced recovery of sensorimotor function in the impaired limbs, decreased body asymmetry, and increased locomotor activity [19]. Also, a recent study demonstrated how administration of BDNF enhanced migration of NPCs from SVZ toward the olfactory bulbs of the animal [20][21][22]. The present paper also emphasizes the importance of preventative measures in the pre-stroke period, particularly discussing the peptide cocaine and amphetamine-regulated transcript (CART) and its potential to reduce cerebral infarction in mice.…”