The journey undertaken by newborn neurons in the adult mouse brain is like the cellular equivalent of the arduous upstream migration of salmon returning to their hatching river. Soon after being born in the subventricular zone near the back of the brain, these cells embark on a long-distance migration to the front-most tip of the brain. Their final destination – the olfactory bulb – is the furthest point from their birth place, and they travel two-thirds of the length of the brain to get there.

Several years ago, a team of researchers from Canada showed that the pathway for this migration – called the rostral migratory stream – is lined with a scaffold of capillaries, and that the young cells crawl along the blood vessels during their journey. In a follow-up study, they now report that the construction and organization of the blood vessel scaffold is orchestrated by star-shaped cells called astrocytes.



Cell migration is a key feature of the developing brain, and the mechanisms underlying these cell movements are well characterised. As a general rule, migrating cells rely on the combined activity of chemical signals to find their way. They set off on their migration in response to a repulsive signal that pushes them away from their birth place and stay on track because their migratory pathway is flanked by a non-permissive signal which prevents them from deviating from the correct route. Finally, as they approach the end of their journey, attractive cues pull them in the right direction. Upon arriving at their destination, the cells turn and migrate into the bulb, then integrate into the existing neural circuits and participate in the processing of smell information.



The migrations that occur in the adult brain involve the same mechanisms. The tissues flanking the migratory pathway secrete a repulsive signalling molecule prevents migrating cells from veering in the wrong direction, and the olfactory bulb itself secretes attractive cues which keep them on track. But the migrations still occur when the bulb itself is surgically removed from the brains of mice, so the chemical signals within it are clearly not essential. Armen Saghatelyan and his colleagues therefore reasoned that the cells might also depend upon a physical substrate to find their way.

To test this, they spliced the gene encoding green fluorescent protein (GFP) into a retrovirus and then injected the virus into the subventricular zone or the rostral migratory stream of mice, so that it would be taken up by the migrating cells. They then labelled the blood vessels by injecting a fluorescent dye into the animals' tails. This showed that blood vessels in the olfactory bulb are arranged parallel to the rostral migratory stream, and that migrating neurons are aligned along the vessels. The researchers also found that the blood vessels at the tip of the bulb are arranged perpendicular to the migration stream, so that they can guide cells into the bulb after they have left the migratory stream.

Using time-lapse imaging, they showed that the cells do indeed migrate along the capillaries running through the olfactory bulb. The vast majority of cells remained closely attached to the vessels for the duration of their migration, and never strayed more than three thousandths of a millimeter away from them. In the few cases when the cells moved further away from the vessel, their leading processes remained attached to it. And once the cells exited the migratory stream at the tip of the bulb, they quickly latched onto the perpendicularly oriented vessels to migrate through the radius of the bulb.

The researchers then showed that attachment of the young neurons to the blood vessels is dependent on a protein called brain-derived neurotrophic factory (BDNF), which is secreted by endothelial cells lining the vessel walls. To do so, they engineered artifical three-dimensional capillary networks from endothelial cells and fibroblast cells (the main constituent of connective tissue), placed them in a culture dish, and added GFP-labelled young neurons isolated from their mice. This revealed that neurons attached themselves to the vessels and migrated along them, and that blocking the interaction between BDNF and its receptor prevented the migration.

In their latest study, Saghatelyan and his colleagues analysed the location of astrocytes and blood vessels in the rostral migratory stream of mice of different ages. They found that the pattern of developing blood vessels in newborn mice follows the appearance of astrocytes in the rostral migratory stream and that their organization closely resembles the distribution of the cells. The pattern of blood vessels in adults was different, but still mirrored the distribution of astrocytes in the rostral migratory stream.

They then showed that astrocytes synthesize and secrete a protein called vascular endothelial growth factor (VEGF), and that this is essential for the proper development of blood vessels in the rostral migratory stream. In one set of experiments, addition of VEGF promoted the growth of blood vessels in a Petri dish, while blocking VEGF synthesis strongly reduced their formation. In another, blocking VEGF signalling in live animals disrupted the growth of blood vessels. As a result of this, the migration route of young neurons was altered; young neurons accumulated in the rostral migratory steam and fewer of them reached the tip of the olfactory bulb.

Astrocytes are one of several types of glial cell found in the brain, all of which were thought of as little more than supporting cells that hold brain tissue together and provide nourishment for neurons. In recent years, however, it has become clear that glail cells - and astrocytes in particular - play other important roles. For example, astrocytes are now known to regulate blood flow through capillaries in the brain, and to regulate signalling between neurons by clasping synapses with their endfeet. They also contribute to information processing by communicating with neurons and with each other, and this new work provides further evidence that they are indispensable for brain function.

References: Bozoyan, L., et al. Astrocytes Control the Development of the Migration-Promoting Vasculature Scaffold in the Postnatal Brain via VEGF Signaling. J. Neurosci. 32: 1687–1704. DOI: 10.1523/JNEUROSCI.5531-11.2012

Snapyan, M., et al. (2009). Vasculature Guides Migrating Neuronal Precursors in the Adult Mammalian Forebrain via Brain-Derived Neurotrophic Factor Signaling. J. Neurosci. 29: 4172-4188. DOI: 10.1523/JNEUROSCI.4956-08.2009.