Neuronal migration depends on blood flow in the adult brain

Reviewer #1 (Public Review):

Summary:

This study provides compelling evidence suggesting that ghrelin, a molecule released in the surroundings of the major adult brain neurogenic niche (V-SVZ) by blood vessels with high blood flow, controls the migration of newborn interneurons towards the olfactory bulbs.

Strengths:

This study is a tour de force as it provides a solid set of data obtained by time-lapse recordings in vivo. The data demonstrate that the migration and guidance of newborn neurons rely on factors released by selective types of blood vessels.

Weaknesses:

Some intermediate conclusions are weak and may be reinforced by additional experiments.

Reviewer #2 (Public Review):

Summary:

The authors establish a close spatial relationship between RMS neurons and blood vessels. They demonstrated that high blood flow was correlated with migratory speed. In vitro, they demonstrate that Ghrelin functions as a motogen that increases migratory speed through augmentation of actin cup formation. The authors proceed to demonstrate through the knockdown of the Ghrelin receptor that fewer RMS neurons reach the OB. They show the opposite is true when the animal is fasted.

Strengths:

Compelling evidence of close association of RMS neurons with blood vessels (tissue clearing 3D), preferentially arterioles. Good use of 2-photon imaging to demonstrate migratory speed and its correlation with blood flow. In vitro analysis of Ghrelin administration to cultured RMS neurons, actin visualization, Ghsr1KD, is solid and compelling.

Weaknesses:

(1) Novelty of findings attenuated due to prior work, especially Li et al., Experimental Neurology 2014. Here, the authors demonstrated that Ghrelin enhances migration in adult-born neurons in the SVZ and RMS.

(2) The evidence for blood delivery of Ghrelin is not very convincing. Fluorescently-labeled Ghrelin appears to be found throughout the brain parenchyma, irrespective of the distance from vessels. It is also not clear from the data whether there is a link between increased blood flow and Ghrelin delivery.

(3) The in vivo link between Ghsr1KD and migratory speed is not established. Given the strong work to open the study on blood flow and migratory speed and the in vitro evidence that migratory speed is augmented by Ghrelin, the paper would be much stronger with direct measurement of migration speed upon Ghsr1KD. Indeed, blood flow should also be measured in this experiment since it would address concerns in 2. If blood flow and ghrelin delivery are linked, one would expect that Ghsr1KD neurons would not exhibit increased migratory speed when associated with slow or fast blood flow vessels.