Abstract
Neuronal migration during embryonic development contributes to functional brain circuitry. Many neurons migrate in morphologically distinct stages that coincide with differentiation, requiring tight spatial regulation. It had been proposed that neurotransmitter-mediated activity could exert this control. Here, we demonstrate that intracellular calcium transients occur in cerebellar neurons of zebrafish embryos during migration. We show that depolarization increases and hyperpolarization reduces the speed of tegmental hindbrain neurons using optogenetic tools and advanced track analysis optimized for in vivo migration. Finally, we introduce a compound screening assay to identify acetylcholine (ACh), glutamate, and glycine as regulators of migration, which act regionally along the neurons’ route. We summarize our findings in a model describing how different neurotransmitters spatially interact to control neuronal migration. The high evolutionary conservation of the cerebellum and hindbrain makes it likely that polarization state-driven motility constitutes an important principle in building a functional brain.
Highlights
The brain is the most complex organ in the body
Previous studies investigating progress along such route have identified neurotransmitters—chemicals that transmit the signals between neurons—as important regulators in neuronal migration using mostly rodent brain slice cultures and cultivated neurons
tegmental hindbrain nuclei neuron (THN) move along a defined route and change their morphology along the way The upper rhombic lip (URL) in zebrafish embryos is a germinal zone along the dorsoposterior surface of the developing cerebellum, which gives rise to different long-distance migrating neurons, such as THNs and cerebellar granule cells, similar to the situation in mammals [29]
Summary
The brain is the most complex organ in the body. It carries out its tasks by networks of neurons that form separate spatial entities, which are often organized into layers or nuclei. Neuronal migration has been studied in various contexts using mostly in vitro assays or in situ rodent brain slices [7,8,9]. These studies have identified a number of molecules involved in cell guidance [10], but the control of forward movement is less understood. Still, these studies have discovered that activity mediated by different neurotransmitters has a complex role in the migration of neurons [11]. It has been proposed that different neurotransmitters act together or sequentially to fine-tune migration [12,26,27], but in vivo data from neurons migrating in their natural environment without incurring tissue damage from invasive procedures are scarce [25,28]
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