Cilia-mediated cerebrospinal fluid flow modulates neuronal and astroglial activity in the zebrafish larval brain

Abstract

The brain uses a specialized system to transport cerebrospinal fluid (CSF). This system consists of interconnected ventricles lined by ependymal cells, which generate a directional flow upon beating of their motile cilia. Motile cilia act jointly with other physiological factors, including active CSF secretion and cardiac pressure gradients, to regulate CSF dynamics. The content and movement of CSF are thought to be important for brain physiology. Yet, the link between cilia-mediated CSF flow and brain function is poorly understood. In this study, we addressed the role of motile cilia-mediated CSF flow on brain development and physiology using zebrafish larvae as a model system. By analyzing mutant animals with paralyzed cilia, we identified that loss of ciliary motility did not alter progenitor proliferation, overall brain morphology, or spontaneous neural activity. Instead, we identified that cilia paralysis led to randomization of brain asymmetry. We also observed altered neuronal responses to photic stimulation, especially in the optic tectum and hindbrain. Since astroglia contact CSF at the ventricular walls and are essential for regulating neuronal activity, we next investigated astroglial activity in motile cilia mutants. Our analyses revealed a striking reduction in astroglial calcium signals both during spontaneous and light-evoked activity. Altogether, our findings highlight a novel role of motile cilia-mediated flow in regulating brain physiology through modulation of neural and astroglial networks.

Ciliogenesis defects after neurulation impact brain development and neuronal activity in larval zebrafish

“…In fact, most genes associated with motile cilia function, e.g., the master regulator of motile ciliogenesis foxj1a and some of its target genes, 30 , 73 were upregulated ( Figure 4C2 , red highlight), suggesting a potential genetic compensation mechanism as observed in the ccdc103 (also known as smh ) and rpgrip1l mutants. 51 , 74 Among genes associated with the GO terms “neurological system process” and “neuron part”, we identified that genes encoding for the grow factor brain-derived neurotrophic factor ( bdnf ), 75 various synaptic proteins ( synaptotagmin , synaptic vesicle glycoprotein 2b , synaptophysin b ) and enzymes involved in serotonin and catecholamine production ( tyrosin and tryptophan hydroxylase ) were downregulated ( Figure 4C3 , red highlights). Finally, genes involved in common cilia-related signaling pathways especially the sonic hedgehog pathway were differentially regulated suggesting a dampened sonic hedgehog pathway 15 , 17 ( Figure 4C4 ).…”

“… 49 Cilia-mediated CSF flow has also been linked to the regulation of neuronal activity in the larval zebrafish brain. 51 …”