Deciphering development and function of the cerebellum using zebrafish
Masahiko Hibi
Graduate School of Science, Nagoya University
The cerebellum is essential for smooth motor control and motor learning, and is increasingly recognized for its roles in cognition and emotion. In cerebellar circuits, granule cells and Purkinje cells—the principal neuronal types—receive extracerebellar inputs. These inputs are integrated by Purkinje cells, which send output signals to downstream targets via cerebellar output neurons. GABAergic interneurons further modulate the activity of granule and Purkinje cells. This basic circuit architecture is widely conserved across vertebrates. In this seminar, I will present our recent analyses of cerebellar neurogenesis and function using the zebrafish model.
Cerebellar neurons differentiate from neural progenitor cells expressing proneural genes such as ptf1a, neurog1, and atoh1. While mammalian studies suggest these genes specify distinct lineages, our findings in zebrafish reveal that multiple cerebellar neuron types—including Purkinje cells, GABAergic interneurons, and granule cells—can differentiate from progenitors co-expressing ptf1a and neurog1. We identified transcription regulators from the Foxp and Skor families as key determinants of Purkinje cell specification. I will describe the mechanisms by which diverse cerebellar neurons differentiate from common progenitors.
The cerebellum also contributes to associative learning, including fear conditioning. When animals are repeatedly exposed to a neutral conditioned stimulus (e.g., visual cue) paired with an aversive unconditioned stimulus such as an electric shock, they learn to associate them and eventually show avoidance in response to the conditioned stimulus alone. Using zebrafish in which granule cells or Purkinje cells are selectively inhibited by botulinum toxin, or in which Purkinje cells are ablated, we showed that cerebellar circuits are involved in active avoidance learning. Disruptions in these circuits are increasingly linked to neuropsychiatric conditions such as autism spectrum disorder. Our work also suggests a role for the zebrafish cerebellum in regulating orienting behavior, a model for social responses.
Finally, I will introduce our ongoing efforts to dissect cerebellar circuit dynamics during fear learning, using in vivo Ca²⁺ imaging and optogenetics in a virtual reality setup. I will present our latest findings and discuss their implications for understanding cerebellar contributions to adaptive behavior.
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