Interactive plasticity mechanisms in the cerebellum

Learning and memory formation require the coordination of multiple plasticity mechanisms—such as synaptic, intrinsic and structural—none of which are sufficient on their own. Although individual mechanisms and their separate effects on neuronal signaling have been well-characterized in vitro, we don’t know how they coordinate, or how that operates in live animals. Leveraging advanced microscopy in the transparent zebrafish brain, our research aims to decipher these complex interactions at the subcellular level and assess their impact on whole-brain dynamics and behavior. Using the cerebellum as a primary model, we will investigate how diverse mechanisms—each with unique functional, spatial, and temporal characteristics—interact within intricate neuronal structures to regulate downstream signaling. With its evolutionarily conserved architecture, the cerebellum offers a valuable framework to elucidate how plasticity mechanisms interact within neural circuits that are directly relevant to human nervous system function in healthy and diseased conditions.

The schematic illustrates local circuits in the zebrafish cerebellum, where Purkinje cells (PCs) integrate parallel fiber (PF) inputs to generate axonal output and influence their downstream targets, the eurydendroid (EuryD) cells. Synaptic plasticity at PF–PC synapses determines how inputs are decoded by PCs. The input–output relationship of PCs is further regulated by intrinsic plasticity, which modulates membrane potential via up- or down-regulation of SK2 channels. Finally, structural plasticity of PC axons may regulate their innervation of EuryD cells. In my lab, we aim to understand how these mechanisms interact to shape downstream signaling.

Cerebellar function development

The cerebellum has been implicated in neurodevelopmental disorders such as ASD and schizophrenia. Though often considered opposite ends of a spectrum, these two disorders share a key feature—sensory processing deficits—which has been linked to cerebellar dysfunction. A critical circuit involved in cerebellar sensory processing is the climbing fiber (CF) pathway, which relays instructive signals, such as sensory prediction errors, from the brainstem to the cerebellum. These signals guide synaptic plasticity and contribute to sensory learning.

Proper CF development ensures that sensory prediction errors are accurately assigned to the relevant context, while improper development may cause misattribution of sensory information in neurodevelopmental disorders, such as schizophrenia and ASD. This study will investigate the mechanisms underlying this developmental algorithm by tracking CF function and morphology in larval zebrafish exposed to manipulated sensory environments or optogenetic/chemogenetic neuronal stimulation. The goal is to determine how sensory experiences shape cerebellar processing during development. Ultimately, these mechanisms will be examined in Grid2 knockout—a shared genetic factor in ASD and schizophrenia characterized by cerebellum-specific pathology. By integrating advanced imaging, optogenetic, and chemogenetic approaches, this study will elucidate fundamental mechanisms of cerebellar circuit maturation in healthy and diseased conditions. 

Climbing fibers (CFs) project from the inferior olive to cerebellar Purkinje cells (PCs), carrying salient information that facilitates cerebellar learning. At early developmental stage, multiple CFs innervate a single PC, but these inputs are pruned during development, leaving only a single CF. PF, parallel fiber. dpf, days post-fertilization.