Synaptic basis of temporal learning in the cerebellum

The National Institute of Neurological Disorders and Stroke awarded $622,687 to the University of Colorado-Denver on August 19, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to investigate the synaptic basis of temporal learning in the cerebellum.

The research examines how synaptic diversity in the cerebellum sculpts granule cell temporal basis sets to enable precise sensory-motor transformations underlying motor behaviors. The project comprises three aims: determining how heterogeneity in mossy fiber-granule cell synaptic strength and short-term plasticity generate diverse granule cell firing patterns using ex vivo patch-clamp recordings and calcium imaging; assessing the in vivo role of synaptic diversity following sensory stimuli and optogenetic stimulation using high-speed two-photon calcium imaging and fluorescent glutamate sensors, with causal perturbations via chemogenetic modulation; and determining how synaptic diversity-dependent granule cell temporal bases encode dynamic mossy fiber inputs during a forelimb-reaching task through pathway-specific imaging, optogenetic mossy fiber stimulation at varying frequencies, and chemogenetic modulation.

Work is performed in Aurora, Colorado. The award period runs through May 31, 2031.

Abstract

Animal survival requires that the brain use dynamic sensory information from the environment to generate precise motor actions. Transient, sequential activation of neurons within a population is a coding framework that can be a substrate for structuring motor actions within a dynamical sensory framework. Such neural sequences are observed across many brain regions and can be used as a set of mathematical functions to learn precisely timed neural activity dynamics. How they are generated and regulated is less well-known. Cerebellar granule cells (GCS) are thought to encode sensory information as a temporal basis, but their population activity on the subsecond timescale has not been measured. This proposal investigates how synaptic diversity in the cerebellum can sculpt GC temporal basis sets to enable precise sensory-motor transformations underlying motor behaviors. Aim 1 will determine how heterogeneity in mossy fiber-granule cell (MF-GC) synaptic strength and short-term plasticity, both within and across cerebellar regions, generate diverse GC firing patterns using EX vivo patch-clamp recordings and calcium imaging. Aim 2 will assess the in vivo role of synaptic diversity following sensory stimuli and optogenetic stimulation of MFS. MF and GC activity will be evaluated with high-speed two-photon calcium imaging, and neurotransmitter release at the MF- GC synapse will be monitored using a fluorescent glutamate sensor (iglusnfr). Causal perturbations using chemogenetic modulation of MF neurotransmitter release will test how synaptic properties influence GC temporal dynamics. Aim 3 will determine how synaptic diversity-dependent GC temporal bases encode dynamic MF inputs during a forelimb-reaching task. This will be achieved using pathway-specific imaging, optogenetic MF stimulation at varying frequencies, and chemogenetic modulation of neurotransmitter release to establish causal links between synaptic dynamics and motor precision. By integrating biophysical analysis of synaptic transmission and spiking, high-speed fluorescence imaging, optogenetic stimulation of different MF pathways, chemogenetic modulation, and behavioral approaches, this work will reveal how synaptic diversity generates a temporally tiled representation in the granule cell layer to support associative learning during a reach-to-grab task. By linking biophysical diversity of synaptic transmission to circuit-level representations and behavior, this work will reveal how short-term synaptic plasticity organizes temporally tiled activity in the cerebellar cortex at the service of learning precise motor behaviors.