The role of cell-type specific circuits for inhibition and disinhibition in cerebellar learning and behavior

Duke University, Durham NC

Investigators

Abstract

ABSTRACT Though the cerebellum has long been known to play a key role in motor control and motor learning, we have yet to establish a cohesive model for cerebellar learning. In large part, this is due to a lack of information about the in vivo activity of discrete cerebellar cell types and their interactions during behavior. In particular, despite their large numbers and extensive connectivity within the cerebellar circuit, little is known about how inhibitory interneurons influence cerebellar processing and learning in awake animals. Molecular layer interneurons (MLIs) represent a large class of cerebellar inhibitory interneurons, and are known to provide GABAergic inhibition to the primary output cells of the cerebellum, the Purkinje cells (PCs). Recent single cell RNAseq experiments have revealed that there are two types of genetically defined MLIs, so called MLI1s and MLI2s. Based on their unique connectivity and firing patterns, we have recently established methods to identify these two subtypes of MLIs in vivo using high density silicon probes (Neuropixels), and discovered that the MLI1s inhibit Purkinje cells while MLI2s disinhibit them. This newly discovered circuit motif provides a major revision to our understanding of cerebellar processing and suggests critical yet distinct roles for these interneuron subtypes in behavior and learning. In this proposal, we will test the hypothesis that MLI2 driven disinhibition and MLI1 driven inhibition are recruited by distinct circuit mechanisms to enable learning and behavior. Specifically, in Aim 1 we will test whether MLI2s can be preferentially recruited by climbing fiber activity to disinhibit PCs and facilitate both LTD and learning. We will use in vivo recordings cell-type specific pharmacology to evaluate the role of disinhibition during learning, and an in vitro brain slice preparation to measure synaptic plasticity in tissue from trained animals. In Aim 2, we will test the hypothesis that learning related changes in the cerebellar cortical circuitry enable preferential recruitment of MLI1-mediated inhibition of PCs to drive behavioral responses after learning, and in particular to regulate the timing of learned movements. We will again use a combination of in vivo and in vitro approaches to determine how the circuit transitions from disinhibition to inhibition across learning. Together these experiments will reveal how specific subtypes of interneurons are engaged to promote learning and proper execution of cerebellar-dependent motor behaviors.