Pathway specific drive of cerebellar Golgi cells reveals integrative rules of cortical inhibition

Abstract

Cerebellar granule cells (GrCs) constitute over half of all neurons in the vertebrate brain and are proposed to decorrelate convergent mossy fiber inputs in service of learning. Interneurons within the granule cell layer, Golgi cells (GoCs), are the primary inhibitors of this vast population and therefore play a major role in influencing the computations performed within the layer. Despite this central function for GoCs, few studies have directly examined how GoCs integrate inputs from specific afferents which vary in density to regulate GrC population activity. We used a variety of methods in mice of either sex to study feedforward inhibition recruited by identified MFs, focusing on features that would influence integration by GrCs. Comprehensive 3D reconstruction and quantification of GoC axonal boutons revealed tightly clustered boutons that focus feedforward inhibition in the neighborhood of GoC somata. Acute whole cell patch clamp recordings from GrCs in brain slices showed that despite high GoC bouton density, fast phasic inhibition was very sparse relative to slow spillover mediated inhibition. Dynamic clamp simulating inhibition combined with optogenetic mossy fiber activation at moderate rates supported a predominant role of slow spillover mediated inhibition in reducing GrC activity. Whole cell recordings from GoCs revealed a role for the density of active MFs in preferentially driving them. Thus, our data provide empirical conformation of predicted rules by which MFs activate GoCs to regulate GrC activity levels.

SIGNIFICANCE STATEMENT

A unifying framework in neural circuit analysis is identifying circuit motifs that subserve common computations. Widefield inhibitory interneurons globally inhibit neighbors and have been studied extensively in the insect olfactory system and proposed to serve pattern separation functions. Cerebellar Golgi cells (GoCs), a type of mammalian widefield inhibitory interneuron observed in the granule cell layer, are well suited to perform normalization or pattern separation functions but the relationship between spatial characteristics of input patterns to GoC mediated inhibition has received limited attention. This study provides unprecedented quantitative structural details of GoCs and identifies a role for population input activity levels in recruiting inhibition using in vitro electrophysiology and optogenetics.