The Cerebellar Cortex

Abstract

The cerebellar cortex is an important system for relating neural circuits and learning. Its promise reflects the longstanding idea that it contains simple, repeated circuit modules with only a few cell types and a single plasticity mechanism that mediates learning according to classical Marr-Albus models. However, emerging data have revealed surprising diversity in neuron types, synaptic connections, and plasticity mechanisms, both locally and regionally within the cerebellar cortex. In light of these findings, it is not surprising that attempts to generate a holistic model of cerebellar learning across different behaviors have not been successful. While the cerebellum remains an ideal system for linking neuronal function with behavior, it is necessary to update the cerebellar circuit framework to achieve its great promise. In this review, we highlight recent advances in our understanding of cerebellar-cortical cell types, synaptic connections, signaling mechanisms, and forms of plasticity that enrich cerebellar processing.

Keywords: Purkinje cell; cerebellar circuit; cerebellar interneurons; climbing fiber; ephaptic signaling; motor learning.

Figure 1.. Basic circuitry and cell types of the cerebellar cortex.

A. Simplified circuit of the cerebellar cortex. B. Dendrogram of the neurons based on RNAseq data reveals additional types and subtypes of neurons in the cerebellar cortex (Kozareva et al., 2021). Abbreviations: climbing fiber (CF), mossy fiber (MF), granule cell (GrC), Golgi cell (GoC), molecular layer interneuron (MLI), Purkinje cell (PC), unipolar brush cells (UBCs), and Purkinje layer interneurons (PLIs).

Figure 2.. Circuit specializations of the input layer of the cerebellar cortex.

A. There are additional cell types and connections in the GrC layer that are neglected in simplified models of the cerebellar cortex: inhibitory feedback from the CbN, UBCs, gap junction coupling between GoCs, and PC feedback to GrCs and UBCs. B. MFs have disparate properties that evoke spiking in GrCs with diverse temporal properties (Chabrol et al., 2015). In this example MF1 has a high initial probability of release and depresses, whereas MF2 has a low initial probability of release and facilitates. GrC spiking evoked by activation of MF1 alone, MF2 alone and coactivation of MF1 and MF2. C. Specialized GABA_A receptors in GrCs mediate inhibition with a conventional fast component (α1 subunit containing). and a slow tonic component (α6δ subunit containing). D. Cerebellar UBCs express elements of the mGluR1 excitatory pathway and the mGluR2 inhibitory pathway in inverse gradients to generate a continuum of temporal responses.

Figure 3.. Additional circuit elements and signaling mechanisms in the molecular layer (ML) and the PC layer (PCL).

A. Schematic showing additional cell types and connections between cells that are not considered in the simplified circuit of the cerebellar cortex (Figure 1). Abbreviations for types of PLIs: Lugaro cell (LC), candelabrum cell (CC), and globular cell (GbC). Known inhibitory (−) and excitatory (+) synapses are shown. B. (left) An expanded view of the ML showing intermingled molecularly and functionally distinct subtypes of MLIs. MLI1s are gap junction coupled with each other, but MLI2s are not (right). The MLI1 population displays a molecular and anatomical gradient of properties. C. CFs, in addition to powerfully and directly exciting PCs, produce a glutamate signal that spills over to excite MLIs and GoCs. CFs also generate extracellular ephaptic signals that suppress firing in neighboring PCs. D. Extracellular ephaptic signals allow MLIs to rapidly inhibit and PCs to rapidly excite neighboring signals. E. PLIs are usually disregarded in considering the circuitry of the cerebellar cortex. PCs powerfully inhibit LCs, GbCs and CCs, and CCs primarily inhibit MLIs leading to disinhibition of PCs.

Figure 4.. Cell types, synapses, circuitry and sites of plasticity.

A. Known sites of plasticity in the cerebellar cortex, showing synapses that undergo LTP and LTD, cell types where excitability and spontaneous activity can be altered, and sites that are known targets of modulators. B. Updated circuit showing the cells and known connections of the cerebellar cortex that could all undergo plasticity. The number of known subtypes of cells are indicted in the inset.