Climbing Fibers Provide Graded Error Signals in Cerebellar Learning

Abstract

The cerebellum plays a critical role in coordinating and learning complex movements. Although its importance has been well recognized, the mechanisms of learning remain hotly debated. According to the classical cerebellar learning theory, depression of parallel fiber synapses instructed by error signals from climbing fibers, drives cerebellar learning. The uniqueness of long-term depression (LTD) in cerebellar learning has been challenged by evidence showing multi-site synaptic plasticity. In Purkinje cells, long-term potentiation (LTP) of parallel fiber synapses is now well established and it can be achieved with or without climbing fiber signals, making the role of climbing fiber input more puzzling. The central question is how individual Purkinje cells extract global errors based on climbing fiber input. Previous data seemed to demonstrate that climbing fibers are inefficient instructors, because they were thought to carry "binary" error signals to individual Purkinje cells, which significantly constrains the efficiency of cerebellar learning in several regards. In recent years, new evidence has challenged the traditional view of "binary" climbing fiber responses, suggesting that climbing fibers can provide graded information to efficiently instruct individual Purkinje cells to learn. Here we review recent experimental and theoretical progress regarding modulated climbing fiber responses in Purkinje cells. Analog error signals are generated by the interaction of varying climbing fibers inputs with simultaneous other synaptic input and with firing states of targeted Purkinje cells. Accordingly, the calcium signals which trigger synaptic plasticity can be graded in both amplitude and spatial range to affect the learning rate and even learning direction. We briefly discuss how these new findings complement the learning theory and help to further our understanding of how the cerebellum works.

Keywords: Purkinje cell; cerebellar learning; climbing fiber; complex spike (CS); error signal.

Figure 1

Schematic of basic cerebellar circuitry. mf, gc, pf, pc, sc, bc, cf, IO designate mossy fiber, granule cell, parallel fiber, Purkinje cell, stellate cell, basket cell, climbing fiber and inferior olive neuron, respectively. “+” and “−” correspond to excitatory and inhibitory synaptic connections, respectively. pf → pc and pf → bc/sc → pc connections form a typical feed-forward-inhibition circuit. Some cell types and connections have been omitted for simplicity (Schematic, created by ourselves).

Figure 2

“All-or-none” climbing fiber responses. Climbing fiber-evoked somatic (black) and dendritic (red) responses measured in the isolated cerebellum of turtles. The climbing fiber was activated by stimulating an inferior olive neuron (IO), reproduced from Hounsgaard and Midtgaard (1989). Somatic complex spikes are characterized by a fast spike followed by several spikelets on top of a plateau potential. © 1989 The Physiological Society, reproduced with permission from Wiley Publishing, Inc.

Figure 3

Schematic of factors modifying climbing fiber responses. From left to right, climbing fiber (cf) responses can be graded by voltage states, concurrent synaptic input, cf-long-term depression (LTD), and spike numbers in a cf-burst. Compared with basal conditions (black): depolarization (blue), concurrent excitatory synapse (orange), cf-LTD (purple) and cf-burst (red, manifested by cf epsc) increases, increases, decreases and increases dendritic Ca²⁺ influx respectively, by modulating dendritic spikes. If concurrent synaptic input is inhibitory, changes are opposite (not illustrated here). For somatic complex spike changes, the existence of both dashed and solid-colored traces suggests that complex spikes can exhibit bidirectional changes depending on the “state,” also implying that somatic complex spikes are poor proxies for dendritic responses. Sketched according to Zang et (; the authors’ open access paper).

Figure 4

Occurrence of somatic and dendritic spikes. Climbing fiber responses at different sites of the Purkinje cell, including axon initial segment (AIS), soma, proximal and distal dendrites. Each spikelet in the complex spike still initiates at the AIS. Reproduced from Zang et (; the authors’ open access paper).

Figure 5

Ca²⁺-determined bidirectional plasticity of parallel fiber synapses. Parallel fiber (pf)-LTD has a higher Ca²⁺ induction threshold (usually induced by conjunctive pf and cf stimulation) than long-term potentiation (LTP; usually induced by pf stimulation in isolation). Depending on the dendritic Ca²⁺ influx, LTP can also be induced by conjunctive pf and cf activation under the condition of cf-LTD, conjunctive inhibition by molecular layer interneuron (MLI), or Purkinje cell (pc)-hyperpolarization. LTD can also be induced by pf in isolation when dendritic spikes occur with strong pf stimulation. Modified from Coesmans et al. (2004).

Figure 6

“Motor clock” and “instruction” by climbing fibers. The phase (timing) of synaptic input in subthreshold oscillations is encoded by the number of axonal spikes in a climbing fiber (cf), manifested by cf epsc. The burst can convert to dendritic spikes and modulate the Ca²⁺ influx to shift the polarity of synaptic changes (top panel) as an “instruction” signal. Simultaneously, the burst can convert to somatic complex spikes and entrain downstream cerebellar nuclei neuron outputs to initiate or modulate movement as a “motor clock” (bottom panel; Schematic, created by ourselves).