Physiology of Cerebellar Reserve: Redundancy and Plasticity of a Modular Machine

Abstract

The cerebellum is endowed with the capacity for compensation and restoration after pathological injury, a property known as cerebellar reserve. Such capacity is attributed to two unique morphological and physiological features of the cerebellum. First, mossy fibers that convey peripheral and central information run mediolaterally over a wide area of the cerebellum, resulting in the innervation of multiple microzones, commonly known as cerebellar functional units. Thus, a single microzone receives redundant information that can be used in pathological conditions. Secondly, the circuitry is characterized by a co-operative interplay among various forms of synaptic plasticity. Recent progress in understanding the mechanisms of redundant information and synaptic plasticity has allowed outlining therapeutic strategies potentiating these neural substrates to enhance the cerebellar reserve, taking advantage of the unique physiological properties of the cerebellum which appears as a modular and potentially reconfiguring brain structure.

Keywords: cerebellar ataxias; cerebellar reserve; long-term depression; synaptic plasticity.

Figure 1

Multiple communication loops with extensive overlaps A: Schematic diagram of the cerebellar circuit. Mossy fiber (MF) inputs from the periphery, the primary motor cortex (M1), and the premotor cortex (PM) are represented by blue, orange, and red lines, respectively. In this diagram, we assume that the sensory afferent and efference copies from the M1are integrated into individual GCs or PCs in the M1 region of the cerebro–cerebellum (CbC). The output from the M1 region of the CbC projects back to the M1 through the dentate nucleus (DN) and the thalamus (Th). CbC, cerebro–cerebellum; CN, cuneate nucleus; IN, interpositus nucleus; PC, Purkinje cells; PN, pontine nuclei; SpC, spino–cerebellum.

Figure 2

A scheme of microzones. A functional congruence between the 2 major input systems (mossy fibers, climbing fibers) is observed anatomically, with a contribution of mossy fibers into multizonal microcomplexes integrated in cerebellar modules subserving the operational aspects of the cerebellar machinery. PF: parallel fiber, CF: climbing fiber, GC granule cell, Go: Golgi cells, Bc: basket cell, IO: inferior olive.

Figure 3

Multiple forms of synaptic plasticity with a special concern of spatial range. (1) STDP: spike timing-dependent plasticity MF–GrC synapse. (2) RP: rebound potentiation at inhibitory interneuron–PC synapse. RP should be induced in PCs innervated by the same CF (microzone). (3) LTP/LTD: Long-term potentiation or long-term depression at StC–PC synapses. This type of plasticity should be part of PC dendrites. (4) LTP: LTP at GrC–PC synapse. The postsynaptic type of LTP should be induced at PF–PC synapse along the same PF, except if conjunctively activated by CF. (5) MF-LTP: LTP at MF–DCN synapse. (6) LTD: LTD at PF–PC synapse. LTD should be induced at PF–PC synapses only when both PF–PC synapse and CF–PC synapse are activated conjunctively. See the text for further details. MF, mossy fiber; PF, parallel fiber; GC, granule cell; StC, stellate cell; PC, Purkinje cell; BC, basket cell; DCN, deep cerebellar nucleus neurons.

Figure 4

Schematic illustration of the effects of neuromodulation therapies. Neuromodulation therapies can modify cerebellar symptoms if the cerebellar reserve is preserved. (A) When etiology-based therapies are available (e.g., abstinence, removal of toxic agents, or diminishment of autoimmune processes,) and disease progression is stopped, neuromodulation therapies should improve cerebellar ataxias (CAs), leading to partial or full recovery of CAs. (B) When disease progression cannot be controlled (e.g., degenerative CA), early intervention by neuromodulation therapies can delay disease progression. Yellow-green arrow indicates the timing of etiology-based therapies, whereas green arrows indicate the timing of neuromodulation therapies.