Axonal Sprouting and Formation of Terminals in the Adult Cerebellum during Associative Motor Learning

Abstract

Plastic changes in the efficacy of synapses are widely regarded to represent mechanisms underlying memory formation. So far, evidence for learning-dependent, new neuronal wiring is limited. In this study, we demonstrate that pavlovian eyeblink conditioning in adult mice can induce robust axonal growth and synapse formation in the cerebellar nuclei. This de novo wiring is both condition specific and region specific because it does not occur in pseudoconditioned animals and is particularly observed in those parts of the cerebellar nuclei that have been implicated to be involved in this form of motor learning. Moreover, the number of new mossy fiber varicosities in these parts of the cerebellar nuclei is positively correlated with the amplitude of conditioned eyelid responses. These results indicate that outgrowth of axons and concomitant occurrence of new terminals may, in addition to plasticity of synaptic efficacy, contribute to the formation of memory.

The Sleeping Cerebellum

“…How sleep promotes consolidation of cerebellum-dependent memories remains a topic for further research. One of the interesting options is that new collaterals from mossy fibers, climbing fibers, and/or nucleocortical afferents sprout in the cerebellar nuclei and cortex overnight and form massive new connections following procedural learning [6,92,93]. This could also explain why cerebellar learning may at first largely depend on rapid plasticity in the cerebellar cortex, and subsequently, as the memory stabilizes, on more gradual plasticity in the cerebellar and Cerebellum-Related Memory Consolidation during Sleep.…”

Motor Learning and the Cerebellum

“…Together with zebrin-positive zone C2, zones C3 and D0 have been shown to respond to periocular stimulation (Hesslow 1994a,b;Mostofi et al 2010). Through tracer, lesion, and stimulation studies, it has become apparent that cells in C2 are more generally receptive to different kinds of stimulation, whereas C3 and D0 are specifically engaged with eyelid behavior, with their Purkinje cell output ultimately tying in to the eyelid muscle circuitry (Yeo et al 1985a(Yeo et al ,b,c, 1986Hesslow 1994a,b;Attwell et al 2001;Boele et al 2010Boele et al , 2013Mostofi et al 2010). …”

Pronounced reduction of acquisition of conditioned eyeblink responses in young adults with focal cerebellar lesions impedes conclusions on the role of the cerebellum in extinction and savings

“…The contribution of the cerebellum to associative learning has been studied in greatest detail in classical delay eyeblink conditioning (McCormick & Thompson, 1984;Yeo, Hardiman, & Glickstein, 1984;Boele, Koekkoek, De Zeeuw, & Ruigrok, 2013;Hesslow, Jirenhed, Rasmussen, & Johansson, 2013;Mauk, Li, Khilkevich, & Halverson, 2014 for recent review). Studies have been performed in various mammals including ferrets, rabbits and mice, but also humans (Woodruff-Pak, 1997 for review).…”