Effects of reversible pharmacological shutdown of cerebellar flocculus on the memory of long-term horizontal vestibulo-ocular reflex adaptation in monkeys

Abstract

The adaptation of the horizontal vestibulo-ocular reflex (HVOR) provides an experimental model for motor learning. Two studies, using cats and mice, respectively, have recently suggested pharmacologically that the memory of adaptation is located multiply in the cerebellum and brainstem. Here, we examined the effects of acute cerebellar flocculus shutdown on the adaptation in four monkeys. Two hours of 0.11 Hz-10° turntable oscillation while viewing a stationary checked-patterned screen through the left–right reversing prism decreased the HVOR gains by 0.16, and 3 days of prism wearing combined with 2 h of daily turntable oscillation decreased the HVOR gains by 0.27. Injections of lidocaine into bilateral flocculi did not affect the nonadapted HVOR gains, but depressed the visual suppression of the HVOR. They recovered the HVOR gains decreased by 2 h of training, but very little affected the HVOR gains decreased by previous 2 days of training. Injections of control Ringer's solution did not affect the gains adapted by 2 h or 3 days of training. These results are consistent with the previous studies, and suggest that the memory trace of adaptation of the HVOR initially resides in the flocculus but later resides, presumably, in the vestibular nuclei in the monkey.

Introduction

The horizontal vestibulo-ocular reflex (HVOR) plays an important role in stabilizing the visual image during animal movement. Whereas the HVOR is performed by a simple neural circuitry involving the vestibular nuclei and cerebellar flocculus, adaptation occurs rapidly when a sufficient amount of retinal slip, i.e., image motion on the retina, is repeatedly presented with head movements (Ito et al., 1974a, Ito et al., 1974b, Gonshor and Melvill-Jones, 1976a, Gonshor and Melvill-Jones, 1976b, Robinson, 1976). The adaptation of the HVOR is regarded as a prototype of motor learning (e.g., Ito, 1984). Many lines of experimental evidence indicate that the flocculus is specifically involved in the adaptation of the HVOR. Lesion (e.g., Nagao, 1983) and single unit recording studies (Ghelarducci et al., 1975, Dufosse et al., 1978, Watanabe, 1985, Nagao, 1989) consistently suggest that the flocculus plays a very important role in the adaptation of the HVOR. Moreover, pharmacological studies using blockers of long-term depression (LTD) of parallel fiber-Purkinje cell synapses (Nagao and Ito, 1991, Li et al., 1995) and gene-manipulated mice that lack LTD (De Zeeuw et al., 1998, Boyden et al., 2006, Hansel et al., 2006) suggest the unique role of cerebellar LTD in the adaptation of the HVOR (Ito, 1989, Ito, 1998).

Whereas the involvement of the cerebellar flocculus in the induction of the adaptation of the HVOR is well demonstrated experimentally as shown above, the site for the memory for adaptation was not clear (Lisberger and Sejnowski, 1992, Lisberger, 1994; also see Melvill-Jones, 2000). Recently, on the basis of pharmacological blockade of signal transmission experiments in cats, Kassardjian et al. (2005) have suggested that the memory for gain-down adaptation of the HVOR induced by 1 h of training is maintained in the flocculus, while that induced by 3 days of training is not maintained there. We have also reported similar results on mouse horizontal optokinetic response (HOKR), using pharmacological and electrophysiological techniques, and suggested that the memory for gain-up adaptation of the HOKR induced by 1 h of training is in the flocculus, but that induced by 3 days of training is in the medial vestibular nucleus to which the flocculus supplies its outputs (Shutoh et al., 2006). In monkeys, we previously suggested by pharmacological shutdown experiments that the memory for 2 h gain-up adaptation of the HVOR is located within the flocculus (Nagao and Kitazawa, 2003). Here, we further examined the location of the memory for the adaptation of the HVOR induced by 3 days of trainings in monkeys. The results are consistent with the previous cat and mouse experiments, and suggest that the memory trace for adaptation is distributed in the flocculus and vestibular nuclei, depending on training history, in monkeys.