Effects of reversible pharmacological shutdown of cerebellar flocculus on the memory of long-term horizontal vestibulo-ocular reflex adaptation in monkeys
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.
Section snippets
Animal preparation
The experimental protocols followed the ‘Principles of Laboratory Animal Care’ (NIH publication No. 80-23, revised in 1996) and were approved by the Research Ethics Committee of the Safety Division of RIKEN. Four male Macaca mulatta (body weight, 5–7 kg) were used (monkeys CI, SH, MAR and VZ). Under general anesthesia by intravenous administration of 50 mg/kg (body weight) of sodium pentobarbital (Nembutal, Dainippon–Sumitomo Pharma, Tokyo, Japan), the monkeys were surgically fitted with six
Effects of flocculus lidocaine injections on nonadapted HVOR
In the entire series of experiments, we first examined the effects of bilateral floccular lidocaine injections on nonadapted HVOR by 0.33 Hz-10° turntable oscillation in the dark, once for the four rhesus monkeys (monkeys CI, MAR, SH and VZ) by referring to our previous study (Nagao and Kitazawa, 2003). We injected 5 μl of 2.5 or 5% lidocaine or control Ringer's solution, first into the left flocculus, and then injected the same amount into the right flocculus in all experiments. The drug
Discussion
In the present study, we injected 2.5 or 5% lidocaine into cerebellar flocculi bilaterally (5 μl for each) to weaken or abolish their inhibitory actions on the vestibular nuclei in 4 monkeys. In all cases, the centers of injections were in the flocculus or its underlying white matter, or the adjacent caudal ventral paraflocculus (Fig. 4). Both the autoradiographical (Martin, 1991) and electrophysiological (Sandkuhler et al., 1987) studies estimated that 8 μl of 10% lidocaine diffused and
Acknowledgements
The authors are very grateful to Dr. Masao Ito (RIKEN Brain Science Institute) for his valuable suggestions throughout the course of experiments and preparation of the manuscript. They are also grateful to Dr. Tadashi Yamazaki (RIKEN-Toyota collaboration unit, RIKEN Brain Science Institute) for his helpful suggestion for analyses of eye movement data. This study was supported by the research funds of RIKEN and a Grant-in-Aid from the Japan Society for the Promotion of Science (No. 1650024).
References (58)
- et al.
Cerebellar function in consolidation of motor memory
Neuron
(2002) - et al.
Selective engagement of plasticity mechanisms for motor memory storage
Neuron
(2006) - et al.
Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex
Neuron
(1998) - et al.
A neuronal correlate in rabbit's cerebellum to adaptive modification of vestibulo-ocular reflex
Brain Res.
(1978) - et al.
Impulse discharges from flocculus Purkinje cells of alert rabbits during visual stimulation combined with horizontal head rotation
Brain Res.
(1975) Cerebellar learning in the vestibulo-ocular reflex
Trends Cogn. Sci.
(1998)- et al.
Visual influence on rabbit horizontal vestibulo-ocular reflex presumably effected via the cerebellar flocculus
Brain Res.
(1974) Two groups of secondary vestibular neurons mediating horizontal canal signals, probably to the ipsilateral medial rectus muscle, under inhibitory influences from the cerebellar flocculus in rabbits
Neurosci. Res.
(1985)Autoradiographic estimation of the extent of reversible inactivation produced by microinjection of lidocaine and muscimol in rat
Neurosci. Lett.
(1991)- et al.
Eye field in the cerebellar flocculus of pigmented rabbits determined with local electrical stimulation
Neurosci. Res.
(1985)
Location of efferent terminals of the primate flocculus and ventral paraflocculus revealed by anterograde axonal transport methods
Neurosci. Res.
Effects of reversible shutdown of the monkey flocculus on the retention of adaptation of horizontal vestibulo-ocular reflex
Neuroscience
Modeling learning in brain stem and cerebellar sites responsible for VOR plasticity
Exp. Brain Res.
Memory trace of motor learning shifts transsynaptically from cerebellar cortex to nuclei for consolidation
Neuroscience
Visual suppression of vestibular nystagmus in rhesus monkeys
Brain Res.
Loss of visual suppression of vestibular nystagmus after flocculus lesion
Brain Res.
Role of the primate flocculus in adaptation of vestibulo-ocular reflex
Neurosci. Res.
Demonstration of zonal projections from the cerebellar flocculus to vestibular nuclei in monkeys (Macaca fuscata)
Neurosci. Lett.
Functional representation of eye movements in the flocculus of monkey (Macaca fuscata)
Neurosci. Lett.
Contribution of the cerebellar flocculus to gaze control during active head movement
J. Neurophysiol.
Dual involvement of G-substrate in motor learning revealed by gene deletion
Proc. Natl. Acad. Sci. U.S.A.
A new approach to understanding adaptive visual-vestibular interactions in the central nervous system
J. Neurophysiol.
Short-term adaptive changes in the human vestibulo-ocular reflex arc
J. Physiol. (Lond.)
Extreme vestibulo-ocular adaptation induced by prolonged optical reversion of vision
J. Physiol. (Lond.)
αCaMKII is essential for cerebellar LTD and motor learning
Neuron
Vestibulo-ocular reflex
The Cerebellum and Neural Control
Long-term depression
Annu. Rev. Neurosci.
Adaptive modification of the rabbit's horizontal vestibulo-ocular reflex during sustained vestibular and optokinetic stimulation
Exp. Brain Res.
Specific patterns of neuronal connections involved in the control of rabbit's vestibulo-ocular reflexes by the cerebellar flocculus
J. Physiol. (Lond.)
Cited by (47)
Learning and forgetting in systems neuroscience: A control perspective
2023, Annual Reviews in Control50 Years Since the Marr, Ito, and Albus Models of the Cerebellum
2021, Neuroscience6.20 - Task-Specific Differentiation of Central Vestibular Neurons and Plasticity During Vestibular Compensation
2020, The Senses: A Comprehensive Reference: Volume 1-7, Second Edition6.26 - Functional Organization of Cerebellar Feed-Back Loops and Plasticity of Influences on Vestibular Function
2020, The Senses: A Comprehensive Reference: Volume 1-7, Second Edition