Neuroscience and Learning: Lessons From Studying the Involvement of a Region of Cerebellar Cortex in Eyeblink Classical Conditioning

Abstract

How the nervous system encodes learning and memory processes has interested researchers for 100 years. Over this span of time, a number of basic neuroscience methods has been developed to explore the relationship between learning and the brain, including brain lesion, stimulation, pharmacology, anatomy, imaging, and recording techniques. In this paper, we summarize how different research approaches can be employed to generate converging data that speak to how structures and systems in the brain are involved in simple associative learning. To accomplish this, we review data regarding the involvement of a particular region of cerebellar cortex (Larsell's lobule HVI) in the widely used paradigm of classical eyeblink conditioning. We also present new data on the role of lobule HVI in eyeblink conditioning generated by combining temporary brain inactivation and singlecell recording methods, an approach that looks promising for further advancing our understanding of relationships between brain and behavior.Key words: classical conditioning, associative learning, cerebellum, brainstem, neuroscience methods, interpositus nucleus, eyelid conditioning _______________________________________________________________________________We have written this article with two purposes in mind. First, we want to provide readers with an overview of how a variety of techniques are used to explore the involvement of structures and systems in the brain in encoding a relatively specific learned behavior, in this case, the involvement of the cerebellum in classical eyeblink conditioning. Second, we want to provide a glimpse of the difficulties inherent in trying to reach a consensus of opinion about what a given brain structure or system contributes to a specific behavior. We do so by providing a summary of our current understanding of what one brain area, lobule HVI of the cerebellar cortex, contributes to the conditioning process. Our overall goal is to convince the reader that a joint behavioral and neuroscience approach to the study of learning, using a variety of levels of analysis and methods, is an effective way to advance our understanding of the science of learning.For nearly thirty years, in several laboratories, experiments have been conducted to establish a causal relation between the cerebellum and simple forms of motor learning.Although much of the empirical progress has been achieved using the rabbit classical eyeblink conditioning paradigm, the work of Thach, Ito, Lisberger and others also has contributed to our understanding of cerebellar contributions to motor learning, as exemplified by work in the monkey and rabbit on the long-term and short-term adaptation of the vestibulo-ocular reflex (e.g., Lisberger, Pavelko, Bronte-Stewart, & Stone, 1994). Despite the advances that have occurred both theoretically and empirically, there is still much work to be done to more firmly identify and define the brain-behavior relationships that are the basis of adaptive movement and behavioral change involving the cerebellum, as well as...

Impaired Motor Learning in the Vestibulo-Ocular Reflex in Mice with Multiple Climbing Fiber Input to Cerebellar Purkinje Cells

“…A recent study reported that Purkinje cells in cerebellar sulci exhibit some degree of multiple climbing fiber innervation, even in adult, wild-type mice, suggesting that some cerebellar regions may function well with multiple climbing fiber innervation (Nishiyama and Linden, 2004). Eyeblink conditioning, the OKR, and rotorod performance all depend on different regions of the cerebellum (Le Marec and Lalonde, 1997;Katoh et al, 1998;Gerwig et al, 2005;Villarreal and Steinmetz, 2005). Thus, a region-dependent effect of multiple climbing fiber innervation could differentially affect these tasks.…”

Localization and characterization of an essential associative memory trace in the mammalian brain

“…Recall that muscimol does not act on axons so the mossy fiber and climbing fiber projections to the cerebellar cortex are intact and fully functional, as is the cortex itself, yet no part or aspect of the memory trace develops in the cortex over the many days of training while the interpositus nucleus is inactivated. This extraordinary result has been repeated independently and exactly in three other laboratories using eyelid conditioning: David Lavond at the University of Southern California using reversible cooling of the interpositus in the rabbit (Clark et al, 1992; was actually the first such study published); Joseph Steinmetz then at the University of Indiana using muscimol in the interpositus of the rabbit (Villarreal and Steinmetz, 2005); and John Freeman at the University of Iowa using muscimol in the intepositus of the rat (Freeman et al, 2005). In all cases there was no savings in post-inactivation training.…”

Neonatal ethanol exposure results in dose-dependent impairments in the acquisition and timing of the conditioned eyeblink response and altered cerebellar interpositus nucleus and hippocampal CA1 unit activity in adult rats

“…While the exact role of the cerebellar cortex in classical eyeblink conditioning remains an issue of debate (Attwell et al, 2002; Freeman and Steinmetz, 2011; Green and Steinmetz, 2005; Hong and Optican, 2008; Koekkoek et al, 2003; Kotani et al, 2006; Wang and Liu, 2011; Yamazaki and Nagao, 2012), one suggestion is that it aids in the establishment of IP plasticity and/or modulates topography of the behavioral response (Steinmetz and Lindquist, 2009; Villarreal and Steinmetz, 2005). Plasticity at the parallel fiber–Purkinje cell synapse occurs as a result of co-activation of the 2 primary sensory inputs to the cerebellum, mossy fibers from granule cells and climbing fibers from the dorsal accessory olive (Thompson and Steinmetz, 2009).…”