Why should the withdrawal o f reinforcement in extinction result in a decrease in the probability o f responding? As discussed earlier, the mechanisms behind extinction learning are not clear, but four main theories have been developed: 1) Unlearning theory (Rescorla and Wagner, 1972); 2) Response inhibition theory (Pavlov, 1927); 3) Response competition theory (see Bouton, 1994); and 4) Non-associative loss theories, such as habituation and latent inhibition (Pavlov, 1927), or a temporary decline in attention to the stimulus (Robbins, 1990).
Previously, a high level o f correlation was demonstrated between the region o f HVI necessary for the performance and acquisition o f NM R conditioning (chapter 3), indicating that the same cerebellar cortical territory controls the performance and acquisition o f conditioned responses. So, measures o f performance can define circuitry necessary for acquisition, although acquisition learning was not directly evaluated in this study. In the present experiment, although all cortical infusions produced impairments o f extinction, there was an inverse relationship between the magnitude o f
extinction and performance impairments. This inverse relationship suggests that differential inactivations have been achieved and differences between extinction and performance/acquisition circuitry may have been revealed.
Extinction learning may therefore involve plasticity in cerebellar circuitry subsidiary to that involved in acquisition learning, consistent with the idea that extinction is not unlearning but is a separate coding process. This finding is compatible with a number o f phenomena which the unlearning theory cannot explain. Effects such as spontaneous recovery, reinstatement, the rapid reacquisition seen following extinction (Napier et al,
1992), or the faster rates o f learning obtained with successive alternating sessions o f acquisition and extinction (Smith and Gormezano, 1965), all clearly demonstrate surviving primary associations.
Consistent with the reported findings here, differences between circuitry supporting acquisition and extinction have also been unmasked in the analysis o f other forms o f learning and memory. The acquisition o f auditory fear conditioning is dependent on the amygdala (LeDoux, 1992), but little is known about the structures involved in extinction. Quirk et al (2000) examined the effect o f lesioning the ventromedial prefrontal cortex (vmPFC), a structure which projects to the amygdala, on the acquisition and extinction o f conditioned fear responses established in rats (tone CS and footshock US). Using a 2 day training protocol, vmPFC lesions had no effect on acquisition and subsequent extinction o f conditioned freezing on day 1. Full extinction was achieved by the end o f day 1. On day 2, control rats recovered only 27% o f their acquired freezing, whereas vmPFC lesioned rats recovered 86%, which was comparable to a group o f subjects that never received any extinction. The conclusion was that the vmPFC is not necessary for the acquisition or within session extinction o f conditioned fear, but is critical for the long-term recall of extinction learning - i.e. the consolidation o f extinction learning.
Similar findings were reported by Morgan et al (1993), who also examined the contribution o f the prefrontal cortex to the acquisition and extinction o f conditioned fear. Freezing behaviour was monitored in control rats and mPFC lesioned rats during both phases o f the experiment. Lesions o f the mPFC had no effect on the rate o f acquisition, whereas the rate o f extinction was significantly slower than that o f controls.
The findings from the experiment reported here are consistent with related findings in other learning tasks and they suggest that learning-related plasticity during acquisition and extinction might be in different regions o f the brain. The extinction o f NMR conditioning may involve plasticity in cerebellar circuitry subsidiary to that involved in the earlier acquisition learning.
More recently, the analysis o f conditioned taste aversion (CTA) in rats revealed differences in the cellular mechanisms o f acquisition and extinction (Berman & Dudai, 2001). During CTA training, subjects learn to associate a taste with delayed malaise. Subsequent extinction training involves repeated presentation o f the conditioned taste, but without the malaise-inducing drug. The insular cortex (IC) in rats is involved with the formation o f long-term CTA memory, which requires muscarinic and P-adrenergic receptors, the mitogen-activated protein kinase (MAPK) E R K l-2 cascade, and the transcription factor Elk-1 (see Berman & Dudai, 2001). Analysis o f extinction learning revealed that extinction o f CTA memory is also dependent on protein synthesis and P- adrenergic receptors in the IC, but independent o f muscarinic receptors and MAPK (Berman & Dudai, 2001). Therefore, the extinction o f CTA shares some molecular mechanisms with acquisition, but differences between acquisition and extinction mechanisms were also revealed.
Further analysis o f molecular mechanisms involved in the acquisition and extinction o f NMR conditioning will provide greater insight into how the cerebellum functions to learn and store motor memories.
Chapter 5
5.1 Introduction
A role for the cerebellum in the regulation o f motor behaviour has been proposed for almost 200 years and it is now generally agreed that the cerebellum functions to produce optimal movements. However, there is still no agreement about whether this role is restricted to the co-ordination and execution o f movements (see Llinas and Welsh,
1993) or whether it includes the storage o f motor memories (Brindley, 1964; Eceles et al, 1967; see also Yeo and Hesslow, 1998).
Classical conditioning o f the rabbit’s nictitating membrane response (NMR) has provided evidence consistent with a cerebellar motor learning hypothesis. Recent studies have used reversible inactivation techniques to examine which neural structures actively contribute to the acquisition and storage o f NM R conditioning. Reversible inactivations o f the cerebellar anterior interpositus (AIP) nucleus prevent the acquisition o f NMR conditioning (Clark et al, 1992; Krupa et al, 1993; Nordholm et al, 1993; Hardiman et al, 1996; Krupa and Thompson, 1997). Inactivations o f cerebellar output, in the superior cerebellar peduncle, do not prevent acquisition (Krupa & Thompson,
1995), suggesting that the essential plasticity for NMR conditioning lies within the cerebellum or precerebellar brainstem structures.
It is suggested that inactivations o f the cerebellar nuclei disturb excitability levels in other components o f the olivo-cortico-nuclear loop (Yeo et al, 1997). Consistent with this idea is the finding that inactivation o f the inferior olive also prevents the acquisition o f NMR conditioning (Welsh & Harvey, 1998). Although these inactivations would have disturbed cerebellar cortical activity indirectly by disrupting activity in the olivo- cortico-nuclear loop, the role o f the cerebellar cortex had not been fully investigated directly with reversible inactivations.
The main focus o f this thesis was to determine whether the circuitry essential for the expression, acquisition and extinction o f NM R conditioning also includes the cerebellar cortex, an important prerequisite in localising the memory trace for NM R conditioning.