Naïve organisms initially produce a reflexive, unconditioned response (UR) (e.g. blink or extension of nictitating membrane) that follows US onset.
After many CS-US pairings, an association is formed such that a learned blink, or conditioned response (CR), occurs and precedes US onset.
The conditions necessary for, and the physiological mechanisms that govern, eyeblink CR learning have been studied across many mammalian species, including mice, rats, guinea pigs, rabbits, ferrets, cats, and humans.
Output from these nuclei control various eye muscles that work synergistically to produce an unconditioned blink response to corneal stimulation (reviewed, Christian & Thompson, 2003).
Electromyogram (EMG) activity of the orbicularis oculi muscle, which controls eyelid closure, is considered to be the most prominent and sensitive component of blinking (Lavond et al., 1990) and is, thus, the most common behaviorally-derived dependent variable in studies of EBC.
David A. McCormick, as a graduate student with Professor Richard F. Thompson, initially identified the cerebellum as the essential structure for learning and executing eyeblink CRs.
The population of cells critical for EBC appears to be restricted to a ~ 1 mm3 area of dorsolateral anterior INP ipsilateral to the conditioned eye.
Recordings of multiple-unit neuronal activity from rabbit INP during eyeblink conditioning have been possible with chronic electrode implants, and have revealed a population of cells that discharge prior to the initiation of the learned eyeblink CR and fire in a pattern of increased response frequency that predicted and modeled the temporal form of the behavioral CR (McCormick et al., 1981; 1982; 1983; Thompson, 1983; 1986; Foy et al., 1984; McCormick & Thompson, 1984a; b; Berthier & Moore, 1990; Gould & Steinmetz, 1996).
Similar results were found in the rat INP (Freeman & Nicholson, 2000; Stanton & Freemen, 2000; Rogers et al., 2001), thus demonstrating that underlying circuitry for this form of learning may be conserved across species.
Although samples of single-unit activity from the INP and surrounding nuclei have revealed a multitude of response patterns during EBC (Tracy, 1995), many of the cells in the anterior dorsolateral INP significantly increase their firing rate in a precise temporal pattern that is delayed from CS onset and precedes CR onset (Foy et al., 1984; Berthier & Moore, 1990).
Taken together, results from lesion, inactivation, and neural recording studies seem to demonstrate that the dorsolateral portion of the anterior interpositus nucleus (INP) of the cerebellum, ipsilateral to the trained eye, is an essential site for CR acquisition and expression in EBC (Lincoln et al., 1982; Lavond et al., 1984a,b).
However recent studies (Nilaweera et al., 2006) found that temporary block of cerebellar output prevented normal acquisition of conditioned responses.
For example, Krupa (1993) inactivated lobule HVI with the GABAA receptor agonist Muscimol and found significant acquisition deficits, but animals eventually learned.
They infused the AMPA receptor antagonist CNQX into HVI during acquisition training and found that CNQX-infused rabbits did not learn the eyeblink CR.
These results are perplexing, given that animals ultimately learned the eyeblink CR in all other cerebellar cortical lesion and inactivation studies.
Electrophysiological recording studies of cerebellar cortex have helped to better understand the role that PCs play in the eyeblink CR learning process.
They found that populations of neurons fire in relation to various aspects of eyeblink training, including CS and US presentation and CR execution.
In a single unit recording study where the individual Purkinje cells were shown to be located in the area controlling blinks and to receive climbing fibre input on US presentations, only inhibitory responses were found.
When paired presentations were reintroduced after extinction, Purkinje cell CRs reappeared rapidly, mirroring the "savings" phenomenon demonstrated at the behavioral level.
Long term depression (LTD) at the PF-PC synapse is hypothesized to have significant functional consequences for learning the behavioral CR in EBC (Ito, 1984).
Therefore, an LTD-mediated decrease in PC activity at the appropriate time during a CS-US interval could release the INP from tonic inhibition and allow for execution of a CR.