Cerebellar cortical inhibition and classical eyeblink conditioning

Abstract

The cerebellum is considered a brain structure in which memories for learned motor responses (e.g., conditioned eyeblink responses) are stored. Within the cerebellum, however, the relative importance of the cortex and the deep nuclei in motor learning͞memory is not entirely clear. In this study, we show that the cerebellar cortex exerts both basal and stimulus-activated inhibition to the deep nuclei. Sequential application of a ␥-aminobutyric acid type A receptor (GABAAR) agonist and a noncompetitive GABAAR antagonist allows selective blockade of stimulus-activated inhibition. By using the same sequential agonist and antagonist methods in behaving animals, we demonstrate that the conditioned response (CR) expression and timing are completely dissociable and involve different inhibitory inputs; although the basal inhibition modulates CR expression, the conditioned stimulus-activated inhibition is required for the proper timing of the CR. In addition, complete blockade of cerebellar deep nuclear GABAARs prevents CR acquisition. Together, these results suggest that different aspects of the memories for eyeblink CRs are encoded in the cerebellar cortex and the cerebellar deep nuclei.learning ͉ memory ͉ cerebellar deep nuclei ͉ cerebellar cortex ͉ ␥-aminobutyric acid B ecause of the highly organized cytoarchitecture of its numerous neurons, the cerebellum has long been considered as a neuronal substrate for some forms of learning and memory (1-4). Accumulating evidence supports this view by demonstrating the critical roles of the cerebellum in motor learning (5-10). On the basis of empirical results and theoretical models, the basic neural circuitries underlying motor learning, such as classical conditioning and vestibulo-ocular-reflex adaptation, have been delineated (6,8,9). For example, in classical eyeblink conditioning, mossy fibers (mf) and climbing fibers (cf) are thought to convey conditioned stimulus (CS) and unconditioned stimulus (US) signals, respectively, to both the cerebellar cortex and the deep nuclei. Various types of synaptic plasticity have been demonstrated in these regions, including parallel fiberPurkinje cell long-term depression (pf-PC LTD) (11, 12) and long-term potentiation (pf-PC LTP) (13), pf-PC ␥-aminobutyric acid (GABA)-transmitting rebound potentiation (14), PC-deep nuclear neuron (DNN) LTD (15, 16), and LTP of extracellular responses in the cerebellar deep nuclei (17). These different types of plasticity may be involved in supporting learning in both the cerebellar cortex and deep nuclei (10,18,19).Although the early theoretical models only concerned the cerebellar cortex, recent studies implicated both the cortex and the deep nuclei in motor learning. Discrete lesions of the cerebellar interpositus nucleus (electrolytically, chemically, reversibly) consistently and completely prevent the acquisition and permanently and completely abolished retention͞expression of classically conditioned eyeblink responses in rabbits, rats, and mice (20-28). Cortical lesions affect various aspects of l...

Cerebellum volume and eyeblink conditioning in schizophrenia

“…Specifically, non-human experiments have determined that activation of the CR is principally controlled by the cerebellar deep nuclei, specifically the interpositus nucleus (McCormick and Thompson, 1984a;Woodruff-Pak et al, 1985;Steinmetz et al, 1991;Sears and Steinmetz, 1991). Inhibitory projections from Purkinje cortical neurons modulate the activity of the interpositus, effectively manipulating the timing of the CR (Mamounas et al, 1987;Bao et al, 2002). Evidence suggests that one locus of CR timing modification is the anterior regions of cerebellar cortex (Green and Steinmetz, 2005), an area wherein lesions disrupt CR onset and peak latencies (McCormick and Thompson, 1984b;Logan, 1991;Perrett et al, 1993;Garcia et al, 1999) and, perhaps, CR acquisition (Lavond and Steinmetz, 1989;Garcia et al, 1999).…”

Learning-Induced Plasticity in Deep Cerebellar Nucleus

“…Early results in rabbits ranged from complete abolition of the learned responses pointing to the cerebellar cortex as the key site (Yeo, 1991) to nominal effects that suggested a more fundamental role for the AIN (McCormick and Thompson, 1984). Numerous subsequent studies measuring closure of the external eyelid or nictitating membrane have reported responses with relatively fixed and short latencies to onset (ϳ80 -150 ms) after direct lesions (McCormick and Thompson, 1984;Perrett et al, 1993;Perrett and Mauk, 1995;Garcia et al, 1999;Medina et al, 2000) or infusing GABA A antagonists into the AIN (Garcia and Mauk, 1998;Medina et al, 2001;Ohyama and Mauk, 2001;Bao et al, 2002;Ohyama et al, 2003;Aksenov et al, 2004). We previously hypothesized that these short-latency responses (SLRs) (see Fig.…”

Blockade of GABAA receptors in the interpositus nucleus modulates expression of conditioned excitation but not conditioned inhibition of the eyeblink response

“…Previous studies demonstrated that picrotoxin produces a transient dose-dependent suppression of conditioned excitation (Bao, Chen, Kim, & Thompson, 2002;Mamounas, Thompson, & Madden, 1987). The nearly complete but transient suppression of CRs at higher doses of picrotoxin temporarily precludes the analysis of its effects on discriminative responding.…”