The neurotransmitter norepinephrine (NE) has been shown to modulate cerebellar-dependent learning and memory. Lesions of the nucleus locus coeruleus or systemic blockade of noradrenergic receptors has been shown to delay the acquisition of several cerebellar-dependent learning tasks To date, no studies have shown a direct involvement of cerebellar noradrenergic activity nor localized the post-synaptic response to cerebellar -noradrenergic receptor signaling. Using ipsilateral, localized infusions into cerebellar lobule HVI and interpositus (IP), we have established that blocking -noradrenergic receptors with propranolol significantly impairs acquisition of conditioned responses. Furthermore, interrupting activation of cAMP-dependent PKA in the cerebellum using Rp-cAMPS completely prevents acquisition. However, neither blocking -adrenergic receptors nor blocking PKA activation significantly interferes with performance of established conditioned responses when administered after the learned response is formed.The neurotransmitter norepinephrine (NE) is strongly implicated in cerebellar-dependent learning and memory in adaptation to a patterned rod runway task (Watson and McElligott 1983;Bickford 1995), in adaptation of the vestibulo-ocular reflex gain (VOR) (Pompeiano et al. 1991), and in cerebellar-dependent delay classical eyelid conditioning (Gould 1998;McCormick and Thompson 1982;Winsky and Harvey 1992;Cartford et al. 2002). The delay form of classical eyelid conditioning is a valuable model for studying NE because the functional anatomy is so well characterized and localization of learning in the cerebellum is strongly supported by the literature. Neurons within cerebellar lobule HVI and the interpositus nucleus (IP) in rabbits and rats show conditioning-related activity (Berthier and Moore 1986;Gould and Steinmetz 1994;Rogers et al. 2001). Classical conditioning of the eyelid response is disrupted by lesions of cerebellar lobule HVI (Yeo et al. 1985;Steinmetz and Sengelaub 1992;Nordholm et al. 1993;Perrett et al. 1993) and is abolished by lesions of cerebellar IP (Clark et al. 1992(Clark et al. , 1997Krupa et al. 1993;Clark and Lavond 1996;Rogers et al. 2001). However, Purkinje cell degeneration mutant (pcd) mice acquire the eyelid response (Chen et al. 1996), and both pcd mice as well as the jaundiced Gunn rat (also a mutant with loss of Purkinje cells) have normal to elevated levels of NE innervation and functional activity in cerebellar cortex and deep nuclei after degeneration of the Purkinje cell layer (Ghetti 1981;Kostrozewa and Harston 1986;Onozuka et al. 1990).Norepinephrine is known to modulate the action of other neurotransmitters in both the cerebellar cortex and the deep nuclei ) and can amplify afferent inputs to cerebellar Purkinje neurons. This effect is mediated through the -noradrenergic receptor (Yeh and Woodward 1983;Woodward et al. 1991). Noradrenergic receptor activation signals a Gprotein-coupled signal transduction cascade in which adenyl cyclase (AC), cyclic-adenosine-monophosphat...
Delay classical eyeblink conditioning (EBC) is an important model of associative, cerebellar dependent learning. Norepinephrine (NE) plays a significant modulatory role in the acquisition of learning; however, other neurotransmitters are also involved. The goal was to determine whether NE, gamma-aminobutyric acid (GABA) and glutamate (GLU) release are observed in cerebellar cortex during EBC, and whether such release was selectively associated with training. Further studies examined the role of the β-noradrenergic receptor in consolidation of the learned response by local infusion of propranolol at 5 – 120 minutes following training into the cerebellar cortex. In vivo microdialysis coupled to EBC was performed to examine neurotransmitter release. An increase in the extracellular level of NE was observed during EBC and was maximal on day 1 and diminished in amplitude with subsequent days of training. No changes in baseline NE release were observed in pseudo-conditioning indicating that NE release is directly related to the associative learning process. The extracellular levels of GABA were also increased selectively during paired training however the magnitude of GABA release increased over days of training. GLU release was observed to increase during both paired and unpaired training, suggesting that learning does not occur prior to the information arriving in the cerebellum. When propranolol was administered at either 5, 60, or 120 minutes post training, there was an inhibition of conditioned responses, these data support the hypothesis that NE is important for consolidation of learning. In another set of experiments we demonstrate that the timing of release of NE, GABA and glutamate are significantly delayed in onset and lengthened in duration in the 22 month old F344 rats. Over days of training the timing of release becomes closer to the timing of training and this is associated with increased learning of conditioned responses in the aged rats.
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