Cerebellar norepinephrine modulates learning of delay classical eyeblink conditioning: Evidence for post-synaptic signaling via PKA

Abstract

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...

Neural circuitry and plasticity mechanisms underlying delay eyeblink conditioning

“…3). Another important circuit-level issue is characterization of the neural mechanisms underlying forebrain modulation of delay conditioning by the amygdala, hippocampus, and cerebral cortex (Berry and Thompson 1979;Neufeld and Mintz 2001;Allen et al 2002;Case et al 2002;Cartford et al 2004;Lee and Kim 2004;Blankenship et al 2005;Taub and Mintz 2010). There is evidence that these systems facilitate delay conditioning, but exactly how this facilitation is achieved is currently mysterious.…”

“…A full discussion of this issue is beyond the scope of this review, but it is important to note that hippocampal theta, amygdala, sensory cortex, and norepinephrine inputs to the learning circuitry described above modulate acquisition of eyeblink conditioning (Berry and Thompson 1979;Neufeld and Mintz 2001;Allen et al 2002;Case et al 2002;Cartford et al 2004;Lee and Kim 2004;Blankenship et al …”

Learning-related postburst afterhyperpolarization reduction in CA1 pyramidal neurons is mediated by protein kinase A

“…Transgenic mice with a constitutively active form of CREB have recently been shown to have CA1 pyramidal neurons with significantly reduced AHPs (28). Interestingly, EBC is also significantly impaired by disruption of the cAMP/PKA pathway in the cerebellum (29), a structure known to be critically involved in learning this task (30).…”

Evoking blinks with natural stimulation and detecting them with a noninvasive optical device: A simple, inexpensive method for use with freely moving animals

“…We have also demonstrated our technique to the Bickford laboratory which has used a version of it successfully (Cartford, Gemma & Bickford, 2002;Cartford, Samec, Fister & Bickford, 2004). The air puff US produces good URs that are free of artifacts and which are readily conditioned in the rat when paired with a CS.…”