Cerebellar norepinephrine depletion and impaired acquisition of specific locomotor tasks in rats

Watson, Mark; McElligott, James G.

doi:10.1016/0006-8993(84)90518-3

Cited by 93 publications

(45 citation statements)

References 37 publications

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“…This result supports the contention that the activity of NE in the cerebellum is important for adaptation and lasting changes related to memory formation. Earlier evidence for this was established using cerebellar NE depletion in a rod-running motor learning paradigm, (Watson and McElligott 1984) as well as with blocking ␤-noradrenergic receptors during adaptation of the VOR (Pompeiano et al 1991). Our subjects did show some indication of learning.…”

Section: Learning and Memory 733supporting

confidence: 72%

“…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.…”

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confidence: 99%

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

Cartford¹,

Samec²,

Fister³

et al. 2004

Learn. Mem.

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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...

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Section: Learning and Memory 733supporting

confidence: 72%

mentioning

confidence: 99%

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

Cartford¹,

Samec²,

Fister³

et al. 2004

Learn. Mem.

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“…These same motor control tests have been used to detect dopaminergic deficits (22,23), and the impairments in DbhϪ/Ϫ mice were reversed by apomorphine, a DA agonist. In addition, the DOPS paradigm we used rescues the motor deficits but does not restore cerebellar NE to DbhϪ/Ϫ mice (24), and selective cerebellar NE depletion in rats does not worsen baseline performance on a motor test nearly identical to the challenging beam traversal (25). These combined data suggest that at least some of the motor impairments observed in DbhϪ/Ϫ mice stem from a loss of dopaminergic tone, not cerebellar dysfunction.…”

Section: Discussionmentioning

confidence: 79%

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Rommelfanger¹,

Edwards

Freeman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

174

116

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Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine ␤-hydroxylase knockout (Dbh؊/؊) mice that lack NE altogether. We detected no motor abnormalities in MPTP-treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh؊/؊ mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh؊/؊ mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh؊/؊ mice. Finally, striatal levels of phospho-ERK-1/2 and ⌬FosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh؊/؊ mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD.dopamine ͉ Parkinson's disease ͉ dyskinesias ͉ dopamine ␤-hydroxylase P arkinson's disease (PD) affects Ϸ1% of the world's aging population (1). Despite this high prevalence and intensive research into its origins, the etiology of PD remains largely unknown. The disease is characterized by degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SN), and symptoms, which tend to manifest when Ϸ80% of striatal DA is lost, include bradykinesia, postural instability, rigidity, and resting tremor. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin, is known to produce parkinsonism in humans and causes severe DA loss in animals (2). Because of its ability to recapitulate the neuropathology of PD, MPTP is used widely in PD research. However, MPTP has been unable to reliably reproduce the motor symptoms of PD in mice, which limits the utility of MPTP-treated mice as an animal model of the disease (3). Differences in mouse strain and experimental paradigms may at least partially account for these inconsistencies.Despite the focus on DA, PD is more accurately described as a multisystem disorder that features a profound albeit underappreciated loss of locus coeruleus (LC) neurons, as well as variable damage to other brain regions (4-6). Postmortem studies indicate that neuronal degeneration in the LC is comparable to that in the substantia nigra pars compacta, and that it may a...

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“…The cerebellum, especially Purkinje cells, is important to the modulation of motor coordination and motor learning tasks regulated by gamma aminobutyric acid (GABA) neuron activity (Mitoma and Konishi, 1999). Previous studies indicate that the cerebellum receives widespread nerve terminal projections from noradrenergic neurons (Watson and McElligott, 1984). GABAergic neurons in the Purkinje cells are stimulated by NA neurons to elicit a prolonged inhibition of Purkinje cell activity (Mitoma and Konishi, 1999).…”

Section: Discussionmentioning

confidence: 99%

Exposure to diesel exhaust during fetal period affects behavior and neurotransmitters in male offspring mice

et al. 2013

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Cerebellar norepinephrine depletion and impaired acquisition of specific locomotor tasks in rats

Cited by 93 publications

References 37 publications

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

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

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Exposure to diesel exhaust during fetal period affects behavior and neurotransmitters in male offspring mice

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