Impaired classical eyeblink conditioning in cerebellar-lesioned and Purkinje cell degeneration (pcd) mutant mice

Chen, L; Bao, Shaowen; Lockard, JM; Jk, Kim; Thompson, R. F.

doi:10.1523/jneurosci.16-08-02829.1996

Cited by 208 publications

(216 citation statements)

References 48 publications

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“…Transgenic mice that loose all cerebellar Purkinje cells within the first two months of life perform significantly worse in eyeblink conditioning than their do wild-type litter mates (Chen et al 1996). Purkinje cell loss or cerebellar cortical aspirations do not prevent the acquisition of CRs.…”

Section: Eyeblink Conditioning In Aging Micementioning

confidence: 93%

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Age-Related Impairment in the 250-Millisecond Delay Eyeblink Classical Conditioning Procedure in C57BL/6 Mice

Vogel¹,

Ewers²,

Ross³

et al. 2002

Learn. Mem.

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In this study we tested 4-, 9-, 12-, and 18-month-old C57BL/6 mice in the 250-msec delay eyeblink classical conditioning procedure to study age-related changes in a form of associative learning. The short life expectancy of mice, complete knowledge about the mouse genome, and the availability of transgenic and knock-out mouse models of age-related impairments make the mouse an excellent species for expanding knowledge on the neurobiologically and behaviorally well-characterized eyeblink classical conditioning paradigm. Based on previous research with delay eyeblink conditioning in rabbits and humans, we predicted that mice would be impaired on this cerebellar-dependent associative learning task in middle-age, at ∼ 9 months. To fully examine age differences in behavior in mice, we used a battery of additional behavioral measures with which to compare young and older mice. These behaviors included the acoustic startle response, prepulse inhibition, rotorod, and the Morris water maze. Mice began to show impairment in cerebellar-dependent tasks such as rotorod and eyeblink conditioning at 9 to 12 months of age. Performance in hippocampally dependent tasks was not impaired in any group, including 18-month-old mice. These results in mice support results in other species, indicating that cerebellar-dependent tasks show age-related deficits earlier in adulthood than do hippocampally dependent tasks.The eyeblink classical conditioning paradigm is a powerful tool for studying learning and memory because it is wellcharacterized on a neurobiological and behavioral basis. In addition, the sensitivity, reliability, and generalization across species that eyeblink conditioning has shown is remarkable. There are more published studies on rabbits and humans tested in eyeblink classical conditioning than on any other form of Pavlovian conditioning. Furthermore, dramatic parallels exist between the effects of normal aging in rabbits and humans in eyeblink conditioning. Given the short life expectancy of mice, the fact that the mouse genome is mapped, and the availability of transgenic and knock-out mouse models of neurodegenerative diseases related to aging, the mouse is an excellent species for expanding knowledge on age effects in eyeblink classical conditioning.

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Section: Eyeblink Conditioning In Aging Micementioning

confidence: 93%

“…Purkinje cell loss or cerebellar cortical aspirations do not prevent the acquisition of CRs. Rather loss of the cerebellar cortical machinery normally engaged in acquisition of CRs slows the rate of acquisition (Lavond and Steinmetz 1989;Chen et al 1996).…”

Section: Eyeblink Conditioning In Aging Micementioning

confidence: 99%

Age-Related Impairment in the 250-Millisecond Delay Eyeblink Classical Conditioning Procedure in C57BL/6 Mice

Vogel¹,

Ewers²,

Ross³

et al. 2002

Learn. Mem.

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“…There was a significant difference in the training condition effect [F(1, 81) ϭ 444.108, P Ͻ 0.0001] and condition ϫ session interaction [F(8, 648) ϭ 119.4, P Ͻ 0.0001] between the two training groups. On the first day of extinction training, there was no significant difference between the two groups that received an additional 4 d of extinction training after 7 d of paired training (days [8][9][10][11] [F(1, 6) ϭ 1.704, P ϭ 0.2396], indicating rapid and successful extinction. The comparison of CR% on the last training day demonstrated a clear difference in the memory state of eyeblink conditioning between the training groups (Fig.…”

Section: Paired But Not Unpaired Groups Acquired a Robust Memory For mentioning

confidence: 99%

“…This hypothesis has been examined repeatedly with lesions (3-7) and inactivation of the AIN (8,9), and in mutant mice with Purkinje cell degeneration (10). Recent observations made using electron microscopy (11) or functional magnetic resonance imaging (12) further support the notion that the basic memory trace is formed in the AIN.…”

mentioning

confidence: 94%

Molecular evidence for two-stage learning and partial laterality in eyeblink conditioning of mice

Park¹,

Onodera²,

Nishimura³

et al. 2006

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

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The anterior interpositus nucleus (AIN) is the proposed site of memory formation of eyeblink conditioning. A large part of the underlying molecular events, however, remain unknown. To elucidate the molecular mechanisms, we examined transcriptional changes in the AIN of mice trained with delay eyeblink conditioning using microarray, quantitative real-time RT-PCR, and in situ hybridization techniques. Microarray analyses suggested that transcriptionally up-regulated gene sets were largely different between early (3-d training) and late (7-d) stages. Quantitative real-time RT-PCR aided by laser microdissection indicated that the expression of representative EARLY genes (Sgk, IkBa, and Plekhf1) peaked at 1-d training in both the paired and unpaired conditioning groups, and was maintained at a higher level in the paired group than in the unpaired group after 3-d training. In situ hybridization revealed increased expression of these genes in broad cerebellar areas, including the AIN, with no hemispheric preferences. In contrast, the expression of representative LATE genes (Vamp1, Camk2d, and Prkcd) was selectively increased in the AIN of the 7-d paired group, with dominance in the ipsilateral AIN. Increased Vamp1 mRNA expression was restricted to the ipsilateral dorsolateral hump, a subregion of the AIN. These expression patterns of two distinct subsets of genes fit well with the twostage learning theory, which proposes emotional and motor learning phases, and support the notion that AIN has a crucial role in memory formation of eyeblink conditioning.gene expression ͉ interpositus nucleus C lassical eyeblink conditioning is conserved among various species. Although the neuronal circuitries are well defined and the cerebellum is considered to be the site of memory formation of the classically conditioned response (CR, i.e., eyeblink) (1), evidence is still conflicting regarding the neural substrate for the memory trace of eyeblink conditioning in the cerebellum.In contrast to the suggestion that the basic memory trace of the CR is formed in the cerebellar cortex (2), accumulating evidence suggests that the anterior interpositus nucleus (AIN) in the deep cerebellar nuclei (DCN) is the site of memory for the association between the conditioned stimulus (CS) and the unconditioned stimulus (US) formed in eyeblink conditioning. This hypothesis has been examined repeatedly with lesions (3-7) and inactivation of the AIN (8, 9), and in mutant mice with Purkinje cell degeneration (10). Recent observations made using electron microscopy (11) or functional magnetic resonance imaging (12) further support the notion that the basic memory trace is formed in the AIN. On the other hand, the cerebellar cortex is implicated as a site of storage for the memory trace of CR timing (13).Although the existence of a Purkinje cell-specific promoter like L7/pcp-2 made it possible to test the relevance of some molecules to cortical function in eyeblink conditioning in vivo (14,15), mechanistic studies at the molecular level of the AIN, which is ...

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“…Abnormalities in eye-blink conditioning have been associated with cerebellar alterations (49). Accordingly, we previously showed that the cerebella of MAO A/B KO, but not MAO A KO, mice exhibit significant reductions of Purkinje cells number and enhancements of the molecular and granule cells layers (16).…”

Section: Mao A/b Ko Mice Showed Enhanced Contextual and Cue Memory Andmentioning

confidence: 96%

Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice

Singh

Bortolato

Bali

et al. 2013

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

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The monoamine oxidase isoenzymes (MAOs) A and B play important roles in the homeostasis of monoaminergic neurotransmitters. The combined deficiency of MAO A and B results in significantly elevated levels of serotonin (5-hydroxytryptamine), norepinephrine, dopamine, and β-phenylethylamine; in humans and mice, these neurochemical changes are accompanied by neurodevelopmental perturbations as well as autistic-like responses. Ample evidence indicates that normal levels of monoamines in the hippocampus, amygdala, frontal cortex, and cerebellum are required for the integrity of learning and memory. Thus, in the present study, the cognitive status of MAO A/B knockout (KO) mice was examined with a wide array of behavioral tests. In comparison with male wild-type littermates, MAO A/B KO mice exhibited abnormally high and overgeneralized fear conditioning and enhanced eye-blink conditioning. These alterations were accompanied by significant increases in hippocampal long-term potentiation and alterations in the relative expression of NMDA glutamate receptor subunits. Our data suggest that chronic elevations of monoamines, because of the absence of MAO A and MAO B, cause functional alterations that are accompanied with changes in the cellular mechanisms underlying learning and memory. The characteristics exhibited by MAO A/B KO mice highlight the potential of these animals as a useful tool to provide further insight into the molecular bases of disorders associated with abnormal monoaminergic profiles.adult neurogenesis | autism-spectrum disorder | cognition M onoaminergic neurotransmitters, such as serotonin (5-HT), norepinephrine (NE), and dopamine (DA), are known to play a critical role in the modulation of mood and emotion, as well as the control of motor, perceptual, and other cognitive functions (1). Abnormal levels of these monoamines have been associated with several neuropsychiatric disorders (2-5). The enzymatic metabolism of these neurotransmitters is mainly catalyzed by monoamine oxidase (MAO), a mitochondrial-bound flavoprotein (6). The two MAO isoenzymes, A and B, are encoded by different genes next to each other on the X chromosome (7), with 70% amino acid identity (8) and identical intron-exon organization (9). MAO A has a higher affinity for 5-HT, NE, and DA (6, 10). In contrast, MAO B prefers phenylethylamine (PEA) as substrate (11), although it can degrade 5-HT, NE, and DA in the absence of MAO A (12). As a consequence, the lack of both isoenzymes in mice results in significantly higher monoamine levels than those observed in single knockout (KO) counterparts (12). The deficiency of both MAO isoenzymes in humans has been found to be associated with severe intellectual and developmental disabilities, hypotonia, failure to thrive, and autisticlike symptoms (including sociocommunicative deficits and perseverative manifestations) (13-15). Although similar alterations were also featured by MAO A KO mice, the severity of the changes was typically more pervasive in MAO A/B KO mice, supporting the idea that the se...

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Impaired classical eyeblink conditioning in cerebellar-lesioned and Purkinje cell degeneration (pcd) mutant mice

Cited by 208 publications

References 48 publications

Age-Related Impairment in the 250-Millisecond Delay Eyeblink Classical Conditioning Procedure in C57BL/6 Mice

Age-Related Impairment in the 250-Millisecond Delay Eyeblink Classical Conditioning Procedure in C57BL/6 Mice

Molecular evidence for two-stage learning and partial laterality in eyeblink conditioning of mice

Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice

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