The neural circuitry and molecular mechanisms underlying delay and trace eyeblink conditioning in mice

Yang, Ying; Chen, Lei; Feng, Hua; Sui, Jian-feng

doi:10.1016/j.bbr.2014.10.006

Cited by 29 publications

(32 citation statements)

References 94 publications

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“…The eyeblink is a reflex in response to corneal stimulation (Yang et al., 2015). In classical eyeblink conditioning, animals learn to associate a conditioned stimulus (CS), such as a tone, with an unconditioned stimulus (US), such as a mild electric shock to the supraorbital nerve, which evokes eyeblinks (Figure S4A).…”

Section: Resultsmentioning

confidence: 99%

Compromised Survival of Cerebellar Molecular Layer Interneurons Lacking GDNF Receptors GFRα1 or RET Impairs Normal Cerebellar Motor Learning

et al. 2017

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SummaryThe role of neurotrophic factors as endogenous survival proteins for brain neurons remains contentious. In the cerebellum, the signals controlling survival of molecular layer interneurons (MLIs) are unknown, and direct evidence for the requirement of a full complement of MLIs for normal cerebellar function and motor learning has been lacking. Here, we show that Purkinje cells (PCs), the target of MLIs, express the neurotrophic factor GDNF during MLI development and survival of MLIs depends on GDNF receptors GFRα1 and RET. Conditional mutant mice lacking either receptor lose a quarter of their MLIs, resulting in compromised synaptic inhibition of PCs, increased PC firing frequency, and abnormal acquisition of eyeblink conditioning and vestibulo-ocular reflex performance, but not overall motor activity or coordination. These results identify an endogenous survival mechanism for MLIs and reveal the unexpected vulnerability and selective requirement of MLIs in the control of cerebellar-dependent motor learning.

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Section: Resultsmentioning

confidence: 99%

Compromised Survival of Cerebellar Molecular Layer Interneurons Lacking GDNF Receptors GFRα1 or RET Impairs Normal Cerebellar Motor Learning

et al. 2017

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“…Even so, there are important differences in the involvement of forebrain structures (Christian and Thompson, 2003). Although the cerebellum is necessary for both, lesions in various forebrain regions affect trace but not delay conditioning (Solomon and Moore, 1975;Berger and Orr, 1983;Woodruff-Pak et al, 1985;Solomon et al, 1986;Moyer et al, 1990;Kalmbach et al, 2009Kalmbach et al, , 2010a.…”

Section: Introductionmentioning

confidence: 99%

“…Using stimulation of mossy fibers as the CS, Kalmbach et al (2010b) established that cerebellar learning requires that CSactivated mossy fiber inputs overlap in time with climbing fiber inputs activated by the US. Subsequently, Kalmbach et al (2011) showed that two mossy fiber inputs, one lasting the duration of a CS and one persisting into the trace interval, were sufficient for the cerebellum to acquire responses with properties that quantitatively match trace eyelid responses with a traditional tone CS. Combined, these findings suggest that the necessary forebrain contribution is to provide the cerebellum with a mossy fiber input that persists into the trace interval to engage cerebellar learning (Clark and Squire, 1998;Siegel et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Cerebellar Processing Common to Delay and Trace Eyelid Conditioning

2018

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Results from previous lesion studies have been interpreted as evidence that the cerebellar cortex plays different roles for delay and trace conditioning of eyelid responses. However, the cerebellar cortex is organized by parasagittal stripes of Purkinje cells (PCs) that converge onto common deep nucleus neurons and receive common or related climbing fiber inputs. Based on this organization, we hypothesized that cerebellar tasks involving the same response system, such as delay and trace eyelid conditioning, would engage the same PCs and that the relationships between PC activity and expression of behavioral responses would be similar for both tasks. To test these hypotheses, we used tetrode recordings from eyelid PCs in rabbits during expression of delay- and trace-conditioned eyelid responses. Previous recording studies during delay conditioning described a strong relationship between eyelid PC activity and the kinematics of conditioned eyelid responses. The present results replicate these findings for delay conditioning and show that the same relationship exists during trace eyelid conditioning. During transitions from delay to trace responding, the relationship between eyelid PCs and behavioral responses was relatively stable. We found that an inverse firing rate model tuned to predict PC activity during one training paradigm could then predict equally well the PC activity during the other training paradigm. These results provide strong evidence that cerebellar cortex processing is similar for delay and trace eyelid conditioning and that the parasagittal organization of the cerebellum, not the conditioning paradigm, dictate which neurons are engaged to produce adaptively timed conditioned responses. A variety of evidence from eyelid conditioning and other cerebellar-dependent behaviors indicates that the cerebellar cortex is necessary for learning and proper timing of cerebellar learned responses. Debates exist about whether trace eyelid conditioning data show that fundamentally different mechanisms operate in the cerebellum during tasks when input from the forebrain is necessary for learning. We show here that learning-related changes in a specific population of Purkinje cells control the timing and amplitude of cerebellar responses the same way regardless of the inputs necessary to learn the task. Our results indicate the parasagittal organization of the cerebellar cortex, not the complexity of inputs to the cerebellum, determines which neurons are engaged in the learning and execution of cerebellar-mediated responses.

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“…Furthermore, there are many behavioral tasks developed to assess the function of these brain regions [9, 26, 221, 231]. This includes the circuits that control the cognitive processes that are most vulnerable to aging, the hippocampus and the prefrontal cortex (PFC) [138].…”

Section: Model Systems and Assays Of Cognitive Functionmentioning

confidence: 99%

Conserved regulators of cognitive aging: From worms to humans

Arey

Murphy

2017

Behavioural Brain Research

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Cognitive decline is a major deficit that arises with age in humans. While some research on the underlying causes of these problems can be done in humans, harnessing the strengths of small model systems, particularly those with well-studied longevity mutants, such as the nematode C. elegans, will accelerate progress. Here we review the approaches being used to study cognitive decline in model organisms and show how simple model systems allow the rapid discovery of conserved molecular mechanisms, which will eventually enable the development of therapeutics to slow cognitive aging.

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The neural circuitry and molecular mechanisms underlying delay and trace eyeblink conditioning in mice

Cited by 29 publications

References 94 publications

Compromised Survival of Cerebellar Molecular Layer Interneurons Lacking GDNF Receptors GFRα1 or RET Impairs Normal Cerebellar Motor Learning

Compromised Survival of Cerebellar Molecular Layer Interneurons Lacking GDNF Receptors GFRα1 or RET Impairs Normal Cerebellar Motor Learning

Cerebellar Processing Common to Delay and Trace Eyelid Conditioning

Conserved regulators of cognitive aging: From worms to humans

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