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Specificity of inferior olive response to stimulus timing.

ABSTRACT: The inferior olive is the sole source of the climbing fiber system, one of the two major afferent systems of the cerebellum; however, its exact role remains unknown. A longstanding hypothesis is that the inferior olive with its unique intrinsic rhythmic firing properties mediates motor timing. However, direct evidence linking the inferior olive to timing behavior has been difficult to demonstrate in animal or human studies likely due to the inhibition of inferior olive responses by self-produced movement. Here we used event-related functional magnetic resonance imaging (fMRI) and a perceptual task that dissociates the temporal from nontemporal attributes of sensory input. Subjects were asked to attend to rhythmically occurring identical visual stimuli and to detect a change in their timing, spatial orientation, or color. Inferior olive activation was seen only when perceiving a change in stimulus timing. These results are consistent with animal studies demonstrating that the inferior olive is especially sensitive to "unexpected" sensory events and further provide evidence supporting the specificity of the inferior olive response to stimulus timing. The results are consistent with the view that the inferior olive and the climbing fiber system mediate the encoding of temporal information required for both motor and nonmotor cognitive processes.

SUBMITTER: Liu T

PROVIDER: S-EPMC2544464 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Specificity of inferior olive response to stimulus timing.

Liu T T Xu D D Ashe J J Bushara K K

Journal of neurophysiology 20080716 3

The inferior olive is the sole source of the climbing fiber system, one of the two major afferent systems of the cerebellum; however, its exact role remains unknown. A longstanding hypothesis is that the inferior olive with its unique intrinsic rhythmic firing properties mediates motor timing. However, direct evidence linking the inferior olive to timing behavior has been difficult to demonstrate in animal or human studies likely due to the inhibition of inferior olive responses by self-produced ...[more]

PMID: 18632890

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Project description:BackgroundAbility to adapt to temperature changes trough the Heat Shock Response (HSR) pathways is one of the most fundamental and clinically relevant cellular response systems. Heat Shock (HS) affects the signalling and gene expression responses of the Nuclear Factor κB (NF-κB) transcription factor, a critical regulator of proliferation and inflammation, however, our quantitative understanding of how cells sense and adapt to temperature changes is limited.MethodsWe used live-cell time-lapse microscopy and mathematical modelling to understand the signalling of the NF-κB system in the human MCF7 breast adenocarcinoma cells in response to pro-inflammatory Interleukin 1β (IL1β) and Tumour Necrosis Factor α (TNFα) cytokines, following exposure to a 37-43 °C range of physiological and clinical temperatures.ResultsWe show that exposure to 43 °C 1 h HS inhibits the immediate NF-κB signalling response to TNFα and IL1β stimulation although uptake of cytokines is not impaired. Within 4 h after HS treatment IL1β-induced NF-κB responses return to normal levels, but the recovery of the TNFα-induced responses is still affected. Using siRNA knock-down of Heat Shock Factor 1 (HSF1) we show that this stimulus-specificity is conferred via the Inhibitory κB kinase (IKK) signalosome where HSF1-dependent feedback regulates TNFα, but not IL1β-mediated IKK recovery post HS. Furthermore, we demonstrate that through the temperature-dependent denaturation and recovery of IKK, TNFα and IL1β-mediated signalling exhibit different temperature sensitivity and adaptation to repeated HS when exposed to a 37-43 °C temperature range. Specifically, IL1β-mediated NF-κB responses are more robust to temperature changes in comparison to those induced by TNFα treatment.ConclusionsWe demonstrate that the kinetics of the NF-κB system following temperature stress is cytokine specific and exhibit differential adaptation to temperature changes. We propose that this differential temperature sensitivity is mediated via the IKK signalosome, which acts as a bona fide temperature sensor trough the HSR cross-talk. This novel quantitative understanding of NF-κB and HSR interactions is fundamentally important for the potential optimization of therapeutic hyperthermia protocols. Video Abstract.

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Specificity of inferior olive response to stimulus timing.

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Specificity of inferior olive response to stimulus timing.

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