Article

Effects of Climbing Fiber Driven Inhibition on Purkinje Neuron Spiking

University of California, Los Angeles, Los Ángeles, California, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 12/2012; 32(50):17988-97. DOI: 10.1523/JNEUROSCI.3916-12.2012
Source: PubMed

ABSTRACT Climbing fiber (CF) input to the cerebellum is thought to instruct associative motor memory formation through its effects on multiple sites within the cerebellar circuit. We used adeno-associated viral delivery of channelrhodopsin-2 (ChR2) to inferior olivary neurons to selectively express ChR2 in CFs, achieving nearly complete transfection of CFs in the caudal cerebellar lobules of rats. As expected, optical stimulation of ChR2-expressing CFs generates complex spike responses in individual Purkinje neurons (PNs); in addition we found that such stimulation recruits a network of inhibitory interneurons in the molecular layer. This CF-driven disynaptic inhibition prolongs the postcomplex spike pause observed when spontaneously firing PNs receive direct CF input; such inhibition also elicits pauses in spontaneously firing PNs not receiving direct CF input. Baseline firing rates of PNs are strongly suppressed by low-frequency (2 Hz) stimulation of CFs, and this suppression is partly relieved by blocking synaptic inhibition. We conclude that CF-driven, disynaptic inhibition has a major influence on PN excitability and contributes to the widely observed negative correlation between complex and simple spike rates. Because they receive input from many CFs, molecular layer interneurons are well positioned to detect the spatiotemporal patterns of CF activity believed to encode error signals. Together, our findings suggest that such inhibition may bind together groups of Purkinje neurons to provide instructive signals to downstream sites in the cerebellar circuit.

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Available from: Tom S Otis, Sep 09, 2014
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    • "Regulation of CF synchrony could be used to control the efficacy of plasticity signals (De Gruijl et al., 2012; Tokuda et al., 2013). For example, sensory events that activate many CFs simultaneously may be particularly effective for triggering NMDA-dependent plasticity in molecular layer interneurons of the cerebellar cortex (Duguid and Smart, 2004), via synchronized spillover of glutamate from multiple CF release sites (Szapiro and Barbour, 2007; Mathews et al., 2012). Another possibility is that CF synchrony could be used to set the strength of the plasticity signals sent by inhibitory PCs to downstream cells of the deep cerebellar nuclei (DCN; Otis et al., 2012), which are the final output of the cerebellum. "
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    ABSTRACT: eLife digest A region of the brain known as the cerebellum plays a key role in learning how to anticipate an event. For example, if you know that a puff of air is going to be directed at your eye, it's a good idea to close it in advance. However, how much you need to close it depends on how strong that puff of air is. A very strong puff might require closing the eye completely to protect it. In contrast, it is probably better to only partially close the eye if you know a lighter puff of air is coming, so that you can still see. Extensive research has focused on how neurons in and around the cerebellum work together to achieve this goal. When an event—such as a puff of air—occurs, signals are sent to large neurons in the cerebellum, called Purkinje cells, by ‘climbing fibers’. However, climbing fibers were thought to be able to respond in only two ways: either they fire in a single burst to signal that an event has occurred, or they don't fire. It was therefore unclear how the finer details of the event (for example, the strength of the puff of air) are transmitted to the cerebellum. Najafi et al. imaged the level of calcium in the cerebellum of mice, as this indicates how active the neurons are. When a puff of air was directed at the eyes of the mice, Najafi et al. saw that the size of the response of the Purkinje cells corresponded with how big the puff of air was. Najafi et al. show that the size of this response, which is based mostly on input from the climbing fibers, is also influenced by input from an additional unknown source. These findings show that Purkinje cells of the cerebellum receive detailed information about the nature of an event, such as a puff of air. What remains to be seen is whether the cerebellum uses this information to learn the correct response, that is how hard to blink to avoid the expected puff. DOI: http://dx.doi.org/10.7554/eLife.03663.002
    eLife Sciences 09/2014; 3:e03663. DOI:10.7554/eLife.03663 · 8.52 Impact Factor
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    • "For example , we did obtain evidence for potential contacts between climbing fibers and interneurons in the molecular layer of the mouse using a light microscopic, double-labeling tracing immuno approach (Galliano et al., 2013a). Indeed, other laboratories have shown a climbing fiber influence on molecular layer interneurons at the physiological level, presumably through extrasynaptic release (Mathews et al., 2012; Szapiro and Barbour, 2007). Instead, our double-labeling approach mentioned above did not reveal potential contacts between climbing fibers and Golgi cells in the granular layer (Galliano et al., 2013a), nor did ultrastructural and electrophysiological studies on the inputs converging on Golgi cells (Cesana et al., 2013). "
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    ABSTRACT: The basic principles of cerebellar function were originally described by Flourens, Cajal, and Marr/Albus/Ito, and they constitute the pillars of what can be considered to be the classic cerebellar doctrine. In their concepts, the main cerebellar function is to control motor behavior, Purkinje cells are the only cortical neuron receiving and integrating inputs from climbing fiber and mossy-parallel fiber pathways, and plastic modification at the parallel fiber synapses onto Purkinje cells constitutes the substrate of motor learning. Yet, because of recent technical advances and new angles of investigation, all pillars of the cerebellar doctrine now face regular re-examination. In this review, after summarizing the classic concepts and recent disputes, we attempt to synthesize an integrated view and propose a revisited version of the cerebellar doctrine.
    Progress in brain research 01/2014; 210C:59-77. DOI:10.1016/B978-0-444-63356-9.00003-0 · 5.10 Impact Factor
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    • "Golgi cells and unipolar brush cells also modulate the discharge of SSs indirectly by synaptically influencing the discharge of granule cells. The discharge of each of these interneurons is modulated by sinusoidal roll tilt (Barmack and Yakhnitsa 2008, 2011a, 2011b; Mathews et al. 2012; Szapiro and Barbour 2007). "
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    ABSTRACT: Cerebellar Purkinje cells are excited by two afferent pathways --- climbing and mossy fibers. Climbing fibers evoke large "complex spikes" (CSs) that discharge at low frequencies. Mossy fibers synapse upon granule cells whose parallel fibers excite Purkinje cells and may contribute to the genesis of "simple spikes" (SSs). Both afferent systems convey vestibular information to folia 9c 10. After making a unilateral labyrinthectomy (UL) in mice, we tested how the discharge of CSs and SSs was changed by the loss of primary vestibular afferent mossy fibers during sinusoidal roll tilt. We recorded from cells identified by juxtacellular neurobiotin labeling. The UL preferentially reduced vestibular modulation of CSs and SSs in folia 8 10 contralateral to the UL. The effects of a UL on Purkinje cell discharge were similar in folia 9c-10, to which vestibular primary afferents project, and in folia 8-9a, to which they do not project, suggesting that vestibular primary afferent mossy fibers were not responsible for the UL induced alteration of SS discharge. UL also induced reduced vestibular modulation of stellate cell discharge contralateral to the UL. We attribute the decreased modulation to reduced vestibular modulation of climbing fibers. In sum, climbing fibers modulate CSs directly and SSs indirectly through activation of stellate cells. While vestibular primary afferent mossy fibers cannot account for the modulated discharge of SSs or stellate cells, the non-specific excitation of Purkinje cells by parallel fibers may set an operating point about which the discharges of SSs are sculpted by climbing fibers.
    Journal of Neurophysiology 08/2013; 110(10). DOI:10.1152/jn.00352.2013 · 3.04 Impact Factor
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