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: 6.34). 12/2012; 32(50):17988-97. DOI: 10.1523/JNEUROSCI.3916-12.2012
Source: PubMed


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.

Download full-text


Available from: Tom S Otis, Sep 09, 2014
  • Source
    • "The resulting CS-activated olivary inhibition could then bear rebound spikes (Bazzigaluppi et al., 2012; De Gruijl et al., 2012) that return to the cerebellum to affect cortical activity in a number of ways. It could influence simple spike suppression through the climbing fiber pause (De Zeeuw et al., 2011), through non-synaptic activation of MLIs (Jö rntell and Ekerot, 2003; Szapiro and Barbour, 2007; Mathews et al., 2012), as well as through several climbing fiber-dependent forms of cerebellar cortical plasticity (Gao et al., 2012). Besides influencing simple spike suppression, it could play a role in higher-order conditioning, allowing the CS to be associated to novel input stimuli, preserving efficiently the same output pathway to the proper motor domain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Three decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink responses (CRs). However, trial-by-trial quantification of this link in awake behaving animals is lacking, and current hypotheses regarding the underlying plasticity mechanisms have diverged from the classical parallel fiber one to the Purkinje cell synapse LTD hypothesis. Here, we establish that acquired simple spike suppression, acquired conditioned stimulus (CS)-related complex spike responses, and molecular layer interneuron (MLI) activity predict the expression of CRs on a trial-by-trial basis using awake behaving mice. Additionally, we show that two independent transgenic mouse mutants with impaired MLI function exhibit motor learning deficits. Our findings suggest multiple cerebellar cortical plasticity mechanisms underlying simple spike suppression, and they implicate the broader involvement of the olivocerebellar module within the interstimulus interval.
    Full-text · Article · Dec 2015 · Cell Reports
  • Source
    • "Cite this article as Cold Spring Harb Perspect Biol 2015;7:a021683 to an increase in complex spike activity (De Zeeuw et al. 1988). Because an increase in complex spike activity suppresses simple spike frequency through cerebellar cortical interneurons in the molecular layer (Mathews et al. 2012; Coddington et al. 2013), this network effect ultimately provides an excellent way to mediate homeostasis of activity within the olivocerebellar modules (Fig. 3B,C). Together, the intrinsically determined simple spike and complex spike activity at rest provide the baseline values around which the Purkinje cells are modulated during natural sensory stimulation, such as that used to induce motor learning. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although our ability to store semantic declarative information can nowadays be readily surpassed by that of simple personal computers, our ability to learn and express procedural memories still outperforms that of supercomputers controlling the most advanced robots. To a large extent, our procedural memories are formed in the cerebellum, which embodies more than two-thirds of all neurons in our brain. In this review, we will focus on the emerging view that different modules of the cerebellum use different encoding schemes to form and express their respective memories. More specifically, zebrin-positive zones in the cerebellum, such as those controlling adaptation of the vestibulo-ocular reflex, appear to predominantly form their memories by potentiation mechanisms and express their memories via rate coding, whereas zebrin-negative zones, such as those controlling eyeblink conditioning, appear to predominantly form their memories by suppression mechanisms and express their memories in part by temporal coding using rebound bursting. Together, the different types of modules offer a rich repertoire to acquire and control sensorimotor processes with specific challenges in the spatiotemporal domain. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Full-text · Article · Sep 2015 · Cold Spring Harbor perspectives in biology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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:
    Full-text · Article · Sep 2014 · eLife Sciences
Show more