scholarly journals Differential spatiotemporal development of Purkinje cell populations and cerebellum-dependent sensorimotor behaviors

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Gerrit Cornelis Beekhof ◽  
Catarina Osório ◽  
Joshua J White ◽  
Scott van Zoomeren ◽  
Hannah van der Stok ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Eyeblink Conditioning ◽  
Rapid Development ◽  
Modular Organization ◽  
Cell Populations ◽  
Activity Levels ◽  
Firing Activity ◽  
The Core ◽  
Cerebellar Modules

Distinct populations of Purkinje cells (PCs) with unique molecular and connectivity features are at the core of the modular organization of the cerebellum. Previously, we showed that firing activity of Purkinje cells differs between ZebrinII-positive (Z+) and -negative (Z−) cerebellar modules (Zhou et al., 2014; Wu et al., 2019). Here, we investigate the timing and extent of PC differentiation during development in mice. We found that several features of PCs, including activity levels, dendritic arborisation, axonal shape and climbing fiber input, develop differentially between nodular and anterior PC populations. Although all PCs show a particularly rapid development in the second postnatal week, anterior PCs typically have a prolonged physiological and dendritic maturation. In line herewith, younger mice exhibit attenuated anterior-dependent eyeblink conditioning, but faster nodular-dependent compensatory eye movement adaptation. Our results indicate that specific cerebellar regions have unique developmental timelines which match with their related, specific forms of cerebellum-dependent behaviors.

scholarly journals Activation of MAP3K DLK and LZK in Purkinje Cells Causes Rapid and Slow Degeneration Depending on Signaling Strength

2020 ◽  
Author(s):  
Yunbo Li ◽  
Erin M Ritchie ◽  
Christopher L. Steinke ◽  
Cai Qi ◽  
Lizhen Chen ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Leucine Zipper ◽  
Activity Levels ◽  
Cell Type ◽  
Cell Degeneration ◽  
Mechanistic Basis ◽  
Cerebellar Purkinje Cells ◽  
Jnk Activation

SummaryThe conserved MAP3K Dual leucine zipper kinases can activate JNK via MKK4 or MKK7. Vertebrate DLK and LZK share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of Mkk7, strongly attenuates Purkinje cell degeneration induced by activation of LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

scholarly journals A recurrent circuit links antagonistic cerebellar modules during associative motor learning

2021 ◽  
Author(s):  
Shogo Ohmae ◽  
Keiko Ohmae ◽  
Shane A Heiney ◽  
Divya Subramanian ◽  
Javier F Medina
Keyword(s):  
Purkinje Cells ◽  
Functional Organization ◽  
Eyeblink Conditioning ◽  
Recurrent Network ◽  
Basic Operation ◽  
Conventional View ◽  
Neural Architecture ◽  
Recurrent Network Dynamics ◽  
Cerebellar Modules ◽  
Specific Error

The neural architecture of the cerebellum is thought to be specialized for performing supervised learning: specific error-related climbing fiber inputs are used to teach sensorimotor associations to small ensembles of Purkinje cells located in functionally distinct modules that operate independently of each other in a purely feedforward manner. Here, we test whether the basic operation of the cerebellum complies with this basic architecture in mice that learned a simple sensorimotor association during eyeblink conditioning. By recording Purkinje cells in different modules and testing whether their responses rely on recurrent circuits, our results reveal three operational principles about the functional organization of the cerebellum that stand in stark contrast to the conventional view: (1) Antagonistic organization, (2) Recurrent network dynamics, and (3) Intermodular communication. We propose that the neural architecture of the cerebellum implements these three operational principles to achieve optimal performance and solve a number of problems in motor control.

Effect of Conditioned Stimulus Parameters on Timing of Conditioned Purkinje Cell Responses

2010 ◽  
Vol 103 (3) ◽  
pp. 1329-1336 ◽  
Author(s):  
Pär Svensson ◽  
Dan-Anders Jirenhed ◽  
Fredrik Bengtsson ◽  
Germund Hesslow
Keyword(s):  
Conditioned Stimulus ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Mossy Fiber ◽  
Eyeblink Conditioning ◽  
Mossy Fibers ◽  
Inhibitory Response ◽  
Cell Responses ◽  
Cerebellar Purkinje Cells ◽  
Adaptive Timing

Pavlovian eyeblink conditioning is a useful experimental model for studying adaptive timing, an important aspect of skilled movements. The conditioned response (CR) is precisely timed to occur just before the onset of the expected unconditioned stimulus (US). The timing can be changed immediately, however, by varying parameters of the conditioned stimulus (CS). It has previously been shown that increasing the intensity of a peripheral CS or the frequency of a CS consisting of a train of stimuli to the mossy fibers shortens the latency of the CR. The adaptive timing of behavioral CRs probably reflects the timing of an underlying learned inhibitory response in cerebellar Purkinje cells. It is not known how the latency of this Purkinje cell CR is controlled. We have recorded form Purkinje cells in conditioned decerebrate ferrets while increasing the intensity of a peripheral CS or the frequency of a mossy fiber CS. We observe changes in the timing of the Purkinje cell CR that match the behavioral effects. The results are consistent with the effect of CS parameters on behavioral CR latency being caused by corresponding changes in Purkinje cell CRs. They suggest that synaptic temporal summation may be one of several mechanisms underlying adaptive timing of movements.

scholarly journals Purkinje cell activity during classical conditioning with different conditional stimuli explains central tenet of Rescorla–Wagner model

2015 ◽  
Vol 112 (45) ◽  
pp. 14060-14065 ◽  
Author(s):  
Anders Rasmussen ◽  
Riccardo Zucca ◽  
Fredrik Johansson ◽  
Dan-Anders Jirenhed ◽  
Germund Hesslow
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Compound Stimulus ◽  
Eyeblink Conditioning ◽  
Unconditional Stimulus ◽  
Cell Activity ◽  
Neural Mechanisms ◽  
Wagner Model ◽  
Central Tenet ◽  
Reinforcement Value

A central tenet of Rescorla and Wagner’s model of associative learning is that the reinforcement value of a paired trial diminishes as the associative strength between the presented stimuli increases. Despite its fundamental importance to behavioral sciences, the neural mechanisms underlying the model have not been fully explored. Here, we present findings that, taken together, can explain why a stronger association leads to a reduced reinforcement value, within the context of eyeblink conditioning. Specifically, we show that learned pause responses in Purkinje cells, which trigger adaptively timed conditioned eyeblinks, suppress the unconditional stimulus (US) signal in a graded manner. Furthermore, by examining how Purkinje cells respond to two distinct conditional stimuli and to a compound stimulus, we provide evidence that could potentially help explain the somewhat counterintuitive overexpectation phenomenon, which was derived from the Rescorla–Wagner model.

scholarly journals Coding of stimulus strength via analog calcium signals in Purkinje cell dendrites of awake mice

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Farzaneh Najafi ◽  
Andrea Giovannucci ◽  
Samuel S-H Wang ◽  
Javier F Medina
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Eyeblink Conditioning ◽  
Climbing Fiber ◽  
Stimulus Strength ◽  
Calcium Signals ◽  
Calcium Spikes ◽  
Conditioning Information ◽  
Teaching Signal ◽  
Purkinje Cell Dendrites

The climbing fiber input to Purkinje cells acts as a teaching signal by triggering a massive influx of dendritic calcium that marks the occurrence of instructive stimuli during cerebellar learning. Here, we challenge the view that these calcium spikes are all-or-none and only signal whether the instructive stimulus has occurred, without providing parametric information about its features. We imaged ensembles of Purkinje cell dendrites in awake mice and measured their calcium responses to periocular airpuffs that serve as instructive stimuli during cerebellar-dependent eyeblink conditioning. Information about airpuff duration and pressure was encoded probabilistically across repeated trials, and in two additional signals in single trials: the synchrony of calcium spikes in the Purkinje cell population, and the amplitude of the calcium spikes, which was modulated by a non-climbing fiber pathway. These results indicate that calcium-based teaching signals in Purkinje cells contain analog information that encodes the strength of instructive stimuli trial-by-trial.

scholarly journals Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yunbo Li ◽  
Erin M Ritchie ◽  
Christopher L Steinke ◽  
Cai Qi ◽  
Lizhen Chen ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Leucine Zipper ◽  
Activity Levels ◽  
Cell Type ◽  
Cell Degeneration ◽  
Mechanistic Basis ◽  
Cerebellar Purkinje Cells ◽  
Jnk Activation

The conserved MAP3K Dual-Leucine-Zipper Kinase (DLK) and Leucine-Zipper-bearing Kinase (LZK) can activate JNK via MKK4 or MKK7. These two MAP3Ks share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of Map2k7, strongly attenuates Purkinje cell degeneration induced by LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

scholarly journals Differential Purkinje cell simple spike activity and pausing behavior related to cerebellar modules

2015 ◽  
Vol 113 (7) ◽  
pp. 2524-2536 ◽  
Author(s):  
Haibo Zhou ◽  
Kai Voges ◽  
Zhanmin Lin ◽  
Chiheng Ju ◽  
Martijn Schonewille
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Spike Activity ◽  
Vestibular Nuclei ◽  
Simple Spike ◽  
Transverse Zone ◽  
Cerebellar Modules ◽  
Lower Temperature ◽  
Cerebellar Purkinje Cells

The massive computational capacity of the cerebellar cortex is conveyed by Purkinje cells onto cerebellar and vestibular nuclei neurons through their GABAergic, inhibitory output. This implies that pauses in Purkinje cell simple spike activity are potentially instrumental in cerebellar information processing, but their occurrence and extent are still heavily debated. The cerebellar cortex, although often treated as such, is not homogeneous. Cerebellar modules with distinct anatomical connectivity and gene expression have been described, and Purkinje cells in these modules also differ in firing rate of simple and complex spikes. In this study we systematically correlate, in awake mice, the pausing in simple spike activity of Purkinje cells recorded throughout the entire cerebellum, with their location in terms of lobule, transverse zone, and zebrin-identified cerebellar module. A subset of Purkinje cells displayed long (>500-ms) pauses, but we found that their occurrence correlated with tissue damage and lower temperature. In contrast to long pauses, short pauses (<500 ms) and the shape of the interspike interval (ISI) distributions can differ between Purkinje cells of different lobules and cerebellar modules. In fact, the ISI distributions can differ both between and within populations of Purkinje cells with the same zebrin identity, and these differences are at least in part caused by differential synaptic inputs. Our results suggest that long pauses are rare but that there are differences related to shorter intersimple spike intervals between and within specific subsets of Purkinje cells, indicating a potential further segregation in the activity of cerebellar Purkinje cells.

scholarly journals A FN-MdV pathway and its role in cerebellar multimodular control of sensorimotor behavior

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiaolu Wang ◽  
Si-yang Yu ◽  
Zhong Ren ◽  
Chris I. De Zeeuw ◽  
Zhenyu Gao
Keyword(s):  
Purkinje Cells ◽  
Motor Neurons ◽  
Eyeblink Conditioning ◽  
Fastigial Nucleus ◽  
Reticular Nucleus ◽  
Eyelid Closure ◽  
Interposed Nucleus ◽  
Conditioned Responses ◽  
Cerebellar Modules ◽  
Synergistic Modulation

AbstractThe cerebellum is crucial for various associative sensorimotor behaviors. Delay eyeblink conditioning (DEC) depends on the simplex lobule-interposed nucleus (IN) pathway, yet it is unclear how other cerebellar modules cooperate during this task. Here, we demonstrate the contribution of the vermis-fastigial nucleus (FN) pathway in controlling DEC. We found that task-related modulations in vermal Purkinje cells and FN neurons predict conditioned responses (CRs). Coactivation of the FN and the IN allows for the generation of proper motor commands for CRs, but only FN output fine-tunes unconditioned responses. The vermis-FN pathway launches its signal via the contralateral ventral medullary reticular nucleus, which converges with the command from the simplex-IN pathway onto facial motor neurons. We propose that the IN pathway specifically drives CRs, whereas the FN pathway modulates the amplitudes of eyelid closure during DEC. Thus, associative sensorimotor task optimization requires synergistic modulation of different olivocerebellar modules each provide unique contributions.

scholarly journals A Novel FN-MdV Pathway and Its Role in Cerebellar Multimodular Control of Sensorimotor Behavior

2020 ◽  
Author(s):  
Xiaolu Wang ◽  
Si-yang Yu ◽  
Zhong Ren ◽  
Chris De Zeeuw ◽  
Zhenyu Gao
Keyword(s):  
Purkinje Cells ◽  
Motor Neurons ◽  
Eyeblink Conditioning ◽  
Fastigial Nucleus ◽  
Reticular Nucleus ◽  
Eyelid Closure ◽  
Interposed Nucleus ◽  
Conditioned Responses ◽  
Cerebellar Modules ◽  
Synergistic Modulation

Abstract The cerebellum is crucial for various associative sensorimotor behaviors. Delay eyeblink conditioning (DEC) depends on the simplex lobule-interposed nucleus (IN) pathway, yet it is unclear how other cerebellar modules cooperate during this task. Here, we demonstrate the contribution of the vermis-fastigial nucleus (FN) pathway in controlling DEC. We found that task-related modulations in vermal Purkinje cells and FN neurons predict conditioned responses (CRs). Coactivation of the FN and the IN allows for the generation of proper motor commands for CRs, but only FN output fine-tunes unconditioned responses. The vermis-FN pathway launches its signal via the contralateral ventral medullary reticular nucleus, which converges with the command from the simplex-IN pathway onto facial motor neurons. We propose that the IN pathway specifically drives CRs whereas the FN pathway modulates the amplitudes of eyelid closure during DEC. Thus, associative sensorimotor task optimization requires synergistic modulation of different olivocerebellar modules that provide unique contributions.

scholarly journals Cerebellar Purkinje cells can differentially modulate coherence between sensory and motor cortex depending on region and behavior

2020 ◽  
Author(s):  
Sander Lindeman ◽  
Lieke Kros ◽  
Sungho Hong ◽  
Jorge F. Mejias ◽  
Vincenzo Romano ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Sensory Stimulation ◽  
Gamma Band ◽  
Modular Organization ◽  
Cell Stimulation ◽  
Site Specific ◽  
Whisker Stimulation ◽  
Cerebellar Purkinje Cells ◽  
Stimulation Of

AbstractCoherence among sensory and motor cortices is indicative of binding of critical functions in perception, motor planning, action and sleep. Evidence is emerging that the cerebellum can impose coherence between cortical areas, but how and when it does so is unclear. Here, we studied coherence between primary somatosensory (S1) and motor (M1) cortices during sensory stimulation of the whiskers in the presence and absence of optogenetic stimulation of cerebellar Purkinje cells in awake mice. Purkinje cell activation enhanced and reduced sensory-induced S1-M1 coherence in the theta and gamma bands, respectively. This impact only occurred when Purkinje cell stimulation was given simultaneously with sensory stimulation; a 20 ms delay was sufficient to alleviate its impact, suggesting the existence of a fast, cerebellar sensory pathway to S1 and M1. The suppression of gamma band coherence upon Purkinje cell stimulation was significantly stronger during trials with relatively large whisker movements, whereas the theta band changes did not show this correlation. In line with the anatomical distribution of the simple spike and complex spike responses to whisker stimulation, this suppression also occurred following focal stimulation of medial crus 2, but not of lateral crus 1. Granger causality analyses and computational modeling of the involved networks suggest that Purkinje cells control S1-M1 coherence most prominently via the ventrolateral thalamus and M1. Our results indicate that coherences between sensory and motor cortices in different frequency ranges can be dynamically modulated by cerebellar input, and that the modulation depends on the behavioral context and is site-specific.Significance StatementCoherent activity between sensory and motor areas is essential in sensorimotor integration. We show here that the cerebellum can differentially affect cortical theta and gamma band coherences evoked by whisker stimulation via a fast ascending and predictive pathway. In line with the functional heterogeneity of its modular organization, the impact of the cerebellum is region-specific and tuned to ongoing motor responses. These data highlight site-specific and context-dependent interactions between the cerebellum and the cerebral cortex that can come into play during a plethora of sensorimotor functions.

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