scholarly journals A biochemical mechanism for time-encoding memory formation within individual synapses of Purkinje cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251172
Author(s):  
Ayush Mandwal ◽  
Javier G. Orlandi ◽  
Christoph Simon ◽  
Jörn Davidsen
Keyword(s):  
Purkinje Cell ◽  
Firing Rate ◽  
G Protein ◽  
Purkinje Cells ◽  
Memory Formation ◽  
Time Interval ◽  
Biochemical Mechanism ◽  
Conditional Response ◽  
Tonic Firing ◽  
Time Encoding

Within the classical eye-blink conditioning, Purkinje cells within the cerebellum are known to suppress their tonic firing rates for a well defined time period in response to the conditional stimulus after training. The temporal profile of the drop in tonic firing rate, i.e., the onset and the duration, depend upon the time interval between the onsets of the conditional and unconditional training stimuli. Direct stimulation of parallel fibers and climbing fiber by electrodes was found to be sufficient to reproduce the same characteristic drop in the firing rate of the Purkinje cell. In addition, the specific metabotropic glutamate-based receptor type 7 (mGluR7) was found responsible for the initiation of the response, suggesting an intrinsic mechanism within the Purkinje cell for the temporal learning. In an attempt to look for a mechanism for time-encoding memory formation within individual Purkinje cells, we propose a biochemical mechanism based on recent experimental findings. The proposed mechanism tries to answer key aspects of the “Coding problem” of Neuroscience by focusing on the Purkinje cell’s ability to encode time intervals through training. According to the proposed mechanism, the time memory is encoded within the dynamics of a set of proteins—mGluR7, G-protein, G-protein coupled Inward Rectifier Potassium ion channel, Protein Kinase A, Protein Phosphatase 1 and other associated biomolecules—which self-organize themselves into a protein complex. The intrinsic dynamics of these protein complexes can differ and thus can encode different time durations. Based on their amount and their collective dynamics within individual synapses, the Purkinje cell is able to suppress its own tonic firing rate for a specific time interval. The time memory is encoded within the effective dynamics of the biochemical reactions and altering these dynamics means storing a different time memory. The proposed mechanism is verified by both a minimal and a more comprehensive mathematical model of the conditional response behavior of the Purkinje cell and corresponding dynamical simulations of the involved biomolecules, yielding testable experimental predictions.

scholarly journals A biochemical mechanism for time-encoding memory formation within individual synapses of Purkinje cells

2019 ◽  
Author(s):  
Ayush Mandwal ◽  
Javier G. Orlandi ◽  
Christoph Simon ◽  
Jörn Davidsen
Keyword(s):  
Purkinje Cell ◽  
Firing Rate ◽  
Purkinje Cells ◽  
Protein Interactions ◽  
Effective Rate ◽  
Memory Formation ◽  
Time Interval ◽  
Biochemical Mechanism ◽  
Tonic Firing ◽  
Time Encoding

AbstractWithin the classical eye-blink conditioning, Purkinje cells within the cerebellum are known to suppress their tonic firing rates for a well defined time period in response to the conditional stimulus after training. The temporal profile of the drop in tonic firing rate, i.e., the onset and the duration, depend upon the time interval between the onsets of the training conditional and unconditional stimulus. Direct stimulation of parallel fibers and climbing fiber by electrodes was found to be sufficient to reproduce the same characteristic drop in the firing rate of the Purkinje cell. In addition, the specific metabotropic glutamate-based receptor type 7 (mGluR7), which resides on the Purkinje cell synapses, was found responsible for the initiation of the response, suggesting an intrinsic mechanism within the Purkinje cell for the temporal learning. In an attempt to look for a mechanism for time-encoding memory formation within individual Purkinje cells, we propose a biochemical mechanism based on recent experimental findings. The proposed model tries to answer key aspects of the “Coding problem” of Neuroscience by focussing on the Purkinje cell’s ability to encode time intervals through training. According to the proposed mechanism, the time memory is encoded within the dynamics of a set of proteins — mGluR7, G-protein, G-protein coupled Inward Rectifier Potassium ion channel, Protein Kinase A and Protein Phosphatase 1 — which self-organize themselves into a protein complex. The intrinsic dynamics of these protein complexes can differ and thus can encode different time durations. Based on their amount and their collective dynamics within individual synapses, the Purkinje cell is able to suppress its own tonic firing rate for a specific time interval. The time memory is encoded within the effective rate constants of the biochemical reactions and altering these rates constants means storing a different time memory. The proposed mechanism is verified by a simplified mathematical model and corresponding dynamical simulations of the involved biomolecules, yielding testable experimental predictions.Author summaryHebbian plasticity is a widely accepted form of learning that can encode memories in our brain. Spike-timing dependent plasticity resulting in Long-term Potentiation or Depression of synapses has become the default mechanistic explanation behind memory formation within a neuronal population. However, recent experiments of conditional eyeblink response in Purkinje cells have challenged this point of view by showing that these mechanisms alone cannot account for time memory formation in the Purkinje cell. To explain the underlying mechanism behind this novel synaptic plasticity, we introduce a biochemical mechanism based on protein interactions occurring within a single synapse. These protein interactions and the associated effective rate constants are sufficient to encode time delays by auto-induced inhibition on a single excitatory synapse, suggesting that synapses are capable of storing more information than previously thought.

Dynamic Synchronization of Purkinje Cell Simple Spikes

2006 ◽  
Vol 96 (6) ◽  
pp. 3485-3491 ◽  
Author(s):  
Soon-Lim Shin ◽  
Erik De Schutter
Keyword(s):  
Purkinje Cell ◽  
Firing Rate ◽  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Cerebellar Nuclei ◽  
Temporal Coding ◽  
Sharp Peak ◽  
Deep Cerebellar Nuclei

Purkinje cells (PCs) integrate all computations performed in the cerebellar cortex to inhibit neurons in the deep cerebellar nuclei (DCN). Simple spikes recorded in vivo from pairs of PCs separated by <100 μm are known to be synchronized with a sharp peak riding on a broad peak, but the significance of this finding is unclear. We show that the sharp peak consists exclusively of simple spikes associated with pauses in firing. The broader, less precise peak was caused by firing-rate co-modulation of faster firing spikes. About 13% of all pauses were synchronized, and these pauses had a median duration of 20 ms. As in vitro studies have reported that synchronous pauses can reliably trigger spikes in DCN neurons, we suggest that the subgroup of spikes causing the sharp peak is important for precise temporal coding in the cerebellum.

scholarly journals A Model for Time Interval Learning in The Purkinje Cell

2018 ◽  
Author(s):  
Daniel Majoral ◽  
Ajmal Zemmar ◽  
Raul Vicente
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Classical Theory ◽  
Biophysical Model ◽  
Calcium Signal ◽  
Time Interval ◽  
Time Intervals ◽  
Delay Conditioning ◽  
Cerebellar Function ◽  
Experimental Findings

AbstractRecent experimental findings indicate that Purkinje cells in the cerebellum represent time intervals by mechanisms other than conventional synaptic weights. This finding adds to the theoretical and experimental observations suggesting the presence of intra-cellular mechanisms for adaptation and processing. To account for these experimental results we developed a biophysical model for time interval learning in a Purkinje cell. The numerical model focuses on a classical delay conditioning task (e.g. eyeblink conditioning) and relies on a few computational steps. In particular, the model posits the activation by the parallel fiber input of a local intra-cellular calcium store which can be modulated by intra-cellular pathways. The reciprocal interaction of the calcium signal with several proteins forming negative and positive feedback loops ensures that the timing of inhibition in the Purkinje cell anticipates the interval between parallel and climbing fiber inputs during training. We show that the model is able to learn along the 150-1000 ms interval range. Finally, we discuss how this model would allow the cerebellum to detect and generate specific spatio-temporal patterns, a classical theory for cerebellar function.Author SummaryThe prevailing view in neurosciences considers synaptic weights between neurons the determinant factor for learning and processing information in the nervous system. Theoretical considerations [1, 2] and experiments [3, 4] examined some potential limitations of this classical paradigm, pointing out that adaptation and computation might also have to rely on other mechanisms besides the learning of synaptic weights. Recent experimental findings [5–7] indicate that Purkinje cells in the cerebellum represent time intervals by mechanisms other than conventional synaptic weights. We propose here a biologically plausible model which complements the modification of synaptic weights for learning one time interval in one synapse of one Purkinje cell. In the model a calcium signal in a small domain keeps track of time. Several molecules read and modify this calcium signal to learn a time interval. We discuss how this model would allow the cerebellum to detect and generate specific patterns in space and time, a classical theory for cerebellar function proposed by Braitenberg [8, 9].

scholarly journals Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jui-Yi Hsieh ◽  
Brittany N Ulrich ◽  
Fadi A Issa ◽  
Meng-chin A Lin ◽  
Brandon Brown ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
High Frequency ◽  
Cerebellar Degeneration ◽  
Cerebellar Development ◽  
Adult Onset ◽  
Tonic Firing ◽  
Cell Excitability ◽  
Dendritic Branching

Mutations in KCNC3, which encodes the Kv3.3 K+ channel, cause spinocerebellar ataxia 13 (SCA13). SCA13 exists in distinct forms with onset in infancy or adulthood. Using zebrafish, we tested the hypothesis that infant- and adult-onset mutations differentially affect the excitability and viability of Purkinje cells in vivo during cerebellar development. An infant-onset mutation dramatically and transiently increased Purkinje cell excitability, stunted process extension, impaired dendritic branching and synaptogenesis, and caused rapid cell death during cerebellar development. Reducing excitability increased early Purkinje cell survival. In contrast, an adult-onset mutation did not significantly alter basal tonic firing in Purkinje cells, but reduced excitability during evoked high frequency spiking. Purkinje cells expressing the adult-onset mutation matured normally and did not degenerate during cerebellar development. Our results suggest that differential changes in the excitability of cerebellar neurons contribute to the distinct ages of onset and timing of cerebellar degeneration in infant- and adult-onset SCA13.

Decrement of the Purkinje Cells Diameter after Oral Intake of Lithium in Albino Rats

2021 ◽  
Vol 15 (8) ◽  
pp. 1788-1789
Author(s):  
Tazeen Kohari ◽  
Farah Malik ◽  
Aftab Ahmad
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Gray Matter ◽  
Oral Intake ◽  
Lithium Carbonate ◽  
Albino Rats ◽  
Cell Diameter ◽  
Group A ◽  
Cerebellar Gray Matter ◽  
Group B

Background: The histology of Cerebellar gray matter consists of a middle Purkinje cells layer with flask shaped Purkinje cells. The field of Neurology has documented that different organic compounds and metals are lethal to the excitatory Purkinje Neurons. Researches have proved Lithium to be hazardous to nervous tissue and especially Cerebellum For the past sixty years Lithium is the favorable drug for treatment of Bipolar Disorder. Aim: To Analyse and record the changes of decrement of the size of Purkinje cell Diameter after chronic Lithium ingestion. Methods: Sixteen albino rats were selected and were treated with lithium for a period of fifteen days and the data for changes in Purkinje cells Diameter was observed. Results: The Observations of Our study showed highly significantly decreased diameter of the Purinje cells in Group B (Lithium Carbonate) animals as compared to Group A Animals which were on Lab Diet Conclusion: The Morphometric Data proved that Lithium Carbonate is Toxic to Purkinje cells, and it educated our Population to use Lithium with caution. Keywords: Purkinje cell Diameter, Gray matter, Hazardous

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 Purkinje Cell Collaterals Enable Output Signals from the Cerebellar Cortex to Feed Back to Purkinje Cells and Interneurons

Neuron ◽  
2016 ◽  
Vol 91 (2) ◽  
pp. 312-319 ◽  
Author(s):  
Laurens Witter ◽  
Stephanie Rudolph ◽  
R. Todd Pressler ◽  
Safiya I. Lahlaf ◽  
Wade G. Regehr
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Cerebellar Cortex

scholarly journals Functionally distinct Purkinje cell types show temporal precision in encoding locomotion

2020 ◽  
Vol 117 (29) ◽  
pp. 17330-17337
Author(s):  
Weipang Chang ◽  
Andrea Pedroni ◽  
Victoria Hohendorf ◽  
Stefania Giacomello ◽  
Masahiko Hibi ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Central Pattern Generators ◽  
Cell Types ◽  
Neuronal Population ◽  
Adult Zebrafish ◽  
Temporal Precision ◽  
Distinct Cell ◽  
Pattern Generators ◽  
Cell Networks

Purkinje cells, the principal neurons of cerebellar computations, are believed to comprise a uniform neuronal population of cells, each with similar functional properties. Here, we show an undiscovered heterogeneity of adult zebrafish Purkinje cells, revealing the existence of anatomically and functionally distinct cell types. Dual patch-clamp recordings showed that the cerebellar circuit contains all Purkinje cell types that cross-communicate extensively using chemical and electrical synapses. Further activation of spinal central pattern generators (CPGs) revealed unique phase-locked activity from each Purkinje cell type during the locomotor cycle. Thus, we show intricately organized Purkinje cell networks in the adult zebrafish cerebellum that encode the locomotion rhythm differentially, and we suggest that these organizational properties may also apply to other cerebellar functions.

scholarly journals Temporal Firing Patterns of Purkinje Cells in the Cerebellar Ventral Paraflocculus During Ocular Following Responses in Monkeys II. Complex Spikes

1998 ◽  
Vol 80 (2) ◽  
pp. 832-848 ◽  
Author(s):  
Yasushi Kobayashi ◽  
Kenji Kawano ◽  
Aya Takemura ◽  
Yuka Inoue ◽  
Toshihiro Kitama ◽  
...  
Keyword(s):  
Firing Rate ◽  
Eye Movement ◽  
Purkinje Cells ◽  
Generalized Linear Model ◽  
Stimulus Motion ◽  
Ocular Following ◽  
Temporal Firing ◽  
Ventral Paraflocculus ◽  
Complex Spikes

Kobayashi, Yasushi, Kenji Kawano, Aya Takemura, Yuka Inoue, Toshihiro Kitama, Hiroaki Gomi, and Mitsuo Kawato. Temporal firing patterns of Purkinje cells in cerebellar ventral paraflocculus during ocular following responses in monkeys. II. Complex spikes. J. Neurophysiol. 80: 832–848, 1998. Many theories of cerebellar motor learning propose that complex spikes (CS) provide essential error signals for learning and modulate parallel fiber inputs that generate simple spikes (SS). These theories, however, do not satisfactorily specify what modality is represented by CS or how information is conveyed by the ultra-low CS firing rate (1 Hz). To further examine the function of CS and the relationship between CS and SS in the cerebellum, CS and SS were recorded in the ventral paraflocculus (VPFL) of awake monkeys during ocular following responses (OFR). In addition, a new statistical method using a generalized linear model of firing probability based on a binomial distribution of the spike count was developed for analysis of the ultra-low CS firing rate. The results of the present study showed that the spatial coordinates of CS were aligned with those of SS and the speed-tuning properties of CS and SS were more linear for eye movement than retinal slip velocity, indicating that CS contain a motor component in addition to the sensory component identified in previous studies. The generalized linear model to reproduce firing probability confirmed these results, demonstrating that CS conveyed high-frequency information with its ultra-low firing frequency and conveyed both sensory and motor information. Although the temporal patterns of the CS were similar to those of the SS when the sign was reversed and magnitude was amplified ∼50 times, the velocity/acceleration coefficient ratio of the eye movement model, an aspect of the CS temporal firing profile, was less than that of the SS, suggesting that CS were more sensory in nature than SS. A cross-correlation analysis of SS that are triggered by CS revealed that short-term modulation, that is, the brief pause in SS caused by CS, does not account for the reciprocal modulation of SS and CS. The results also showed that three major aspects of the CS and SS individual cell firing characteristics were negatively correlated on a cell-to-cell basis: the preferred direction of stimulus motion, the mean percent change in firing rate induced by upward stimulus motion, and patterns of temporal firing probability. These results suggest that CS may contribute to long-term interactions between parallel and climbing fiber inputs, such as long-term depression and/or potentiation.

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