Browse
Submit Data
Databases
API
Help

Dataset Information

7 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A model for time interval learning in the Purkinje cell.

ABSTRACT: Recent experimental findings indicate that Purkinje cells in the cerebellum represent time intervals by mechanisms other than conventional synaptic weights. These findings add to the theoretical and experimental observations suggesting the presence of intra-cellular mechanisms for adaptation and processing. To account for these experimental results we propose a new 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 systematically test the model ability to learn time intervals at the 150-1000 ms time scale, while observing that learning can also extend to the multiple seconds scale. In agreement with experimental observations we also show that the number of pairings required to learn increases with inter-stimulus interval. Finally, we discuss how this model would allow the cerebellum to detect and generate specific spatio-temporal patterns, a classical theory for cerebellar function.

SUBMITTER: Majoral D

PROVIDER: S-EPMC7034954 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Cerebellar Purkinje cell activity drives motor learning.

Project description:The climbing fiber input to the cerebellar cortex is thought to provide instructive signals that drive the induction of motor skill learning. We found that optogenetic activation of Purkinje cells, the sole output neurons of the cerebellar cortex, can also drive motor learning in mice. This dual control over the induction of learning by climbing fibers and Purkinje cells can expand the learning capacity of motor circuits.

| S-EPMC3966616 | biostudies-literature

A biologically plausible model of time-scale invariant interval timing.

Project description:The temporal durations between events often exert a strong influence over behavior. The details of this influence have been extensively characterized in behavioral experiments in different animal species. A remarkable feature of the data collected in these experiments is that they are often time-scale invariant. This means that response measurements obtained under intervals of different durations coincide when plotted as functions of relative time. Here we describe a biologically plausible model of an interval timing device and show that it is consistent with time-scale invariant behavior over a substantial range of interval durations. The model consists of a set of bistable units that switch from one state to the other at random times. We first use an abstract formulation of the model to derive exact expressions for some key quantities and to demonstrate time-scale invariance for any range of interval durations. We then show how the model could be implemented in the nervous system through a generic and biologically plausible mechanism. In particular, we show that any system that can display noise-driven transitions from one stable state to another can be used to implement the timing device. Our work demonstrates that a biologically plausible model can qualitatively account for a large body of data and thus provides a link between the biology and behavior of interval timing.

| S-EPMC2825317 | biostudies-literature

Disruption of neonatal Purkinje cell function underlies injury-related learning deficits.

Project description:It is hypothesized that perinatal cerebellar injury leads to long-term functional deficits due to circuit dysmaturation. Using a novel integration of GCaMP6f fiber photometry with automated measurement of cerebellar behavior using the ErasmusLadder, we causally link cerebellar injury to altered Purkinje cell responses during maladaptive behavior. Chemogenetic inhibition of neonatal Purkinje cells is sufficient to phenocopy the effects of perinatal cerebellar injury. Our results uncover a direct link between perinatal cerebellar injury and activity-dependent maturation of cerebellar cortex.

| S-EPMC7980280 | biostudies-literature

Neonatal brain injury causes cerebellar learning deficits and Purkinje cell dysfunction.

Project description:Premature infants are more likely to develop locomotor disorders than term infants. In a chronic sub-lethal hypoxia (Hx) mouse model of neonatal brain injury, we recently demonstrated the presence of cellular and physiological changes in the cerebellar white matter. We also observed Hx-induced delay in Purkinje cell (PC) arborization. However, the behavioral consequences of these cellular alterations remain unexplored. Using the Erasmus Ladder to study cerebellar behavior, we report the presence of locomotor malperformance and long-term cerebellar learning deficits in Hx mice. Optogenetics experiments in Hx mice reveal a profound reduction in spontaneous and photoevoked PC firing frequency. Finally, treatment with a gamma-aminobutyric acid (GABA) reuptake inhibitor partially rescues locomotor performance and improves PC firing. Our results demonstrate a long-term miscoordination phenotype characterized by locomotor malperformance and cerebellar learning deficits in a mouse model of neonatal brain injury. Our findings also implicate the developing GABA network as a potential therapeutic target for prematurity-related locomotor deficits.

| S-EPMC6089917 | biostudies-literature

Interval-based secretomics unravels the time-dependent acute phase response in hepatocyte model systems

Project description:Mass spectrometry based secretomics approaches preferentially utilize serum-free culture conditions to circumvent serum induced interference and enable sufficient analytical depth. However, this negatively affects a wide range of cellular functions and thus reduces the biological relevance. Moreover, the experimental time range is limited by the viability of cells under serum free culture conditions which results in potentially missing out a large fraction of transcriptionally regulated secretion events and feedback-loops. We present an “interval-based” secretomics workflow, that addresses the shortcomings of the serum-free secretomics approach, by probing protein secretion rates in short serum-free time windows. We applied this approach to unravel the time-resolved secretion in the hepatocyte model systems HepG2 and HepaRG after stimulation of the acute-phase response (APR), a cellular reaction to inflammatory stimuli that typically manifests over days. The integration of relative quantification using tandem mass tags (TMT) enabled precise monitoring of time dependent changes in the secretome over days. Cell line and cytokine specific changes were observed: IL1b directed the APR towards pathogen defense over three distinct chronological phases. In contrast, IL6 directed the APR towards regeneration. Cell surface shedding was pronounced upon IL1b stimulation and small molecule inhibition of ADAM and matrix metalloproteases identified induced as well as constitutive shedding events. Inhibition of ADAM proteases by TAPI-0 not only led to reduced shedding of the sorting receptor SORT1, but also an attenuated cytokine response suggesting a direct link between cell surface shedding and cytokine secretion rates.

2022-05-04 | PXD027821 | Pride

Mixed Selectivity in the Cerebellar Purkinje-Cell Response during Visuomotor Association Learning.

Project description:Although the cerebellum has been traditionally considered to be exclusively involved in motor control, recent anatomic and clinical studies show that it also has a role in reward-processing. However, the way in which the movement-related and the reward-related neural activity interact at the level of the cerebellar cortex and contribute toward learning is still unclear. Here, we studied the simple spike activity of Purkinje cells in the mid-lateral cerebellum when 2 male monkeys learned to associate a right or left-hand movement with one of two visual symbolic cues. These cells had distinctly different discharge patterns between an overtrained symbol-hand association and a novel symbol-hand association, responding in association with the movement of both hands, although the kinematics of the movement did not change between the two conditions. The activity change was not related to the pattern of the visual symbols, the movement kinematics, the monkeys' reaction times, or the novelty of the visual symbols. The simple spike activity changed throughout the learning process, but the concurrent complex spikes did not instruct that change. Although these neurons also have reward-related activity, the reward-related and movement-related signals were independent. We suggest that this mixed selectivity may facilitate the flexible learning of difficult reinforcement learning problems.SIGNIFICANCE STATEMENT The cerebellum receives both motor-related and reward-related information. However, it is unclear how these two signals interact at the level of cerebellar cortex and contribute to learning nonmotor skills. Here we show that in the mid-lateral cerebellum, the reward information is encoded independently from the motor information such that during reward-based learning, only the reward information carried by the Purkinje cells inform learning while the motor information remains unchanged with learning.

| S-EPMC9087720 | biostudies-literature

Purkinje-cell plasticity and cerebellar motor learning are graded by complex-spike duration.

Project description:Behavioural learning is mediated by cellular plasticity, such as changes in the strength of synapses at specific sites in neural circuits. The theory of cerebellar motor learning relies on movement errors signalled by climbing-fibre inputs to cause long-term depression of synapses from parallel fibres to Purkinje cells. However, a recent review has called into question the widely held view that the climbing-fibre input is an 'all-or-none' event. In anaesthetized animals, there is wide variation in the duration of the complex spike (CS) caused in Purkinje cells by a climbing-fibre input. Furthermore, the amount of plasticity in Purkinje cells is graded according to the duration of electrically controlled bursts in climbing fibres. The duration of bursts depends on the 'state' of the inferior olive and therefore may be correlated across climbing fibres. Here we provide a potential functional context for these mechanisms during motor learning in behaving monkeys. The magnitudes of both plasticity and motor learning depend on the duration of the CS responses. Furthermore, the duration of CS responses seems to be a meaningful signal that is correlated across the Purkinje-cell population during motor learning. We suggest that during learning, longer bursts in climbing fibres lead to longer-duration CS responses in Purkinje cells, more calcium entry into Purkinje cells, larger synaptic depression, and stronger learning. The same graded impact of instructive signals for plasticity and learning might occur throughout the nervous system.

| S-EPMC4132823 | biostudies-literature

Cerebellar-dependent motor learning is based on pruning a Purkinje cell population response.

Project description:The improvement of motor behavior, based on experience, is a form of learning that is critically dependent on the cerebellum. A well studied example of cerebellar motor learning is short-term saccadic adaptation (STSA). In STSA, information on saccadic errors is used to improve future saccades. The information optimizing saccade metrics is conveyed by Purkinje cells simple spikes (PC-SS) because they are the critical input to the premotor circuits for saccades. We recorded PC-SS of monkeys undergoing STSA to reveal the code used for improving behavior. We found that the discharge of individual PC-SS was unable to account for the behavioral changes. The PC-SS population burst (PB), however, exhibited changes that closely paralleled the qualitatively different changes of saccade kinematics associated with gain-increase and gain-decrease STSA, respectively. Gain-increase STSA, characterized by an increase in saccade duration, replicates the relationship between saccade duration and the end of the PB valid for unadapted saccades. In contrast, gain-decrease STSA, which sports normal saccade duration but reduced saccadic velocity, is characterized by a PB that ends well before the adapted saccade. This suggests that the duration of normal as well as gain-increased saccades is determined by appropriately setting the end of PB end. However, the duration of gain-decreased saccades is apparently not modified by the cerebellum because the PB signals ends too early to determine saccade end. In summary, STSA, and most probably cerebellar-dependent learning in general, is based on optimizing the shape of a PC-SS population response.

| S-EPMC2438246 | biostudies-literature

Autonomous Purkinje cell activation instructs bidirectional motor learning through evoked dendritic calcium signaling.

Project description:The signals in cerebellar Purkinje cells sufficient to instruct motor learning have not been systematically determined. Therefore, we applied optogenetics in mice to autonomously excite Purkinje cells and measured the effect of this activity on plasticity induction and adaptive behavior. Ex vivo, excitation of channelrhodopsin-2-expressing Purkinje cells elicits dendritic Ca2+ transients with high-intensity stimuli initiating dendritic spiking that additionally contributes to the Ca2+ response. Channelrhodopsin-2-evoked Ca2+ transients potentiate co-active parallel fiber synapses; depression occurs when Ca2+ responses were enhanced by dendritic spiking. In vivo, optogenetic Purkinje cell activation drives an adaptive decrease in vestibulo-ocular reflex gain when vestibular stimuli are paired with relatively small-magnitude Purkinje cell Ca2+ responses. In contrast, pairing with large-magnitude Ca2+ responses increases vestibulo-ocular reflex gain. Optogenetically induced plasticity and motor adaptation are dependent on endocannabinoid signaling, indicating engagement of this pathway downstream of Purkinje cell Ca2+ elevation. Our results establish a causal relationship among Purkinje cell Ca2+ signal size, opposite-polarity plasticity induction, and bidirectional motor learning.

| S-EPMC8042043 | biostudies-literature

Semiparametric estimation of the accelerated failure time model with partly interval-censored data.

Project description:Partly interval-censored (PIC) data arise when some failure times are exactly observed while others are only known to lie within certain intervals. In this article, we consider efficient semiparametric estimation of the accelerated failure time (AFT) model with PIC data. We first generalize the Buckley-James estimator for right-censored data to PIC data. Then, we develop a one-step estimator by deriving and estimating the efficient score for the regression parameters. We show that under mild regularity conditions the generalized Buckley-James estimator is consistent and asymptotically normal and the one-step estimator is consistent and asymptotically normal with a covariance matrix that attains the semiparametric efficiency bound. We conduct extensive simulation studies to examine the performance of the proposed estimators in finite samples and apply our methods to data derived from an AIDS study.

| S-EPMC5785785 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data