scholarly journals Multidimensional cerebellar computations for flexible kinematic control of movements

2022 ◽  
Author(s):  
Akshay Markanday ◽  
Sungho Hong ◽  
Junya Inoue ◽  
Erik De Schutter ◽  
Peter Thier
Keyword(s):  
Purkinje Cells ◽  
Mossy Fibers ◽  
Error Feedback ◽  
Error Type ◽  
Kinematic Control ◽  
Flexible Control ◽  
Feed Forward Network ◽  
Saccade Task ◽  
Movement Parameters ◽  
Specific Error

Both the environment and our body keep changing dynamically. Hence, ensuring movement precision requires adaptation to multiple demands occurring simultaneously. Here we show that the cerebellum performs the necessary multi-dimensional computations for the flexible control of different movement parameters depending on the prevailing context. This conclusion is based on the identification of a manifold-like activity in both mossy fibers (MF, network input) and Purkinje cells (PC, output), recorded from monkeys performing a saccade task. Unlike MFs, the properties of PC manifolds developed selective representations of individual movement parameters. Error feedback-driven climbing fiber input modulated the PC manifolds to predict specific, error type-dependent changes in subsequent actions. Furthermore, a feed-forward network model that simulated MF-to-PC transformations revealed that amplification and restructuring of the lesser variability in the MF activity is a pivotal circuit mechanism. Therefore, flexible control of movement by the cerebellum crucially depends on its capacity for multi-dimensional computations.

scholarly journals Cerebellar implementation of movement sequences through feedback

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Andrei Khilkevich ◽  
Juan Zambrano ◽  
Molly-Marie Richards ◽  
Michael Dean Mauk
Keyword(s):  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
General Framework ◽  
Eyelid Conditioning ◽  
Mossy Fibers ◽  
Learning Processes ◽  
Single Component ◽  
Associate Learning ◽  
Stimulation Of

Most movements are not unitary, but are comprised of sequences. Although patients with cerebellar pathology display severe deficits in the execution and learning of sequences (Doyon et al., 1997; Shin and Ivry, 2003), most of our understanding of cerebellar mechanisms has come from analyses of single component movements. Eyelid conditioning is a cerebellar-mediated behavior that provides the ability to control and restrict inputs to the cerebellum through stimulation of mossy fibers. We utilized this advantage to test directly how the cerebellum can learn a sequence of inter-connected movement components in rabbits. We show that the feedback signals from one component are sufficient to serve as a cue for the next component in the sequence. In vivo recordings from Purkinje cells demonstrated that all components of the sequence were encoded similarly by cerebellar cortex. These results provide a simple yet general framework for how the cerebellum can use simple associate learning processes to chain together a sequence of appropriately timed responses.

Quantitative and qualitative analyses of clock drawing in frontotemporal dementia and Alzheimer's disease

2006 ◽  
Vol 12 (2) ◽  
pp. 159-165 ◽  
Author(s):  
MERVIN BLAIR ◽  
ANDREW KERTESZ ◽  
PAUL MCMONAGLE ◽  
WILDA DAVIDSON ◽  
NIKOLETTA BODI
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontotemporal Dementia ◽  
Control Group ◽  
Cognitive Screening ◽  
Focal Lesions ◽  
Error Type ◽  
Clock Drawing Test ◽  
Clock Drawing ◽  
Specific Error

The clock drawing test (CDT) is a widely used cognitive screening test. It is useful in identifying focal lesions and cognitive deficits in dementia groups. Lately, several studies attempted its use to differentiate between dementia subtypes. Although many studies have examined the CDT in dementia populations, research into the use of clock drawing in frontotemporal dementia (FTD) is limited. We examined quantitative (global) and qualitative (specific error type) differences on the CDT between FTD (n = 36) and Alzheimer's disease (AD; n = 25) patients and controls without dementia (n = 25). Results showed significantly lower overall scores in the dementia groups compared to the control group, whereas FTD patients scored significantly higher than the AD group. On qualitative analysis, the FTD group had fewer stimulus bound responses, conceptual deficits, and spatial or planning errors compared to the AD group. In conclusion, both global and error analysis of the CDT helped discriminate the FTD group from controls and AD patients. (JINS, 2006, 12, 159–165.)

Multiple Erythroid Ankyrin Isoforms in the Mouse Cerebellum: Differential Localization in Purkinje Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1725-1725
Author(s):  
Connie B. Birkenmeier ◽  
Timothy H. Young ◽  
Jane E. Barker ◽  
Luanne L. Peters
Keyword(s):  
Axonal Transport ◽  
Purkinje Cells ◽  
Granule Cell ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
Granule Cell Layer ◽  
Specific Marker ◽  
Functional Link ◽  
Mouse Cerebellum ◽  
And Function

Abstract The erythroid ankyrin gene (Ank1) produces a large and varied number of isoforms due to alternative splicing of the mRNA. In addition to expression in erythroid tissues, some of these Ank1 proteins are highly expressed in the Purkinje cells (PKC) of the mouse cerebellum. Mice deficient in Ank1 as a result of a mutation in the Ank1 gene (normoblastosis, nb) show a progressive loss of PKCs with an attendant ataxia. We have generated a panel of Ank1 antibodies to aid in sorting out the expression pattern and function of Ank1 proteins in the cerebellum. Two of these antibodies are specific to the alternatively spliced A and B COOH-terminal segments of Ank1. Immunohistochemical (IHC) experiments using these antibodies show strikingly different patterns of localization. Anti-C-termA (α-A) stains the PKC cell body and dendrites while anti-C-termB (α-B) is restricted to the PKC membrane. Both antibodies stain structures in the granule cell layer (GCL) including the granule cell membrane (α-B) and structures known as glomeruli where granule cell dendrites synapse with mossy fiber axons (α-A and α-B). Mossy fibers are a major afferent system that inputs to the cerebellum. α-A, α-B, antibodies to the α-1 subunit of Na+/K+ATPase (NaK-α1) and anti-Synapsin 1, a specific marker for synaptic vesicles, all co-localize in the glomeruli, suggesting a possible functional link. PKC membrane staining with α-B is absent in nb/nb cerebellum whereas PKC staining with α-A is unaffected. GCL staining with both antibodies is reduced in the mutant and this deficit may be important to PKC survival since granule cell axons are a major input system to PKC dendrites. Immunoblots stained with α-A and α-B are consistent with the IHC findings. In addition to the typical large isoforms (∼210kD) that are deficient in the nb mutant, immunoblots of cerebellar lysates reveal a number of small Ank1 related proteins ranging in size from 17 to 50 kD. The α-A and α-B banding patterns are unaffected by the nb mutation suggesting that they may be produced by splicing out the exon containing the nb mutation (E36) or by using an alternative promoter in the 3′ end of the gene as was found for the small Ank1 isoforms in skeletal muscle. Additional IHC findings using GFP-tagged PKC show a PKC axonopathy in nb/nb cerebellum. PKC axons exhibit multiple swellings that accumulate with age raising the possibility that axonal transport is abnormal in the nb PKCs. In summary 1) immunoblots reveal multiple previously undescribed small Ank1 isoforms in cerebellum, 2) two of the alternate Ank1 COOH-termini show very different localization in PKC suggesting distinct functions for the Ank1 proteins carrying them, 3) in the GCL, antibodies to the two COOH-termini co-localize with antibodies to the Na+/K+ATPase α-1 subunit in synaptic densities, 4) deficiencies of Ank1 in the GCL of nb/nb mice may influence PKC survival and 5) axonal transport may be affected in nb/nb PKC. These findings indicate that Ank1 proteins play a more varied role in the cerebellum than previously suspected and suggest new directions for the study of Ank1 function.

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.

scholarly journals Adaptive Balance in Posterior Cerebellum

2021 ◽  
Vol 12 ◽  
Author(s):  
Neal H. Barmack ◽  
Vito Enrico Pettorossi
Keyword(s):  
Purkinje Cells ◽  
Stellate Cell ◽  
Semicircular Canals ◽  
Mossy Fibers ◽  
Vestibular Nuclei ◽  
Three Dimensions ◽  
Optokinetic Stimulation ◽  
Afferent Pathways ◽  
Vestibular Nuclear Neurons ◽  
Self Motion

Vestibular and optokinetic space is represented in three-dimensions in vermal lobules IX-X (uvula, nodulus) and hemisphere lobule X (flocculus) of the cerebellum. Vermal lobules IX-X encodes gravity and head movement using the utricular otolith and the two vertical semicircular canals. Hemispheric lobule X encodes self-motion using optokinetic feedback about the three axes of the semicircular canals. Vestibular and visual adaptation of this circuitry is needed to maintain balance during perturbations of self-induced motion. Vestibular and optokinetic (self-motion detection) stimulation is encoded by cerebellar climbing and mossy fibers. These two afferent pathways excite the discharge of Purkinje cells directly. Climbing fibers preferentially decrease the discharge of Purkinje cells by exciting stellate cell inhibitory interneurons. We describe instances adaptive balance at a behavioral level in which prolonged vestibular or optokinetic stimulation evokes reflexive eye movements that persist when the stimulation that initially evoked them stops. Adaptation to prolonged optokinetic stimulation also can be detected at cellular and subcellular levels. The transcription and expression of a neuropeptide, corticotropin releasing factor (CRF), is influenced by optokinetically-evoked olivary discharge and may contribute to optokinetic adaptation. The transcription and expression of microRNAs in floccular Purkinje cells evoked by long-term optokinetic stimulation may provide one of the subcellular mechanisms by which the membrane insertion of the GABAA receptors is regulated. The neurosteroids, estradiol (E2) and dihydrotestosterone (DHT), influence adaptation of vestibular nuclear neurons to electrically-induced potentiation and depression. In each section of this review, we discuss how adaptive changes in the vestibular and optokinetic subsystems of lobule X, inferior olivary nuclei and vestibular nuclei may contribute to the control of balance.

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 The thin ret(raction) line: biomedical journal responses to incorrect non-targeting nucleotide sequence reagents in human gene knockdown publications

2021 ◽  
Author(s):  
Jennifer A. Byrne ◽  
Yasunori Park ◽  
Rachael A. West ◽  
Amanda Capes-Davis ◽  
Bertrand Favier ◽  
...  
Keyword(s):  
Nucleotide Sequence ◽  
Scientific Literature ◽  
Human Gene ◽  
Editorial Staff ◽  
Negative Control ◽  
Gene Knockdown ◽  
Error Type ◽  
Biomedical Journals ◽  
Specific Error ◽  
Specific Reagent

AbstractThe capacity of the scientific literature to self-correct is of vital importance, but few studies have compared post-publication journal responses to specific error types. We have compared journal responses to a specific reagent error in 31 human gene knockdown publications, namely a non-targeting or negative control nucleotide sequence that is instead predicted to target a human gene. The 31 papers published by 13 biomedical journals generated 26 published responses (14 retractions, 5 expressions of concern, 7 author corrections which included one resolved expression of concern) as well as 6 stated decisions to take no action. Variations in published responses were noted both between journals and by 4 journals that published different responses to at least 2 papers. A subset of published responses revealed conflicting explanations for the wrongly identified control reagent, despite 30/31 papers obtaining their gene knockdown reagents from the same external supplier. Viewed collectively, different journal responses to human gene knockdown publications with a common reagent error type suggest that editorial staff require more support to interpret post-publication notifications of incorrect nucleotide sequence reagents. We propose a draft template to facilitate the communication, interpretation and investigation of published errors, including errors affecting research reagents.

scholarly journals A Cerebellar Computational Mechanism for Delay Conditioning at Precise Time Intervals

2020 ◽  
Vol 32 (11) ◽  
pp. 2069-2084
Author(s):  
Terence D. Sanger ◽  
Mitsuo Kawato
Keyword(s):  
Conditioned Stimulus ◽  
Purkinje Cells ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
Long Term Potentiation ◽  
Time Intervals ◽  
Delay Conditioning ◽  
Precise Time

The cerebellum is known to have an important role in sensing and execution of precise time intervals, but the mechanism by which arbitrary time intervals can be recognized and replicated with high precision is unknown. We propose a computational model in which precise time intervals can be identified from the pattern of individual spike activity in a population of parallel fibers in the cerebellar cortex. The model depends on the presence of repeatable sequences of spikes in response to conditioned stimulus input. We emulate granule cells using a population of Izhikevich neuron approximations driven by random but repeatable mossy fiber input. We emulate long-term depression (LTD) and long-term potentiation (LTP) synaptic plasticity at the parallel fiber to Purkinje cell synapse. We simulate a delay conditioning paradigm with a conditioned stimulus (CS) presented to the mossy fibers and an unconditioned stimulus (US) some time later issued to the Purkinje cells as a teaching signal. We show that Purkinje cells rapidly adapt to decrease firing probability following onset of the CS only at the interval for which the US had occurred. We suggest that detection of replicable spike patterns provides an accurate and easily learned timing structure that could be an important mechanism for behaviors that require identification and production of precise time intervals.

Potentiation of mossy fiber-evoked EPSPs in turtle cerebellar Purkinje cells by the metabotropic glutamate receptor agonist 1S,3R-ACPD

1992 ◽  
Vol 67 (4) ◽  
pp. 1006-1008 ◽  
Author(s):  
G. A. Kinney ◽  
N. T. Slater
Keyword(s):  
Nmda Receptor ◽  
Purkinje Cells ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
Nmda Receptor Antagonist ◽  
Metabotropic Glutamate ◽  
Cerebellar Purkinje Cells ◽  
Glutamate Receptor Agonist

1. The effects of the metabotropic glutamate receptor (mGluR) agonist 1S,3R-ACPD on excitatory postsynaptic potentials (EPSPs) evoked by stimulation of mossy fibers (MF) and parallel fibers (PF) were examined in turtle cerebellar Purkinje cells. 2. 1S,3R-ACPD (1-25 microM) reversibly potentiated the amplitude of the MF-evoked EPSPs and revealed a late, slow EPSP component, but was without effect on PF-evoked EPSPs. The potentiation of both components of MF-evoked EPSPs was dose dependent, with an ED50 of approximately 3 microM. At higher doses (15-25 microM) 1S,3R-ACPD produced a direct depolarization of Purkinje cells in 57% of cells examined. 3. The enhancement of MF EPSPs by 1S,3R-ACPD was blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonovalerate (AP-5), but not by the mGluR antagonist L-2-amino-3-phosphonopionic acid (L-AP3; 1 mM), or the 1R,3S isomer of ACPD (25-500 microM). 4. The results demonstrate that mGluR activation by 1S,3R-ACPD produces a potent, stereospecific facilitation of NMDA receptor-mediated transmission at the MF-granule cell synapse.

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