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 Learned response sequences in cerebellar Purkinje cells

2017 ◽  
Vol 114 (23) ◽  
pp. 6127-6132 ◽  
Author(s):  
Dan-Anders Jirenhed ◽  
Anders Rasmussen ◽  
Fredrik Johansson ◽  
Germund Hesslow
Keyword(s):  
Purkinje Cells ◽  
Interstimulus Interval ◽  
Response Pattern ◽  
Mossy Fiber ◽  
Eyeblink Conditioning ◽  
Complex Motor ◽  
Cerebellar Purkinje Cells ◽  
Single Response ◽  
The Right ◽  
Stimulation Of

Associative learning in the cerebellum has previously focused on single movements. In eyeblink conditioning, for instance, a subject learns to blink at the right time in response to a conditional stimulus (CS), such as a tone that is repeatedly followed by an unconditional corneal stimulus (US). During conditioning, the CS and US are transmitted by mossy/parallel fibers and climbing fibers to cerebellar Purkinje cells that acquire a precisely timed pause response that drives the overt blink response. The timing of this conditional Purkinje cell response is determined by the CS–US interval and is independent of temporal patterns in the input signal. In addition to single movements, the cerebellum is also believed to be important for learning complex motor programs that require multiple precisely timed muscle contractions, such as, for example, playing the piano. In the present work, we studied Purkinje cells in decerebrate ferrets that were conditioned using electrical stimulation of mossy fiber and climbing fiber afferents as CS and US, while alternating between short and long interstimulus intervals. We found that Purkinje cells can learn double pause responses, separated by an intermediate excitation, where each pause corresponds to one interstimulus interval. The results show that individual cells can not only learn to time a single response but that they also learn an accurately timed sequential response pattern.

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.

scholarly journals Kir3 channel blockade in the cerebellar cortex suppresses performance of classically conditioned Purkinje cell responses

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Fredrik Johansson ◽  
Germund Hesslow
Keyword(s):  
Purkinje Cell ◽  
G Protein ◽  
Cerebellar Cortex ◽  
Conditional Stimulus ◽  
Eyeblink Conditioning ◽  
Detectable Effect ◽  
Spontaneous Firing ◽  
Metabotropic Receptors ◽  
Cell Responses ◽  
Cerebellar Purkinje Cells

Abstract In the eyeblink conditioning paradigm, cerebellar Purkinje cells learn to respond to the conditional stimulus with an adaptively timed pause in its spontaneous firing. Evidence suggests that the pause is elicited by glutamate released from parallel fibers and acting on metabotropic receptors (mGluR7) which initiates a delayed-onset suppression of firing. We suggested that G protein activation of hyperpolarizing Kir3 channels (or ‘GIRK’, G protein-coupled inwardly-rectifying K+ channels) could be part of such a mechanism. Application of the Kir3 antagonist Tertiapin-LQ locally in the superficial layers of the cerebellar cortex in decerebrate ferrets suppressed normal performance of Purkinje cell pause responses to the conditional stimulus. Importantly, there was no detectable effect on spontaneous firing. These findings suggest that intact functioning of Kir3 channels in the cerebellar cortex is required for normal conditioned Purkinje cell responses.

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 Expression of the yes proto-oncogene in cerebellar Purkinje cells.

1989 ◽  
Vol 9 (10) ◽  
pp. 4545-4549 ◽  
Author(s):  
M Sudol ◽  
C F Kuo ◽  
L Shigemitsu ◽  
A Alvarez-Buylla
Keyword(s):  
In Situ Hybridization ◽  
Purkinje Cell ◽  
Gene Product ◽  
Purkinje Cells ◽  
Immunofluorescent Staining ◽  
Cell Degeneration ◽  
Functional Studies ◽  
Cerebellar Purkinje Cells ◽  
The Brain

To identify the kinds of cells in the brain that express the yes proto-oncogene, we examined chicken brains by using immunofluorescent staining and in situ hybridization. Both approaches showed that the highest level of the yes gene product was in cerebellar Purkinje cells. In addition, we analyzed Purkinje cell degeneration (pcd) mutant mice. The level of yes mRNA in cerebella of pcd mutants was four times lower than that found in cerebella of normal littermates. Our studies point to Purkinje cells as an attractive model for functional studies of the yes protein.

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 Spike burst–pause dynamics of Purkinje cells regulate sensorimotor adaptation

2018 ◽  
Author(s):  
Niceto R. Luque ◽  
Francisco Naveros ◽  
Richard R. Carrillo ◽  
Eduardo Ros ◽  
Angelo Arleo
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Vestibular Nuclei ◽  
Response Patterns ◽  
Spike Burst ◽  
Vor Adaptation ◽  
Cell Firing ◽  
Cerebellar Purkinje Cells ◽  
Oculomotor Adaptation

AbstractCerebellar Purkinje cells mediate accurate eye movement coordination. However, it remains unclear how oculomotor adaptation depends on the interplay between the characteristic Purkinje cell response patterns, namely tonic, bursting, and spike pauses. Here, a spiking cerebellar model assesses the role of Purkinje cell firing patterns in vestibular ocular reflex (VOR) adaptation. The model captures the cerebellar microcircuit properties and it incorporates spike-based synaptic plasticity at multiple cerebellar sites. A detailed Purkinje cell model reproduces the three spike-firing patterns that are shown to regulate the cerebellar output. Our results suggest that pauses following Purkinje complex spikes (bursts) encode transient disinhibition of targeted medial vestibular nuclei, critically gating the vestibular signals conveyed by mossy fibres. This gating mechanism accounts for early and coarse VOR acquisition, prior to the late reflex consolidation. In addition, properly timed and sized Purkinje cell bursts allow the ratio between long-term depression and potentiation (LTD/LTP) to be finely shaped at mossy fibre-medial vestibular nuclei synapses, which optimises VOR consolidation. Tonic Purkinje cell firing maintains the consolidated VOR through time. Importantly, pauses are crucial to facilitate VOR phase-reversal learning, by reshaping previously learnt synaptic weight distributions. Altogether, these results predict that Purkinje spike burst-pause dynamics are instrumental to VOR learning and reversal adaptation.Author SummaryCerebellar Purkinje cells regulate accurate eye movement coordination. However, it remains unclear how cerebellar-dependent oculomotor adaptation depends on the interplay between Purkinje cell characteristic response patterns: tonic, high-frequency bursting, and post-complex spike pauses. We explore the role of Purkinje spike burst-pause dynamics in VOR adaptation. A biophysical model of Purkinje cell is at the core of a spiking network model, which captures the cerebellar microcircuit properties and incorporates spike-based synaptic plasticity mechanisms at different cerebellar sites. We show that Purkinje spike burst-pause dynamics are critical for (1) gating the vestibular-motor response association during VOR acquisition; (2) mediating the LTD/LTP balance for VOR consolidation; (3) reshaping synaptic efficacy distributions for VOR phase-reversal adaptation; (4) explaining the reversal VOR gain discontinuities during sleeping.

scholarly journals TRPC3 is essential for functional heterogeneity of cerebellar Purkinje cells

2018 ◽  
Author(s):  
Bin Wu ◽  
Francois G.C. Blot ◽  
Aaron B. Wong ◽  
Catarina Osório ◽  
Youri Adolfs ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Transient Receptor Potential ◽  
Eyeblink Conditioning ◽  
Receptor Potential ◽  
Cellular Heterogeneity ◽  
Loss Of Function ◽  
Functional Heterogeneity ◽  
Homogeneous Population ◽  
Cerebellar Purkinje Cells

AbstractDespite the canonical homogenous character of its organization, the cerebellum plays differential computational roles in distinct types of sensorimotor behaviors. However, the molecular and cell physiological underpinnings are unclear. Here we determined the contribution of transient receptor potential cation channel type C3 (TRPC3) to signal processing in different cerebellar modules. Using gain-of-function and loss-of-function mouse models, we found that TRPC3 controls the simple spike activity of zebrin-negative (Z–), but not of zebrin-positive (Z+), Purkinje cells. Moreover, in vivo TRPC3 also regulated complex spike firing and its interaction with simple spikes exclusively in Z– Purkinje cells. Finally, we found that eyeblink conditioning, related to Z– modules, but not compensatory eye movement adaptation, linked to Z+ modules, was affected in TRPC3 loss-of-function mice. Together, our results indicate that TRPC3 is essential for the cellular heterogeneity that introduces distinct physiological properties in an otherwise homogeneous population of Purkinje cells, conjuring functional heterogeneity in cerebellar sensorimotor integration.

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