Cerebellar Cortex Contributions to the Expression and Timing of Conditioned Eyelid Responses

We used micro-infusions during eyelid conditioning in rabbits to investigate the relative contributions of cerebellar cortex and the underlying deep nuclei (DCN) to the expression of cerebellar learning. These tests were conducted using two forms of cerebellum-dependent eyelid conditioning for which the relative roles of cerebellar cortex and DCN are controversial: delay conditioning, which is largely unaffected by forebrain lesions, and trace conditioning, which involves interactions between forebrain and cerebellum. For rabbits trained with delay conditioning, silencing cerebellar cortex by micro-infusions of the local anesthetic lidocaine unmasked stereotyped short-latency responses. This was also the case after extinction as observed previously with reversible blockade of cerebellar cortex output. Conversely, increasing cerebellar cortex activity by micro-infusions of the GABAA antagonist picrotoxin reversibly abolished conditioned responses. Effective cannula placements were clustered around the primary fissure and deeper in lobules hemispheric lobule IV (HIV) and hemispheric lobule V (HV) of anterior lobe. In well-trained trace conditioned rabbits, silencing this same area of cerebellar cortex or reversibly blocking cerebellar cortex output also unmasked short-latency responses. Because Purkinje cells are the sole output of cerebellar cortex, these results provide evidence that the expression of well-timed conditioned responses requires a well-timed decrease in the activity of Purkinje cells in anterior lobe. The parallels between results from delay and trace conditioning suggest similar contributions of plasticity in cerebellar cortex and DCN in both instances.

Download Full-text

Cerebellar implementation of movement sequences through feedback

eLife ◽

10.7554/elife.37443 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 10

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.

Download Full-text

Temporal Patterns of Inputs to Cerebellum Necessary and Sufficient for Trace Eyelid Conditioning

Journal of Neurophysiology ◽

10.1152/jn.00169.2010 ◽

2010 ◽

Vol 104 (2) ◽

pp. 627-640 ◽

Cited By ~ 29

Author(s):

Brian E. Kalmbach ◽

Tatsuya Ohyama ◽

Michael D. Mauk

Keyword(s):

Eyelid Conditioning ◽

Granule Cells ◽

Mossy Fiber ◽

Mossy Fibers ◽

Trace Conditioning ◽

Trace Interval ◽

The Us ◽

Conditioned Responses ◽

Necessary And Sufficient ◽

Stimulation Of

Trace eyelid conditioning is a form of associative learning that requires several forebrain structures and cerebellum. Previous work suggests that at least two conditioned stimulus (CS)-driven signals are available to the cerebellum via mossy fiber inputs during trace conditioning: one driven by and terminating with the tone and a second driven by medial prefrontal cortex (mPFC) that persists through the stimulus-free trace interval to overlap in time with the unconditioned stimulus (US). We used electric stimulation of mossy fibers to determine whether this pattern of dual inputs is necessary and sufficient for cerebellar learning to express normal trace eyelid responses. We find that presenting the cerebellum with one input that mimics persistent activity observed in mPFC and the lateral pontine nuclei during trace eyelid conditioning and another that mimics tone-elicited mossy fiber activity is sufficient to produce responses whose properties quantitatively match trace eyelid responses using a tone. Probe trials with each input delivered separately provide evidence that the cerebellum learns to respond to the mPFC-like input (that overlaps with the US) and learns to suppress responding to the tone-like input (that does not). This contributes to precisely timed responses and the well-documented influence of tone offset on the timing of trace responses. Computer simulations suggest that the underlying cerebellar mechanisms involve activation of different subsets of granule cells during the tone and during the stimulus-free trace interval. These results indicate that tone-driven and mPFC-like inputs are necessary and sufficient for the cerebellum to learn well-timed trace conditioned responses.

Download Full-text

Cerebellar cortical activity during antagonist cocontraction and reciprocal inhibition of forearm muscles

Journal of Neurophysiology ◽

10.1152/jn.1984.51.1.32 ◽

1984 ◽

Vol 51 (1) ◽

pp. 32-49 ◽

Cited By ~ 77

Author(s):

R. C. Frysinger ◽

D. Bourbonnais ◽

J. F. Kalaska ◽

A. M. Smith

Keyword(s):

Purkinje Cells ◽

Cerebellar Cortex ◽

Discharge Frequency ◽

Wrist Movement ◽

Movement Velocity ◽

Wrist Position ◽

Forearm Muscles ◽

Antagonist Muscles ◽

Primary Fissure ◽

Flexion And Extension

Monkeys were trained to perform a maintained isometric grip of the thumb and forefinger that elicited a simultaneous cocontraction of the antagonist muscles of the forearm. The same monkeys were also trained to flex and extend the wrist against a stop with the fingers extended and to maintain an isometric wrist position for 1.0-1.5 s. During wrist movement, some of the synergist forearm muscles contracted during both flexion and extension. However, during the maintained isometric wrist position, the prime mover and synergist muscles were reciprocally active or silent. In the culmen-simplex region of the cerebellar cortex bordering on the primary fissure, 62% of the Purkinje cells that were identified by the climbing fiber discharge and that changed firing frequency decreased activity during maintained prehension. Almost all of these same Purkinje cells were reciprocally active during isometric wrist flexion and extension, although three neurons had similar discharge patterns during movements in both directions. In contrast, 79% of the unidentified neurons recorded from the same region of the cerebellar cortex increased discharge frequency during prehension. In general, most of these same neurons had reciprocal patterns of discharge during wrist movement even though a few cells were active during the dynamic phase in both directions. Together, the Purkinje cells and the unidentified neurons with bidirectional response patterns were thought to be related to muscles active during both flexion and extension wrist movements. No cells were found that increased discharge with the static isometric wrist torque exerted in both directions. The discharge frequency of some Purkinje and some unidentified neurons could be shown to be related to prehensile force as well as wrist movement velocity and isometric wrist torque. These data suggest that the discharge of about two-thirds of the Purkinje cells related to forearm muscles located along the borders of the primary fissure may depend on whether antagonist muscles are activated reciprocally or coactively. As a consequence, these cells may play a role in the selection or alternation between either of these two modes of muscular contraction. The increased discharge of the remaining one-third of the Purkinje cells excited during antagonist coactivation may provide inhibition of nuclear cells to stabilize the posture at joints other than the wrist and fingers or, alternatively, they may act to reduce nuclear cell discharge in proportion to the intensity of cutaneous stimulation.

Download Full-text

Localization in the Cerebellar Hemisphere of Climbing-Fiber Responses Evoked from the Trigeminal Nerve in the Cat

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y74-150 ◽

1974 ◽

Vol 52 (6) ◽

pp. 1147-1153 ◽

Cited By ~ 6

Author(s):

T. S. Miles ◽

J. D. Cooke ◽

M. Wiesendanger

Keyword(s):

Purkinje Cells ◽

Cerebellar Cortex ◽

Anterior Lobe ◽

Cerebellar Hemisphere ◽

Projection Area ◽

Field Potentials ◽

Facial Skin ◽

Almost All ◽

Climbing Fiber Responses ◽

Stimulation Of

The area of cerebellar cortex to which climbing fibers (CF) project from trigeminal cutaneous afferents has been established in pentobarbital-anesthetized cats. This area is centered upon the ipsilateral lobule HVI, with some overlap onto adjoining folia of the anterior lobe (lobule V) and onto crus Ia of lobule HVIIA. At almost all points within the projection area, CF field potentials of various amplitudes could be elicited by stimulation of more than one trigeminal branch. Hence the general somatotopic arrangement was a complex pattern of inputs converging onto many points from spatially related areas of facial skin. Convergence from more than one nerve was also seen on 32 of 47 single Purkinje cells.

Download Full-text

Faculty Opinions recommendation of Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1027281.334919 ◽

2005 ◽

Cited By ~ 1

Author(s):

Albert La Spada

Keyword(s):

Fragile X Syndrome ◽

Purkinje Cells ◽

Eyelid Conditioning ◽

Fragile X ◽

Parallel Fiber

Download Full-text

Transcranial direct current stimulation of cerebellum alters spiking precision in cerebellar cortex: A modeling study of cellular responses

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009609 ◽

2021 ◽

Vol 17 (12) ◽

pp. e1009609

Author(s):

Xu Zhang ◽

Roeland Hancock ◽

Sabato Santaniello

Keyword(s):

Purkinje Cells ◽

Cerebellar Cortex ◽

Direct Current ◽

Transcranial Direct Current Stimulation ◽

Cellular Response ◽

Cerebellar Neurons ◽

Direct Current Stimulation ◽

Repolarization Phase ◽

Cerebellar Tdcs ◽

Complex Spikes

Transcranial direct current stimulation (tDCS) of the cerebellum has rapidly raised interest but the effects of tDCS on cerebellar neurons remain unclear. Assessing the cellular response to tDCS is challenging because of the uneven, highly stratified cytoarchitecture of the cerebellum, within which cellular morphologies, physiological properties, and function vary largely across several types of neurons. In this study, we combine MRI-based segmentation of the cerebellum and a finite element model of the tDCS-induced electric field (EF) inside the cerebellum to determine the field imposed on the cerebellar neurons throughout the region. We then pair the EF with multicompartment models of the Purkinje cell (PC), deep cerebellar neuron (DCN), and granule cell (GrC) and quantify the acute response of these neurons under various orientations, physiological conditions, and sequences of presynaptic stimuli. We show that cerebellar tDCS significantly modulates the postsynaptic spiking precision of the PC, which is expressed as a change in the spike count and timing in response to presynaptic stimuli. tDCS has modest effects, instead, on the PC tonic firing at rest and on the postsynaptic activity of DCN and GrC. In Purkinje cells, anodal tDCS shortens the repolarization phase following complex spikes (-14.7 ± 6.5% of baseline value, mean ± S.D.; max: -22.7%) and promotes burstiness with longer bursts compared to resting conditions. Cathodal tDCS, instead, promotes irregular spiking by enhancing somatic excitability and significantly prolongs the repolarization after complex spikes compared to baseline (+37.0 ± 28.9%, mean ± S.D.; max: +84.3%). tDCS-induced changes to the repolarization phase and firing pattern exceed 10% of the baseline values in Purkinje cells covering up to 20% of the cerebellar cortex, with the effects being distributed along the EF direction and concentrated in the area under the electrode over the cerebellum. Altogether, the acute effects of tDCS on cerebellum mainly focus on Purkinje cells and modulate the precision of the response to synaptic stimuli, thus having the largest impact when the cerebellar cortex is active. Since the spatiotemporal precision of the PC spiking is critical to learning and coordination, our results suggest cerebellar tDCS as a viable therapeutic option for disorders involving cerebellar hyperactivity such as ataxia.

Download Full-text

Stereotyped spatial patterns of functional synaptic connectivity in the cerebellar cortex

eLife ◽

10.7554/elife.09862 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 33

Author(s):

Antoine M Valera ◽

Francesca Binda ◽

Sophie A Pawlowski ◽

Jean-Luc Dupont ◽

Jean-François Casella ◽

...

Keyword(s):

Purkinje Cells ◽

Cerebellar Cortex ◽

Granule Cell ◽

Motor Coordination ◽

Molecular Layer ◽

Granule Cell Layer ◽

Synaptic Organization ◽

Cerebellar Modules ◽

Activity Dependent

Motor coordination is supported by an array of highly organized heterogeneous modules in the cerebellum. How incoming sensorimotor information is channeled and communicated between these anatomical modules is still poorly understood. In this study, we used transgenic mice expressing GFP in specific subsets of Purkinje cells that allowed us to target a given set of cerebellar modules. Combining in vitro recordings and photostimulation, we identified stereotyped patterns of functional synaptic organization between the granule cell layer and its main targets, the Purkinje cells, Golgi cells and molecular layer interneurons. Each type of connection displayed position-specific patterns of granule cell synaptic inputs that do not strictly match with anatomical boundaries but connect distant cortical modules. Although these patterns can be adjusted by activity-dependent processes, they were found to be consistent and predictable between animals. Our results highlight the operational rules underlying communication between modules in the cerebellar cortex.

Download Full-text

The Effect of Induced Diabetes Mellitus on the Cerebellar Cortex of Adult Male Rat and the Possible Protective Role of Oxymatrine: A Histological, Immunohistochemical and Biochemical Study

10.21203/rs.3.rs-300672/v1 ◽

2021 ◽

Author(s):

Amany Mohamed Shalaby ◽

Adel Mohamed Aboregela ◽

Mohamed Ali Alabiad ◽

Mona Tayssir Sadek

Keyword(s):

Diabetes Mellitus ◽

Purkinje Cells ◽

Cerebellar Cortex ◽

Adult Male ◽

Protective Role ◽

Diabetic Rats ◽

Male Rats ◽

Group I ◽

Group Ii

Abstract Diabetes mellitus (DM) represents a widespread metabolic disease with a well-known neurotoxicity in both central and peripheral nervous systems. Oxymatrine is a traditional Chinese herbal medicine that has various pharmacological activities including; anti-oxidant, anti-apoptotic and anti-inflammatory potentials. The present work aimed to study the impact of diabetes mellitus on the cerebellar cortex of adult male albino rat and to evaluate the potential protective role of oxymatrine using different histological methods. Fifty-five adult male rats were randomly divided into three groups: group I served as control, group II was given oxymatrine (80 mg/kg/day) orally for 8 weeks and group III was given a single dose of streptozotocin (50mg/kg) intaperitoneally to induce diabetes. Then diabetic rats were subdivided into two subgroups: subgroup IIIa that received no additional treatment and subgroup IIIb that received oxymatrine similar to group II. The diabetic group revealed numerous changes in the Purkinje cell layer in the form of multilayer arrangement of Purkinje cells, shrunken cells with deeply stained nuclei as well as focal loss of the Purkinje cells. A significant increment in GFAP and synaptophysin expression was reported. Transmission electron microscopy showed irregularity and splitting of myelin sheaths in the molecular layer, dark shrunken Purkinje cells with ill-defined nuclei, dilated Golgi saccules and dense granule cells with irregular nuclear outlines in the granular layer. In contrast, these changes were less evident in diabetic rats that received oxymatrine. In conclusion, Oxymatrine could protect the cerebellar cortex against changes induced by DM.

Download Full-text