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Annual Review of Neuroscience Jul 2022The cerebellar cortex is an important system for relating neural circuits and learning. Its promise reflects the longstanding idea that it contains simple, repeated... (Review)
Review
The cerebellar cortex is an important system for relating neural circuits and learning. Its promise reflects the longstanding idea that it contains simple, repeated circuit modules with only a few cell types and a single plasticity mechanism that mediates learning according to classical Marr-Albus models. However, emerging data have revealed surprising diversity in neuron types, synaptic connections, and plasticity mechanisms, both locally and regionally within the cerebellar cortex. In light of these findings, it is not surprising that attempts to generate a holistic model of cerebellar learning across different behaviors have not been successful. While the cerebellum remains an ideal system for linking neuronal function with behavior, it is necessary to update the cerebellar circuit framework to achieve its great promise. In this review, we highlight recent advances in our understanding of cerebellar-cortical cell types, synaptic connections, signaling mechanisms, and forms of plasticity that enrich cerebellar processing.
Topics: Cerebellar Cortex; Cerebellum; Learning; Neuronal Plasticity; Purkinje Cells
PubMed: 35803588
DOI: 10.1146/annurev-neuro-091421-125115 -
Neuroscience Letters Jan 2019The cerebellum has a well-established role in controlling motor functions such coordination, balance, posture, and skilled learning. There is mounting evidence that it... (Review)
Review
The cerebellum has a well-established role in controlling motor functions such coordination, balance, posture, and skilled learning. There is mounting evidence that it might also play a critical role in non-motor functions such as cognition and emotion. It is therefore not surprising that cerebellar defects are associated with a wide array of diseases including ataxia, dystonia, tremor, schizophrenia, dyslexia, and autism spectrum disorder. What is intriguing is that a seemingly uniform circuit that is often described as being "simple" should carry out all of these behaviors. Analyses of how cerebellar circuits develop have revealed that such descriptions massively underestimate the complexity of the cerebellum. The cerebellum is in fact highly patterned and organized around a series of parasagittal stripes and transverse zones. This topographic architecture partitions all cerebellar circuits into functional modules that are thought to enhance processing power during cerebellar dependent behaviors. What are arguably the most remarkable features of cerebellar topography are the developmental processes that produce them. This review is concerned with the genetic and cellular mechanisms that orchestrate cerebellar patterning. We place a major focus on how Purkinje cells control multiple aspects of cerebellar circuit assembly. Using this model, we discuss evidence for how "zebra-like" patterns in Purkinje cells sculpt the cerebellum, how specific genetic cues mediate the process, and how activity refines the patterns into an adult map that is capable of executing various functions. We also discuss how defective Purkinje cell patterning might impact the pathogenesis of neurological conditions.
Topics: Animals; Cerebellar Diseases; Cerebellum; Humans; Purkinje Cells
PubMed: 29746896
DOI: 10.1016/j.neulet.2018.05.013 -
Neuron Oct 2022Dysregulation of long interspersed nuclear element 1 (LINE-1, L1), a dominant class of transposable elements in the human genome, has been linked to neurodegenerative...
Dysregulation of long interspersed nuclear element 1 (LINE-1, L1), a dominant class of transposable elements in the human genome, has been linked to neurodegenerative diseases, but whether elevated L1 expression is sufficient to cause neurodegeneration has not been directly tested. Here, we show that the cerebellar expression of L1 is significantly elevated in ataxia telangiectasia patients and strongly anti-correlated with the expression of epigenetic silencers. To examine the role of L1 in the disease etiology, we developed an approach for direct targeting of the L1 promoter for overexpression in mice. We demonstrated that L1 activation in the cerebellum led to Purkinje cell dysfunctions and degeneration and was sufficient to cause ataxia. Treatment with a nucleoside reverse transcriptase inhibitor blunted ataxia progression by reducing DNA damage, attenuating gliosis, and reversing deficits of molecular regulators for calcium homeostasis in Purkinje cells. Our study provides the first direct evidence that L1 activation can drive neurodegeneration.
Topics: Animals; Humans; Mice; Ataxia; Calcium; Cerebellum; DNA Transposable Elements; Nucleosides; Purkinje Cells; Reverse Transcriptase Inhibitors; Long Interspersed Nucleotide Elements
PubMed: 36070749
DOI: 10.1016/j.neuron.2022.08.011 -
Experimental Neurology Dec 2021The dystonias are a group of disorders characterized by excessive muscle contractions leading to abnormal repetitive movements or postures. In blepharospasm, the face is...
BACKGROUND
The dystonias are a group of disorders characterized by excessive muscle contractions leading to abnormal repetitive movements or postures. In blepharospasm, the face is affected, leading to excessive eye blinking and spasms of muscles around the eyes. The pathogenesis of blepharospasm is not well understood, but several imaging studies have implied subtle structural defects in several brain regions, including the cerebellum.
OBJECTIVE
To delineate cerebellar pathology in brains collected at autopsy from 7 human subjects with blepharospasm and 9 matched controls.
METHODS
Sections from 3 cerebellar regions were sampled and processed using Nissl and silver impregnation stains. Purkinje neurons were the focus of the evaluation, along with as several other subtle pathological features of cerebellar dysfunction such as Purkinje neuron axonal swellings (torpedo bodies), proliferation of basket cell processes around Purkinje neurons (hairy baskets), empty baskets (missing Purkinje neurons), and displacement of cell soma from their usual location (ectopic Purkinje neurons).
RESULTS
The results revealed a significant reduction in Purkinje neuron and torpedo body density, but no changes in any of the other measures.
CONCLUSIONS
These findings demonstrate subtle neuropathological changes similar to those reported for subjects with cervical dystonia. These findings may underly some of the subtle imaging changes reported for blepharospasm.
Topics: Aged; Aged, 80 and over; Blepharospasm; Cerebellum; Female; Humans; Male; Middle Aged; Purkinje Cells
PubMed: 34464652
DOI: 10.1016/j.expneurol.2021.113855 -
Cells Sep 2022Despite their homogeneous appearance, Purkinje cells are remarkably diverse with respect to their molecular phenotypes, physiological properties, afferent and efferent... (Review)
Review
Despite their homogeneous appearance, Purkinje cells are remarkably diverse with respect to their molecular phenotypes, physiological properties, afferent and efferent connectivity, as well as their vulnerability to insults. Heterogeneity in Purkinje cells arises early in development, with molecularly distinct embryonic cell clusters present soon after Purkinje cell specification. Traditional methods have characterized cerebellar development and cell types, including Purkinje cell subtypes, based on knowledge of selected markers. However, recent single-cell RNA sequencing studies provide vastly increased resolution of the whole cerebellar transcriptome. Here we draw together the results of multiple single-cell transcriptomic studies in developing and adult cerebellum in both mouse and human. We describe how this detailed transcriptomic data has increased our understanding of the intricate development and function of Purkinje cells and provides first clues into features specific to human cerebellar development.
Topics: Animals; Biomarkers; Cerebellum; Humans; Mice; Nerve Tissue Proteins; Phenotype; Purkinje Cells
PubMed: 36139493
DOI: 10.3390/cells11182918 -
Pharmacological Research May 2023Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are...
Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.
Topics: Mice; Animals; Cerebellar Ataxia; Purkinje Cells; Microglia; Tumor Necrosis Factor-alpha; Cerebellum; Cytokines
PubMed: 37068531
DOI: 10.1016/j.phrs.2023.106773 -
Brain Research Sep 2015The mechanisms underlying cerebellar learning are reviewed with an emphasis on old arguments and new perspectives on eyeblink conditioning. Eyeblink conditioning has... (Review)
Review
The mechanisms underlying cerebellar learning are reviewed with an emphasis on old arguments and new perspectives on eyeblink conditioning. Eyeblink conditioning has been used for decades a model system for elucidating cerebellar learning mechanisms. The standard model of the mechanisms underlying eyeblink conditioning is that there two synaptic plasticity processes within the cerebellum that are necessary for acquisition of the conditioned response: (1) long-term depression (LTD) at parallel fiber-Purkinje cell synapses and (2) long-term potentiation (LTP) at mossy fiber-interpositus nucleus synapses. Additional Purkinje cell plasticity mechanisms may also contribute to eyeblink conditioning including LTP, excitability, and entrainment of deep nucleus activity. Recent analyses of the sensory input pathways necessary for eyeblink conditioning indicate that the cerebellum regulates its inputs to facilitate learning and maintain plasticity. Cerebellar learning during eyeblink conditioning is therefore a dynamic interactive process which maximizes responding to significant stimuli and suppresses responding to irrelevant or redundant stimuli. This article is part of a Special Issue entitled SI: Brain and Memory.
Topics: Animals; Cerebellum; Conditioning, Eyelid; Humans; Neuronal Plasticity; Purkinje Cells; Synapses
PubMed: 25289586
DOI: 10.1016/j.brainres.2014.09.062 -
Cerebellum (London, England) Dec 2018The climbing fiber-Purkinje cell circuit is one of the most powerful and highly conserved in the central nervous system. Climbing fibers exert a powerful excitatory... (Review)
Review
The climbing fiber-Purkinje cell circuit is one of the most powerful and highly conserved in the central nervous system. Climbing fibers exert a powerful excitatory action that results in a complex spike in Purkinje cells and normal functioning of the cerebellum depends on the integrity of climbing fiber-Purkinje cell synapse. Over the last 50 years, multiple hypotheses have been put forward on the role of the climbing fibers and complex spikes in cerebellar information processing and motor control. Central to these theories is the nature of the interaction between the low-frequency complex spike discharge and the high-frequency simple spike firing of Purkinje cells. This review examines the major hypotheses surrounding the action of the climbing fiber-Purkinje cell projection, discussing both supporting and conflicting findings. The review describes newer findings establishing that climbing fibers and complex spikes provide predictive signals about movement parameters and that climbing fiber input controls the encoding of behavioral information in the simple spike firing of Purkinje cells. Finally, we propose the dynamic encoding hypothesis for complex spike function that strives to integrate established and newer findings.
Topics: Action Potentials; Animals; Models, Neurological; Motor Activity; Olivary Nucleus; Purkinje Cells
PubMed: 29982917
DOI: 10.1007/s12311-018-0960-3 -
Current Biology : CB Feb 2022Coordination of bilateral movements is essential for a large variety of animal behaviors. The olivocerebellar system is critical for the control of movement, but its...
Coordination of bilateral movements is essential for a large variety of animal behaviors. The olivocerebellar system is critical for the control of movement, but its role in bilateral coordination has yet to be elucidated. Here, we examined whether Purkinje cells encode and influence synchronicity of left-right whisker movements. We found that complex spike activity is correlated with a prominent left-right symmetry of spontaneous whisker movements within parts, but not all, of Crus1 and Crus2. Optogenetic stimulation of climbing fibers in the areas with high and low correlations resulted in symmetric and asymmetric whisker movements, respectively. Moreover, when simple spike frequency prior to the complex spike was higher, the complex spike-related symmetric whisker protractions were larger. This finding alludes to a role for rebound activity in the cerebellar nuclei, which indeed turned out to be enhanced during symmetric protractions. Tracer injections suggest that regions associated with symmetric whisker movements are anatomically connected to the contralateral cerebellar hemisphere. Together, these data point toward the existence of modules on both sides of the cerebellar cortex that can differentially promote or reduce the symmetry of left and right movements in a context-dependent fashion.
Topics: Action Potentials; Animals; Cerebellum; Movement; Optogenetics; Purkinje Cells; Vibrissae
PubMed: 35016009
DOI: 10.1016/j.cub.2021.12.020 -
Cerebellum (London, England) Oct 2022After decades of study, a comprehensive understanding of cerebellar function remains elusive. Several hypotheses have been put forward over the years, including that the... (Review)
Review
After decades of study, a comprehensive understanding of cerebellar function remains elusive. Several hypotheses have been put forward over the years, including that the cerebellum functions as a forward internal model. Integrated into the forward model framework is the long-standing view that Purkinje cell complex spike discharge encodes error information. In this brief review, we address both of these concepts based on our recordings of cerebellar Purkinje cells over the last decade as well as newer findings from the literature. During a high-dimensionality tracking task requiring continuous error processing, we find that complex spike discharge provides a rich source of non-error signals to Purkinje cells, indicating that the classical error encoding role ascribed to climbing fiber input needs revision. Instead, the simple spike discharge of Purkinje cells carries robust predictive and feedback signals of performance errors, as well as kinematics. These simple spike signals are consistent with a forward internal model. We also show that the information encoded in the simple spike is dynamically adjusted by the complex spike firing. Synthesis of these observations leads to the hypothesis that complex spikes convey behavioral state changes, possibly acting to select and maintain forward models.
Topics: Action Potentials; Biomechanical Phenomena; Cerebellum; Movement; Purkinje Cells
PubMed: 35471627
DOI: 10.1007/s12311-022-01406-3