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Nature Jun 2014Behavioural 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...
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.
Topics: Action Potentials; Animals; Axons; Calcium; Learning; Long-Term Synaptic Depression; Macaca mulatta; Male; Motor Skills; Neuronal Plasticity; Olivary Nucleus; Purkinje Cells
PubMed: 24814344
DOI: 10.1038/nature13282 -
Cell Reports May 2023Within the cerebellar cortex, mossy fibers (MFs) excite granule cells (GCs) that excite Purkinje cells (PCs), which provide outputs to the deep cerebellar nuclei (DCNs)....
Within the cerebellar cortex, mossy fibers (MFs) excite granule cells (GCs) that excite Purkinje cells (PCs), which provide outputs to the deep cerebellar nuclei (DCNs). It is well established that PC disruption produces motor deficits such as ataxia. This could arise from either decreases in ongoing PC-DCN inhibition, increases in the variability of PC firing, or disruption of the flow of MF-evoked signals. Remarkably, it is not known whether GCs are essential for normal motor function. Here we address this issue by selectively eliminating calcium channels that mediate transmission (Ca2.1, Ca2.2, and Ca2.3) in a combinatorial manner. We observe profound motor deficits but only when all Ca2 channels are eliminated. In these mice, the baseline rate and variability of PC firing are unaltered, and locomotion-dependent increases in PC firing are eliminated. We conclude that GCs are indispensable for normal motor performance and that disruption of MF-induced signals impairs motor performance.
Topics: Mice; Animals; Cerebellum; Neurons; Purkinje Cells; Cerebellar Cortex; Signal Transduction
PubMed: 37141091
DOI: 10.1016/j.celrep.2023.112429 -
Journal of Neuroscience Research Sep 2018Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of cerebellar degenerative disorders, characterized by progressive gait unsteadiness, hand...
Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of cerebellar degenerative disorders, characterized by progressive gait unsteadiness, hand incoordination, and dysarthria. Ataxia type 1 (SCA1) is caused by the expansion of a CAG trinucleotide repeat in the SCA1 gene resulting in the atypical extension of a polyglutamine (polyQ) tract within the ataxin-1 protein. Our main objective was to investigate the mitochondrial oxidative metabolism in the cerebellum of transgenic SCA1 mice. SCA1 transgenic mice develop clinical features in the early life stages (around 5 weeks of age) presenting pathological cerebellar signs with concomitant progressive Purkinje neuron atrophy and relatively little cell loss; this evidence suggests that the SCA1 phenotype is not the result of cell death per se, but a possible effect of cellular dysfunction that occurs before neuronal demise. We studied the mitochondrial oxidative metabolism in cerebellar cells from both homozygous and heterozygous transgenic SCA1 mice, aged 2 and 6 months. Histochemical examination showed a cytochrome-c-oxidase (COX) deficiency in the Purkinje cells (PCs) of both heterozygous and homozygous mice, the oxidative defect being more prominent in older mice, in which the percentage of COX-deficient PC was up to 30%. Using a laser-microdissector, we evaluated the mitochondrial DNA (mtDNA) content on selectively isolated COX-competent and COX-deficient PC by quantitative Polymerase Chain Reaction and we found mtDNA depletion in those with oxidative dysfunction. In conclusion, the selective oxidative metabolism defect observed in neuronal PC expressing mutant ataxin occurs as early as 8 weeks of age thus representing an early step in the PC degeneration process in SCA1 disease.
Topics: Animals; Ataxin-1; Cytochrome-c Oxidase Deficiency; DNA, Mitochondrial; Disease Models, Animal; Female; Male; Mice, Transgenic; Purkinje Cells; Spinocerebellar Ataxias
PubMed: 30113722
DOI: 10.1002/jnr.24263 -
ELife Apr 2022The ability to accurately control our posture and perceive our spatial orientation during self-motion requires knowledge of the motion of both the head and body....
The ability to accurately control our posture and perceive our spatial orientation during self-motion requires knowledge of the motion of both the head and body. However, while the vestibular sensors and nuclei directly encode head motion, no sensors directly encode body motion. Instead, the integration of vestibular and neck proprioceptive inputs is necessary to transform vestibular information into the body-centric reference frame required for postural control. The anterior vermis of the cerebellum is thought to play a key role in this transformation, yet how its Purkinje cells transform multiple streams of sensory information into an estimate of body motion remains unknown. Here, we recorded the activity of individual anterior vermis Purkinje cells in alert monkeys during passively applied whole-body, body-under-head, and head-on-body rotations. Most Purkinje cells dynamically encoded an intermediate representation of self-motion between head and body motion. Notably, Purkinje cells responded to both vestibular and neck proprioceptive stimulation with considerable heterogeneity in their response dynamics. Furthermore, their vestibular responses were tuned to head-on-body position. In contrast, targeted neurons in the deep cerebellar nuclei are known to unambiguously encode either head or body motion across conditions. Using a simple population model, we established that combining responses of~40-50 Purkinje cells could explain the responses of these deep cerebellar nuclei neurons across all self-motion conditions. We propose that the observed heterogeneity in Purkinje cell response dynamics underlies the cerebellum's capacity to compute the dynamic representation of body motion required to ensure accurate postural control and perceptual stability in our daily lives.
Topics: Animals; Cerebellum; Head Movements; Macaca; Motion; Purkinje Cells
PubMed: 35467528
DOI: 10.7554/eLife.75018 -
Disease Models & Mechanisms Jun 2024Purkinje cell dysfunction disrupts movement and causes disorders such as ataxia. Recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation....
Purkinje cell dysfunction disrupts movement and causes disorders such as ataxia. Recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxic mouse model generated by silencing Purkinje cell neurotransmission (L7Cre;Vgatfx/fx) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity was unaltered in the mutant mice, although their sleep parameters and ECoG patterns were modified. The L7Cre;Vgatfx/fx mutant mice had decreased wakefulness and rapid eye movement (REM) sleep, whereas non-REM sleep was increased. The mutants had an extended latency to REM sleep, which is also observed in human patients with ataxia. Spectral analysis of ECoG signals revealed alterations in the power distribution across different frequency bands defining sleep. Therefore, Purkinje cell dysfunction may influence wakefulness and equilibrium of distinct sleep stages in ataxia. Our findings posit a connection between cerebellar dysfunction and disrupted sleep and underscore the importance of examining cerebellar circuit function in sleep disorders.
Topics: Animals; Purkinje Cells; Wakefulness; Ataxia; Sleep; Sleep, REM; Mice; Circadian Rhythm; Disease Models, Animal; Male
PubMed: 38563553
DOI: 10.1242/dmm.050379 -
Neuroscience May 2021Cerebellar development has a remarkably protracted morphogenetic timeline that is coordinated by multiple cell types. Here, we discuss the intriguing cellular... (Review)
Review
Cerebellar development has a remarkably protracted morphogenetic timeline that is coordinated by multiple cell types. Here, we discuss the intriguing cellular consequences of interactions between inhibitory Purkinje cells and excitatory granule cells during embryonic and postnatal development. Purkinje cells are central to all cerebellar circuits, they are the first cerebellar cortical neurons to be born, and based on their cellular and molecular signaling, they are considered the master regulators of cerebellar development. Although rudimentary Purkinje cell circuits are already present at birth, their connectivity is morphologically and functionally distinct from their mature counterparts. The establishment of the Purkinje cell circuit with its mature firing properties has a temporal dependence on cues provided by granule cells. Granule cells are the latest born, yet most populous, neuronal type in the cerebellar cortex. They provide a combination of mechanical, molecular and activity-based cues that shape the maturation of Purkinje cell structure, connectivity and function. We propose that the wiring of Purkinje cells for function falls into two developmental phases: an initial phase that is guided by intrinsic mechanisms and a later phase that is guided by dynamically-acting cues, some of which are provided by granule cells. In this review, we highlight the mechanisms that granule cells use to help establish the unique properties of Purkinje cell firing.
Topics: Cerebellum; Humans; Infant, Newborn; Interneurons; Neurogenesis; Neurons; Purkinje Cells
PubMed: 32554107
DOI: 10.1016/j.neuroscience.2020.06.010 -
ENeuro 2016It has been known for a long time that GABAergic Purkinje cells in the cerebellar cortex, as well as their target neurons in the cerebellar nuclei, are spontaneously...
It has been known for a long time that GABAergic Purkinje cells in the cerebellar cortex, as well as their target neurons in the cerebellar nuclei, are spontaneously active. The cerebellar output will, therefore, depend on how input is integrated into this spontaneous activity. It has been shown that input from climbing fibers originating in the inferior olive controls the spontaneous activity in Purkinje cells. While blocking climbing fiber input to the Purkinje cells causes a dramatic increase in the firing rate, increased climbing fiber activity results in reduced Purkinje cell activity. However, the exact calibration of this regulation has not been examined systematically. Here we examine the relation between climbing fiber stimulation frequency and Purkinje cell activity in unanesthetized decerebrated ferrets. The results revealed a gradual suppression of Purkinje cell activity, starting at climbing fiber stimulation frequencies as low as 0.5 Hz. At 4 Hz, Purkinje cells were completely silenced. This effect lasted an average of 2 min after the stimulation rate was reduced to a lower level. We also examined the effect of sustained climbing fiber stimulation on overt behavior. Specifically, we analyzed conditioned blink responses, which are known to be dependent on the cerebellum, while stimulating the climbing fibers at different frequencies. In accordance with the neurophysiological data, the conditioned blink responses were suppressed at stimulation frequencies of ≥4 Hz.
Topics: Action Potentials; Afferent Pathways; Animals; Conditioning, Eyelid; Ferrets; Male; Purkinje Cells
PubMed: 26839917
DOI: 10.1523/ENEURO.0067-15.2015 -
Cerebellum (London, England) Jun 2022Gerbrandus Jelgersma published extensively on the (pathological) anatomy of the cerebellum between 1886 and 1934. Based on his observations on the double innervation of...
Gerbrandus Jelgersma published extensively on the (pathological) anatomy of the cerebellum between 1886 and 1934. Based on his observations on the double innervation of the Purkinje cells, he formulated a hypothesis on the function of the cerebellum. Both afferent systems of the cerebellum, the mossy fiber-parallel fiber system and the climbing fibers terminate on the Purkinje cell dendrites. According to Jelgersma, the mossy fiber-parallel fiber system is derived from the pontine nuclei and the inferior olive, and would transmit the movement images derived from the cerebral cortex. Spinocerebellar climbing fibers would transmit information about the execution of the movement. When the Purkinje cell compares these inputs and notices a difference between instruction and execution, it sends a correction through the descending limb of the superior cerebellar peduncle to the anterior horn cells. Jelgersma postulates that this cerebro-cerebellar coordination system shares plasticity with other nervous connections because nerve cell dendritic protrusions possess what he called amoeboid mobility: dendritic protrusions can be extended or retracted and are so able to create new connections or to abolish them. Jelgersma's theories are discussed against the background of more recent theories of cerebellar function that, similarly, are based on the double innervation of the Purkinje cells. The amoeboid hypothesis is traced to its roots in the late nineteenth century.
Topics: Cerebellar Cortex; Cerebellum; Neurons; Olivary Nucleus; Purkinje Cells
PubMed: 34383219
DOI: 10.1007/s12311-021-01273-4 -
ELife Apr 2020Although the cerebellum is traditionally associated with balance and motor function, it also plays wider roles in affective and cognitive behaviors. Evidence suggests...
Although the cerebellum is traditionally associated with balance and motor function, it also plays wider roles in affective and cognitive behaviors. Evidence suggests that the cerebellar vermis may regulate aggressive behavior, though the cerebellar circuits and patterns of activity that influence aggression remain unclear. We used optogenetic methods to bidirectionally modulate the activity of spatially-delineated cerebellar Purkinje cells to evaluate the impact on aggression in mice. Increasing Purkinje cell activity in the vermis significantly reduced the frequency of attacks in a resident-intruder assay. Reduced aggression was not a consequence of impaired motor function, because optogenetic stimulation did not alter motor performance. In complementary experiments, optogenetic inhibition of Purkinje cells in the vermis increased the frequency of attacks. These results suggest Purkinje cell activity in the cerebellar vermis regulates aggression, and further support the importance of the cerebellum in driving affective behaviors that could contribute to neurological disorders.
Topics: Aggression; Animals; Behavior, Animal; Cerebellar Vermis; Cerebellum; Mice; Optogenetics; Purkinje Cells
PubMed: 32343225
DOI: 10.7554/eLife.53229 -
PloS One 2012Oligodendrocyte differentiation is temporally regulated during development by multiple factors. Here, we investigated whether the timing of oligodendrocyte...
Oligodendrocyte differentiation is temporally regulated during development by multiple factors. Here, we investigated whether the timing of oligodendrocyte differentiation might be controlled by neuronal differentiation in cerebellar organotypic cultures. In these cultures, the slices taken from newborn mice show very few oligodendrocytes during the first week of culture (immature slices) whereas their number increases importantly during the second week (mature slices). First, we showed that mature cerebellar slices or their conditioned media stimulated oligodendrocyte differentiation in immature slices thus demonstrating the existence of diffusible factors controlling oligodendrocyte differentiation. Using conditioned media from different models of slice culture in which the number of Purkinje cells varies drastically, we showed that the effects of these differentiating factors were proportional to the number of Purkinje cells. To identify these diffusible factors, we first performed a transcriptome analysis with an Affymetrix array for cerebellar cortex and then real-time quantitative PCR on mRNAs extracted from fluorescent flow cytometry sorted (FACS) Purkinje cells of L7-GFP transgenic mice at different ages. These analyses revealed that during postnatal maturation, Purkinje cells down-regulate Sonic Hedgehog and up-regulate vitronectin. Then, we showed that Sonic Hedgehog stimulates the proliferation of oligodendrocyte precursor cells and inhibits their differentiation. In contrast, vitronectin stimulates oligodendrocyte differentiation, whereas its inhibition with blocking antibodies abolishes the conditioned media effects. Altogether, these results suggest that Purkinje cells participate in controlling the timing of oligodendrocyte differentiation in the cerebellum through the developmentally regulated expression of diffusible molecules such as Sonic Hedgehog and vitronectin.
Topics: Animals; Animals, Newborn; Cell Differentiation; Cell Proliferation; Cerebellum; Down-Regulation; Hedgehog Proteins; Mice; Mice, Transgenic; Oligodendroglia; Purkinje Cells; Up-Regulation; Vitronectin
PubMed: 23155445
DOI: 10.1371/journal.pone.0049015