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Cerebellum (London, England) Dec 2022This paper presents a model of learning by the cerebellar circuit. In the traditional and dominant learning model, training teaches finely graded parallel fibre synaptic...
This paper presents a model of learning by the cerebellar circuit. In the traditional and dominant learning model, training teaches finely graded parallel fibre synaptic weights which modify transmission to Purkinje cells and to interneurons that inhibit Purkinje cells. Following training, input in a learned pattern drives a training-modified response. The function is that the naive response to input rates is displaced by a learned one, trained under external supervision. In the proposed model, there is no weight-controlled graduated balance of excitation and inhibition of Purkinje cells. Instead, the balance has two functional states-a switch-at synaptic, whole cell and microzone level. The paper is in two parts. The first is a detailed physiological argument for the synaptic learning function. The second uses the function in a computational simulation of pattern memory. Against expectation, this generates a predictable outcome from input chaos (real-world variables). Training always forces synaptic weights away from the middle and towards the limits of the range, causing them to polarise, so that transmission is either robust or blocked. All conditions teach the same outcome, such that all learned patterns receive the same, rather than a bespoke, effect on transmission. In this model, the function of learning is gating-that is, to select patterns that trigger output merely, and not to modify output. The outcome is memory-operated gate activation which operates a two-state balance of weight-controlled transmission. Group activity of parallel fibres also simultaneously contains a second code contained in collective rates, which varies independently of the pattern code. A two-state response to the pattern code allows faithful, and graduated, control of Purkinje cell firing by the rate code, at gated times.
Topics: Cerebellum; Purkinje Cells; Learning; Axons; Interneurons
PubMed: 34757585
DOI: 10.1007/s12311-021-01325-9 -
The Neuroscientist : a Review Journal... Apr 2011The cerebellum's role in sensory-motor control and adaptation is undisputed. However, a key hypothesis pertaining to the function of cerebellar circuitry lacks... (Review)
Review
The cerebellum's role in sensory-motor control and adaptation is undisputed. However, a key hypothesis pertaining to the function of cerebellar circuitry lacks experimental support. It is universally assumed that the discharge of mossy fibers accounts for modulation of Purkinje cell "simple spikes" (SSs). This assumption acts as a prism through which all other functions of cerebellar circuitry are viewed. The vestibulo-cerebellum (nodulus and uvula) receives a large, unilateral, vestibular primary afferent mossy fiber projection. We can test its role in modulating Purkinje cell SSs by recording the modulated activity of both mossy fiber terminals and Purkinje cell SSs evoked by identical natural vestibular stimulation. Sinusoidal rotation about the longitudinal axis (roll) modulates the activity of vestibular primary afferent mossy and climbing fibers as well as Purkinje cell SSs and complex spikes (CSs). Remarkably, vestibular primary afferent mossy fibers discharge 180 degrees out of phase with SSs. This indicates that mossy fibers cannot account for SS modulation unless an inhibitory synapse is interposed between mossy fibers or vestibular climbing fibers and Purkinje cells. The authors review several experiments that address the relative contributions of mossy and climbing fiber afferents to the modulation of SSs. They conclude that climbing fibers, not mossy fibers, are primarily responsible for the modulation of SSs as well as CSs and they propose revised functions for these two afferent systems.
Topics: Action Potentials; Animals; Cerebellum; Humans; Nerve Fibers; Nerve Net; Neural Pathways; Purkinje Cells; Vestibule, Labyrinth
PubMed: 21362689
DOI: 10.1177/1073858410380251 -
The Journal of Physiology Jan 2017Purkinje cells are the sole output of the cerebellar cortex and fire two distinct types of action potential: simple spikes and complex spikes. Previous studies have...
KEY POINTS
Purkinje cells are the sole output of the cerebellar cortex and fire two distinct types of action potential: simple spikes and complex spikes. Previous studies have mainly considered complex spikes as unitary events, even though the waveform is composed of varying numbers of spikelets. The extent to which differences in spikelet number affect simple spike activity (and vice versa) remains unclear. We found that complex spikes with greater numbers of spikelets are preceded by higher simple spike firing rates but, following the complex spike, simple spikes are reduced in a manner that is graded with spikelet number. This dynamic interaction has important implications for cerebellar information processing, and suggests that complex spike spikelet number may maintain Purkinje cells within their operational range.
ABSTRACT
Purkinje cells are central to cerebellar function because they form the sole output of the cerebellar cortex. They exhibit two distinct types of action potential: simple spikes and complex spikes. It is widely accepted that interaction between these two types of impulse is central to cerebellar cortical information processing. Previous investigations of the interactions between simple spikes and complex spikes have mainly considered complex spikes as unitary events. However, complex spikes are composed of an initial large spike followed by a number of secondary components, termed spikelets. The number of spikelets within individual complex spikes is highly variable and the extent to which differences in complex spike spikelet number affects simple spike activity (and vice versa) remains poorly understood. In anaesthetized adult rats, we have found that Purkinje cells recorded from the posterior lobe vermis and hemisphere have high simple spike firing frequencies that precede complex spikes with greater numbers of spikelets. This finding was also evident in a small sample of Purkinje cells recorded from the posterior lobe hemisphere in awake cats. In addition, complex spikes with a greater number of spikelets were associated with a subsequent reduction in simple spike firing rate. We therefore suggest that one important function of spikelets is the modulation of Purkinje cell simple spike firing frequency, which has implications for controlling cerebellar cortical output and motor learning.
Topics: Action Potentials; Animals; Cats; Female; Male; Purkinje Cells; Rats, Sprague-Dawley; Rats, Wistar
PubMed: 27265808
DOI: 10.1113/JP272259 -
Science (New York, N.Y.) Jul 2023Canonically, each Purkinje cell (PC) in the adult cerebellum receives only one climbing fiber (CF) from the inferior olive. Underlying current theories of cerebellar...
Canonically, each Purkinje cell (PC) in the adult cerebellum receives only one climbing fiber (CF) from the inferior olive. Underlying current theories of cerebellar function is the notion that this highly conserved one-to-one relationship renders Purkinje dendrites into a single computational compartment. However, we discovered that multiple primary dendrites are a near-universal morphological feature in humans. Using tract tracing, immunolabeling, and in vitro electrophysiology, we found that in mice ~25% of mature multibranched cells receive more than one CF input. Two-photon calcium imaging in vivo revealed that separate dendrites can exhibit distinct response properties to sensory stimulation, indicating that some multibranched cells integrate functionally independent CF-receptive fields. These findings indicate that PCs are morphologically and functionally more diverse than previously thought.
Topics: Animals; Humans; Mice; Axons; Dendrites; Purkinje Cells; Synapses
PubMed: 37499000
DOI: 10.1126/science.adi1024 -
Learning & Memory (Cold Spring Harbor,... 2006The current study examined the effects of globally depleting Purkinje cells in the cerebellar cortex with the immunotoxin OX7-saporin on acquisition and extinction of... (Comparative Study)
Comparative Study
The current study examined the effects of globally depleting Purkinje cells in the cerebellar cortex with the immunotoxin OX7-saporin on acquisition and extinction of delay eyeblink conditioning in rats. Rats were given OX7-saporin or saline 2 wk before the start of eyeblink conditioning. The rats that reached a performance criterion of two consecutive days with 80% or greater conditioned responses were given 5 d of extinction training followed by 2 d of reacquisition training. Rats that received infusions of OX7-saporin had 77.2%-97.9% Purkinje cell loss and exhibited impaired acquisition and extinction. The amount of Purkinje cell loss was correlated with the magnitude of the acquisition and extinction impairments. The highest correlations between Purkinje cell number and the rate of acquisition were in lobule HVI and the anterior lobe. The highest negative correlation between Purkinje cell number and the percentage of conditioned responses during extinction was in the anterior lobe. The results indicate that cerebellar Purkinje cells, particularly in the anterior lobe and lobule HVI, play significant roles in acquisition and extinction of eyeblink conditioning.
Topics: Analysis of Variance; Animals; Antibodies, Monoclonal; Association Learning; Cell Count; Cerebellum; Conditioning, Eyelid; Extinction, Psychological; Immunoconjugates; Immunotoxins; Male; N-Glycosyl Hydrolases; Neurotoxins; Purkinje Cells; Rats; Rats, Long-Evans; Regression Analysis; Ribosome Inactivating Proteins, Type 1; Saporins
PubMed: 16741286
DOI: 10.1101/lm.168506 -
The Journal of Neuroscience : the... May 1997Purkinje cells are among the most resistant neurons to axotomy and the most refractory to axonal regeneration. By using organotypic cultures, we have studied age- and...
Purkinje cells are among the most resistant neurons to axotomy and the most refractory to axonal regeneration. By using organotypic cultures, we have studied age- and environment-related factors implicated in Purkinje cell survival and axonal regeneration. Most Purkinje cells taken from 1- to 5-d-old rats, the period in which these neurons are engaged in intense synaptogenesis and dendritic remodeling, die 1 week after plating, whereas if cultured before or after this period, Purkinje cells survive, even in the absence of deep nuclear neurons, their postsynaptic targets. Cerebellar slices taken from 10-d-old rats and kept in vitro for 1 week acquire a cellular composition resembling mature cerebellum. Their Purkinje cells are resistant to axotomy, but even when confronted with permissive environments (sciatic nerves or fetal cerebellar slices), their axons do not regenerate. In contrast, fetal rat and mouse Purkinje cells are able to regenerate their axons on mature cerebellar slices. This regeneration is massive, and the regrowing axons invade all cerebellar regions of the apposed mature slices, including white matter. These results show that Purkinje cell survival and axonal regeneration are age-related and independent from environmental constraints. Moreover, our observations suggest strongly that the onset of synaptogenesis of Purkinje cell axons could provide a signal to turn off their growth program and that, thereafter, permissive microenvironment alone is unable to reestablish such a program.
Topics: Animals; Axons; Calbindins; Cell Culture Techniques; Cell Survival; Cells, Cultured; Cellular Senescence; Cerebellar Nuclei; Denervation; Female; Mice; Mice, Knockout; Nerve Regeneration; Nerve Tissue Proteins; Pregnancy; Purkinje Cells; Rats; Rats, Wistar; S100 Calcium Binding Protein G; Sciatic Nerve
PubMed: 9133392
DOI: 10.1523/JNEUROSCI.17-10-03710.1997 -
Scientific Reports Mar 2020The cerebellum coordinates voluntary movements for balanced motor activity in a normal gravity condition. It remains unknown how hypergravity is associated with...
The cerebellum coordinates voluntary movements for balanced motor activity in a normal gravity condition. It remains unknown how hypergravity is associated with cerebellum-dependent motor behaviors and Purkinje cell's activities. In order to investigate the relationship between gravity and cerebellar physiology, we measured AMPA-mediated fast currents and mGluR1-mediated slow currents of cerebellar Purkinje cells along with cerebellum-dependent behaviors such as the footprint and irregular ladder under a hypergravity condition. We found abnormal animal behaviors in the footprint and irregular ladder tests under hypergravity. They are correlated with decreased AMPA and mGluR1-mediated synaptic currents of Purkinje cells. These results indicate that gravity regulates the activity of Purkinje cells, thereby modulating cerebellum-dependent motor outputs.
Topics: Animals; Behavior, Animal; Cerebellum; Hypergravity; Male; Motor Activity; Purkinje Cells; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
PubMed: 32157179
DOI: 10.1038/s41598-020-61453-w -
ELife Dec 2022The function of a feedback inhibitory circuit between cerebellar Purkinje cells and molecular layer interneurons (MLIs) was defined by combining optogenetics, neuronal...
The function of a feedback inhibitory circuit between cerebellar Purkinje cells and molecular layer interneurons (MLIs) was defined by combining optogenetics, neuronal activity recordings both in cerebellar slices and in vivo, and computational modeling. Purkinje cells inhibit a subset of MLIs in the inner third of the molecular layer. This inhibition is non-reciprocal, short-range (less than 200 μm) and is based on convergence of one to two Purkinje cells onto MLIs. During learning-related eyelid movements in vivo, the activity of a subset of MLIs progressively increases as Purkinje cell activity decreases, with Purkinje cells usually leading the MLIs. Computer simulations indicate that these relationships are best explained by the feedback circuit from Purkinje cells to MLIs and that this feedback circuit plays a central role in making cerebellar learning efficient.
Topics: Feedback; Cerebellum; Purkinje Cells; Interneurons; Neurons
PubMed: 36480240
DOI: 10.7554/eLife.77603 -
Proceedings of the National Academy of... Mar 2008The small GTPase Rac controls cell morphology, gene expression, and reactive oxygen species formation. Manipulations of Rac activity levels in the cerebellum result in...
The small GTPase Rac controls cell morphology, gene expression, and reactive oxygen species formation. Manipulations of Rac activity levels in the cerebellum result in motor coordination defects, but activators of Rac in the cerebellum are unknown. P-Rex family guanine-nucleotide exchange factors activate Rac. We show here that, whereas P-Rex1 expression within the brain is widespread, P-Rex2 is specifically expressed in the Purkinje neurons of the cerebellum. We have generated P-Rex2(-/-) and P-Rex1(-/-)/P-Rex2(-/-) mice, analyzed their Purkinje cell morphology, and assessed their motor functions in behavior tests. The main dendrite is thinned in Purkinje cells of P-Rex2(-/-) pups and dendrite structure appears disordered in Purkinje cells of adult P-Rex2(-/-) and P-Rex1(-/-)/P-Rex2(-/-) mice. P-Rex2(-/-) mice show a mild motor coordination defect that progressively worsens with age and is more pronounced in females than in males. P-Rex1(-/-)/P-Rex2(-/-) mice are ataxic, with reduced basic motor activity and abnormal posture and gait, as well as impaired motor coordination even at a young age. We conclude that P-Rex1 and P-Rex2 are important regulators of Purkinje cell morphology and cerebellar function.
Topics: Aging; Animals; Behavior, Animal; Brain; Dendrites; Fertility; GTPase-Activating Proteins; Gene Expression Regulation; Health; Lung; Mice; Mice, Knockout; Motor Activity; Organ Specificity; Purkinje Cells
PubMed: 18334636
DOI: 10.1073/pnas.0712324105 -
The Journal of Neuroscience : the... May 2015How Purkinje cell (PC) activity may be altered by learning is central to theories of the cerebellum. Pavlovian eyelid conditioning, because of how directly it engages...
How Purkinje cell (PC) activity may be altered by learning is central to theories of the cerebellum. Pavlovian eyelid conditioning, because of how directly it engages the cerebellum, has helped reveal many aspects of cerebellar learning and the underlying mechanisms. Theories of cerebellar learning assert that climbing fiber inputs control plasticity at synapses onto PCs, and thus PCs control the expression of learned responses. We tested this assertion by recording 184 eyelid PCs and 240 non-eyelid PCs during the expression of conditioned eyelid responses (CRs) in well trained rabbits. By contrasting the responses of eyelid and non-eyelid PCs and by contrasting the responses of eyelid PCs under conditions that produce differently timed CRs, we test the hypothesis that learning-related changes in eyelid PCs contribute to the learning and adaptive timing of the CRs. We used a variety of analyses to test the quantitative relationships between eyelid PC responses and the kinematic properties of the eyelid CRs. We find that the timing of eyelid PC responses varies systematically with the timing of the behavioral CRs and that there are differences in the magnitude of eyelid PC responses between larger-CR, smaller-CR, and non-CR trials. However, eyelid PC activity does not encode any single kinematic property of the behavioral CRs at a fixed time lag, nor does it linearly encode CR amplitude. Even so, the results are consistent with the hypothesis that learning-dependent changes in PC activity contribute to the adaptively timed expression of conditioned eyelid responses.
Topics: Animals; Biomechanical Phenomena; Conditioning, Classical; Eyelids; Male; Purkinje Cells; Rabbits; Time Factors
PubMed: 25995469
DOI: 10.1523/JNEUROSCI.3663-14.2015