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David Coutnay Marr (1945–1980)s
Published in Andrew P. Wickens, Key Thinkers in Neuroscience, 2018
Marr’s paper is widely recognised as a milestone in the history of the cerebellum, which not only integrated information from neuroanatomy and physiology but also produced several predictions that could be experimentally tested and adopted in computer modelling. Needless to say, it generated an enormous amount of research. Perhaps the most important prediction of the theory was that motor learning should be accompanied by facilitatory changes in the synaptic strength between the parallel fibres and the Purkinje cells – especially if there is synchronised climbing fibre activity. This theory has been tested by Masao Ito and his colleagues at the University of Tokyo, who recorded from the cerebellum in animals made to undergo a procedure whereby the eyes remain fixed on an object while the head is turning (known as the vestibulo-ocular reflex). Their work has shown that when a Purkinje cell receives synchronised input from the climbing and parallel fibres, it becomes persistently depressed (or inhibited). Although this contradicts Marr, who thought such synchronisation should lead to Purkinje excitation, it does not refute his general idea of cerebellar learning. Nor does it alter the fundamental role of Purkinje cells in his theory.
Discuss the anatomy of the cerebellum, including its blood supply and neuronal connections
Published in Nathaniel Knox Cartwright, Petros Carvounis, Short Answer Questions for the MRCOphth Part 1, 2018
Nathaniel Knox Cartwright, Petros Carvounis
Two types of afferent fibres enter the cerebellar cortex: – climbing fibres originate in the contralateral inferior olivary nucleus and form powerful excitatory synapses with Purkinje cells– all other cerebellar afferents enter as mossy fibres and terminate in the granular layer.
ENTRIES A–Z
Published in Philip Winn, Dictionary of Biological Psychology, 2003
function as inhibitory INTERNEURONS. The Purkinje cell layer contains the impressive Purkinje cells, arranged in a single layer. These are large neurons, with cell bodies 50-80 pm wide and exceptionally extensive dendritic fields that extend into the molecular layer. The axons run down through the white matter to the deep cerebellar nuclei (where they form synapses and use GABA as their neurotransmitter): this is the only output of the cerebellar cortex. The Purkinje cell layer has two main inputs: one from MOSSY FIBRES, the other from CLIMBING FIBRES. These are discriminated both anatomically and electrophysiologically. The mossy fibres come from the granule cell layer (including the CEREBELLAR GLOMERULI) which provide the parallel fibres in the molecular layer, with which Purkinje cell dendrites make contact. Some 200000 parallel fibres contact each Purkinje cell. The climbing fibres come from outside the cerebellum—from the INFERIOR OLIVE. Axons from the inferior olive come directly through to the Purkinje cells, each fibre making multiple synaptic contacts with approximately ten Purkinje cells. Electro physiologically, mossy fibre activation produces very powerful and complex action potentials (see ACTION POTENTIAL) in Purkinje cells. Climbing fibres induce straightforward action potentials. The third layer of the cerebellar cortex is the granular layer, packed with small granule cells and the cerebellar glomeruli, complexes formed by granule cells and mossy fibres. This layer is astonishingly dense: there are more neurons in the human granule cell layer of the cerebellum than there are in the cerebral cortex.
Phoria Adaptation: The Ghost in the Machine
Published in Journal of Binocular Vision and Ocular Motility, 2020
When prisms are placed before one eye of an orthotropic patient, the visual image discordance is interpreted as an error signal. Adaptation and learning to correct motor error signals is modulated at the level of the vestibulocerebellum.10,69 It, therefore, seems likely that phoria adaptation is similarly mediated by both climbing and mossy fibers within the cerebellum, which implement modifiable, adaptive, and “plastic” responses10 (Figure 3).70 The cerebellum receives continuous information via the mossy fiber system. The climbing fiber system originates from the inferior olivary nucleus and provides a powerful timing and error signal to Purkinje cells. The inferior olivary nucleus acts as a comparator of motor commands from the cerebral cortex, brainstem nuclei and receives feedback from receptors via the spinal cord, visual system, or vestibular organs. The inferior olive senses the error and recalibrates the tonic firing of the Purkinje cells. The increased frequency of inferior olivary nucleus discharge and complex spikes in the Purkinje cells triggers long-term depression of the synapse between the parallel fibers and the Purkinje cells, thereby resetting the single spike discharge rate to produce the necessary motor learning and adaptation. The Purkinje cell provides profound inhibition via GABA to the cerebellar nuclei, which provide the output of the cerebellum. It is therefore likely that the neural circuitry subserving phoria adaptation is not localized to a specific area but modulated by cortical, midbrain, and cerebellar circuitry.10,65,66
Brain circuits and neurochemical systems in essential tremor: insights into current and future pharmacotherapeutic approaches
Published in Expert Review of Neurotherapeutics, 2018
Sara M Schaefer, Ana Vives Rodriguez, Elan D Louis
Topiramate has earned a level B designation for the treatment of ET [44]. The use of topiramate for ET has been explored in one double-blind placebo-controlled study, which demonstrated an approximate 20% improvement in tremor as evaluated by clinical rating scales, but as with benzodiazepines, significant side effects were reported leading to a high dropout rate (about 40%) [54]. Topiramate acts through multiple mechanisms, including (1) potentiation of GABAA receptors with α6 > 4 > 1 subunits and (2) blocking of sodium and calcium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and others [20]. GABAA receptors with α6 subunits are found almost exclusively in cerebellar granule cells; potentiation of these receptors reduces excitation of PC cells through parallel fibers, decreasing PC inhibitory output, and causing motor incoordination [35,55,56]. One would think that this would serve to worsen tremor, as PC GABAergic output would be downregulated, so it may be topiramate’s effect on α4 or α1 GABAA receptor subunits that explain its efficacy in tremor [56]. Such competing effects could explain the mediocre efficacy of topiramate for ET. Topiramate’s blockade of AMPA receptors is also important to consider, given the high density of AMPA receptors at climbing fiber-PC synapses [57]. This is particularly interesting in light of recent postmortem studies in ET patients that have demonstrated changes at climbing fiber-PC synapses [58].
Active caspase-3 upregulation is augmented in at-risk cerebellar Purkinje cells following inferior olive chemoablation in the shaker mutant rat: an immunofluorescence study
Published in Neurological Research, 2019
In shaker mutant rats, spatially restricted populations of cerebellar PCs start degeneration at 7 week of age that continues till 14 week of age during the natural phenotypic manifestation of the shaker mutation [2]. Climbing fibers, which arise from brainstem inferior olivary neurons, dynamically regulate PC structure and function [7]. Inferior olive (IO) could modify adult-onset hereditary PC death in the shaker mutant rat [8]. A previously described drug regimen, using 3-acetylpyridine, harmaline and nicotinamide, selectively and completely ablated inferior olivary neurons within 6 days of the injections [9].