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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 -
Neurobiology of Learning and Memory Nov 2019The developmental trajectory of the formation of cerebellar circuitry has significant implications for locomotor plasticity and adaptive learning at later stages. While... (Review)
Review
The developmental trajectory of the formation of cerebellar circuitry has significant implications for locomotor plasticity and adaptive learning at later stages. While there is a wealth of knowledge on the development of locomotor behavior in human infants, children, and adolescents, pre-clinical animal models have fallen behind on the study of the emergence of behavioral motifs in locomotor function across postnatal development. Since cerebellar development is protracted, it is subject to higher risk of genetic or environmental disruption, potentially leading to abnormal behavioral development. This highlights the need for more sophisticated and specific functional analyses of adaptive cerebellar behavior within the context of whole-body locomotion across the entire span of postnatal development. Here we review evidence on cerebellar contribution to adaptive locomotor behavior, highlighting methodologies employed to quantify and categorize behavior at different developmental stages, with the ultimate goal of following the course of early behavioral alterations in neurodevelopmental disorders. Since experimental paradigms used to study cerebellar behavior are lacking in both specificity and applicability to locomotor contexts, we highlight the use of the Erasmus Ladder - an advanced, computerized, fully automated system to quantify adaptive cerebellar learning in conjunction with locomotor function. Finally, we emphasize the need to develop objective, quantitative, behavioral tasks which can track changes in developmental trajectories rather than endpoint measurement at the adult stage of behavior.
Topics: Animals; Cerebellum; Humans; Locomotion; Neurodevelopmental Disorders
PubMed: 29723669
DOI: 10.1016/j.nlm.2018.04.016 -
Cerebellum (London, England) Feb 2023The presence of auto-antibodies that target synaptic machinery proteins was documented recently in immune-mediated cerebellar ataxias. The autoantigens include glutamic... (Review)
Review
The presence of auto-antibodies that target synaptic machinery proteins was documented recently in immune-mediated cerebellar ataxias. The autoantigens include glutamic acid decarboxylase 65 (GAD65), voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluRdelta). GAD65 is involved in the synthesis, packaging, and release of GABA, whereas the other three play important roles in the induction of long-term depression (LTD). Thus, the auto-antibodies toward these synaptic molecules likely impair fundamental synaptic machineries involved in unique functions of the cerebellum, potentially leading to the development of cerebellar ataxias (CAs). This concept has been substantiated recently by a series of physiological studies. Anti-GAD65 antibody (Ab) acts on the terminals of inhibitory neurons that suppress GABA release, whereas anti-VGCC, anti-mGluR1, and anti-GluR Abs impair LTD induction. Notably, the mechanisms that link synaptic dysfunction with the manifestations of CAs can be explained by disruption of the "internal models." The latter can be divided into three levels. First, since chained inhibitory neurons shape the output signals through the mechanism of disinhibition/inhibition, impairments of GABA release and LTD distort the conversion process from the "internal model" to the output signals. Second, these antibodies impair the induction of synaptic plasticity, rebound potentiation, and LTD, on Purkinje cells, resulting in loss of restoration and compensation of the distorted "internal models." Finally, the cross-talk between glutamate and microglia/astrocytes could involve a positive feedback loop that accelerates excitotoxicity. This mini-review summarizes the pathophysiological mechanisms and aims to establish the basis of "auto-antibody-induced cerebellar synaptopathies."
Topics: Humans; Cerebellar Ataxia; Cerebellum; Purkinje Cells; Neurons; gamma-Aminobutyric Acid
PubMed: 35064896
DOI: 10.1007/s12311-021-01359-z -
Cerebellum (London, England) Apr 2024The cerebellum is a key player in many brain functions and a major topic of neuroscience research. However, the cerebellar nuclei (CN), the main output structures of the... (Review)
Review
The cerebellum is a key player in many brain functions and a major topic of neuroscience research. However, the cerebellar nuclei (CN), the main output structures of the cerebellum, are often overlooked. This neglect is because research on the cerebellum typically focuses on the cortex and tends to treat the CN as relatively simple output nuclei conveying an inverted signal from the cerebellar cortex to the rest of the brain. In this review, by adopting a nucleocentric perspective we aim to rectify this impression. First, we describe CN anatomy and modularity and comprehensively integrate CN architecture with its highly organized but complex afferent and efferent connectivity. This is followed by a novel classification of the specific neuronal classes the CN comprise and speculate on the implications of CN structure and physiology for our understanding of adult cerebellar function. Based on this thorough review of the adult literature we provide a comprehensive overview of CN embryonic development and, by comparing cerebellar structures in various chordate clades, propose an interpretation of CN evolution. Despite their critical importance in cerebellar function, from a clinical perspective intriguingly few, if any, neurological disorders appear to primarily affect the CN. To highlight this curious anomaly, and encourage future nucleocentric interpretations, we build on our review to provide a brief overview of the various syndromes in which the CN are currently implicated. Finally, we summarize the specific perspectives that a nucleocentric view of the cerebellum brings, move major outstanding issues in CN biology to the limelight, and provide a roadmap to the key questions that need to be answered in order to create a comprehensive integrated model of CN structure, function, development, and evolution.
Topics: Cerebellar Nuclei; Cerebellum; Neurons
PubMed: 36781689
DOI: 10.1007/s12311-022-01506-0 -
Cerebellum (London, England) Feb 2020The cerebellum is relevant for virtually all aspects of behavior in health and disease. Cerebellar findings are common across all kinds of neuroimaging studies of brain...
The cerebellum is relevant for virtually all aspects of behavior in health and disease. Cerebellar findings are common across all kinds of neuroimaging studies of brain function and dysfunction. A large and expanding body of literature mapping motor and non-motor functions in the healthy human cerebellar cortex using fMRI has served as a tool for interpreting these findings. For example, results of cerebellar atrophy in Alzheimer's disease in caudal aspects of Crus I/II and medial lobule IX can be interpreted by consulting a large number of task, resting-state, and gradient-based reports that describe the functional characteristics of these specific aspects of the cerebellar cortex. Here, we provide a concise summary that outlines organizational principles observed consistently across these studies of normal cerebellar organization. This basic framework may be useful for investigators performing or reading experiments that require a functional interpretation of human cerebellar topography.
Topics: Cerebellar Cortex; Cerebellar Diseases; Cerebellum; Humans; Magnetic Resonance Imaging; Nerve Net
PubMed: 31707620
DOI: 10.1007/s12311-019-01083-9 -
Neuroscience May 2021The cerebellum forms regular neural network structures consisting of a few major types of neurons, such as Purkinje cells, granule cells, and molecular layer... (Review)
Review
The cerebellum forms regular neural network structures consisting of a few major types of neurons, such as Purkinje cells, granule cells, and molecular layer interneurons, and receives two major inputs from climbing fibers and mossy fibers. Its regular structures consist of three well-defined layers, with each type of neuron designated to a specific location and forming specific synaptic connections. During the first few weeks of postnatal development in rodents, the cerebellum goes through dynamic changes via proliferation, migration, differentiation, synaptogenesis, and maturation, to create such a network structure. The development of this organized network structure presumably relies on the communication between developing elements in the network, including not only individual neurons, but also their dendrites, axons, and synapses. Therefore, it is reasonable that extracellular signaling via synaptic transmission, secreted molecules, and cell adhesion molecules, plays important roles in cerebellar network development. Although it is not yet clear as to how overall cerebellar development is orchestrated, there is indeed accumulating lines of evidence that extracellular signaling acts toward the development of individual elements in the cerebellar networks. In this article, we introduce what we have learned from many studies regarding the extracellular signaling required for cerebellar network development, including our recent study suggesting the importance of unbiased synaptic inputs from parallel fibers.
Topics: Axons; Cerebellum; Neurons; Purkinje Cells; Synapses
PubMed: 32502568
DOI: 10.1016/j.neuroscience.2020.05.036 -
Neuroscience and Biobehavioral Reviews Dec 2017The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, innervates extensive areas throughout the brain and is implicated... (Review)
Review
The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, innervates extensive areas throughout the brain and is implicated in a variety of autonomic and cognitive functions. Alterations in the LC-noradrenergic system have been associated with healthy ageing and neuropsychiatric disorders including Parkinson's disease, Alzheimer's disease and depression. The last decade has seen advances in imaging the structure and function of the LC, and this paper systematically reviews the methodology and outcomes of sixty-nine structural and functional MRI studies of the LC in humans. Structural MRI studies consistently showed lower LC signal intensity and volume in clinical groups compared to healthy controls. Within functional studies, the LC was activated by a variety of tasks/stimuli and had functional connectivity to a range of brain regions. However, reported functional LC location coordinates were widely distributed compared to previously published neuroanatomical locations. Methodological and demographic factors potentially contributing to these differences are discussed, together with recommendations to optimize the reliability and validity of future LC imaging studies.
Topics: Humans; Image Processing, Computer-Assisted; Locus Coeruleus; Magnetic Resonance Imaging
PubMed: 29107830
DOI: 10.1016/j.neubiorev.2017.10.023 -
Brain Stimulation 2023Low-intensity ultrasound is a noninvasive neuromodulation technique with the potential to focally manipulate deep brain activity at millimeter-scale resolution. However,...
BACKGROUND
Low-intensity ultrasound is a noninvasive neuromodulation technique with the potential to focally manipulate deep brain activity at millimeter-scale resolution. However, there have been controversies over the direct influence of ultrasound on neurons, due to an indirect auditory activation. Besides, the capacity of ultrasound to stimulate the cerebellum remains underestimated.
OBJECTIVE
To validate the direct neuromodulation effects of ultrasound on the cerebellar cortex from both cellular and behavioral levels.
METHODS
Two-photon calcium imaging were used to measure the neuronal responses of cerebellar granule cells (GrCs) and Purkinje cells (PCs) to ultrasound application in awake mice. And a mouse model of paroxysmal kinesigenic dyskinesia (PKD), in which direct activation of the cerebellar cortex leads to dyskinetic movements, was used to assess the ultrasound-induced behavioral responses.
RESULTS
Low-intensity ultrasound stimulus (0.1 W/cm) evoked rapidly increased and sustained neural activity in GrCs and PCs at targeted region, while no significant changes in calcium signals were observed responding to off-target stimulus. The efficacy of ultrasonic neuromodulation relies on acoustic dose modified by ultrasonic duration and intensity. In addition, transcranial ultrasound reliably triggered dyskinesia attacks in proline-rich transmembrane protein 2 (Prrt2) mutant mice, suggesting that the intact cerebellar cortex were activated by ultrasound.
CONCLUSION
Low-intensity ultrasound directly activates the cerebellar cortex in a dose-dependent manner, and thus serves as a promising tool for cerebellar manipulation.
Topics: Mice; Animals; Calcium; Cerebellum; Brain; Neurons; Purkinje Cells
PubMed: 37245844
DOI: 10.1016/j.brs.2023.05.012 -
Neuroscience Feb 2022
Topics: Action Potentials; Cerebellum; Purkinje Cells
PubMed: 35031082
DOI: 10.1016/j.neuroscience.2021.12.007 -
Cerebellum (London, England) Apr 2015Various lines of evidence accumulated over the past 30 years indicate that the cerebellum, long recognized as essential for motor control, also has considerable... (Review)
Review
Various lines of evidence accumulated over the past 30 years indicate that the cerebellum, long recognized as essential for motor control, also has considerable influence on perceptual processes. In this paper, we bring together experts from psychology and neuroscience, with the aim of providing a succinct but comprehensive overview of key findings related to the involvement of the cerebellum in sensory perception. The contributions cover such topics as anatomical and functional connectivity, evolutionary and comparative perspectives, visual and auditory processing, biological motion perception, nociception, self-motion, timing, predictive processing, and perceptual sequencing. While no single explanation has yet emerged concerning the role of the cerebellum in perceptual processes, this consensus paper summarizes the impressive empirical evidence on this problem and highlights diversities as well as commonalities between existing hypotheses. In addition to work with healthy individuals and patients with cerebellar disorders, it is also apparent that several neurological conditions in which perceptual disturbances occur, including autism and schizophrenia, are associated with cerebellar pathology. A better understanding of the involvement of the cerebellum in perceptual processes will thus likely be important for identifying and treating perceptual deficits that may at present go unnoticed and untreated. This paper provides a useful framework for further debate and empirical investigations into the influence of the cerebellum on sensory perception.
Topics: Animals; Biological Evolution; Cerebellum; Consensus; Humans; Models, Neurological; Neural Pathways; Pain; Perception
PubMed: 25479821
DOI: 10.1007/s12311-014-0627-7