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Neuroscience Letters Jan 2019What the cerebellum does to sensorimotor and vestibular control, it also does to cognition, emotion, and autonomic function. This hypothesis is based on the theories of... (Review)
Review
What the cerebellum does to sensorimotor and vestibular control, it also does to cognition, emotion, and autonomic function. This hypothesis is based on the theories of dysmetria of thought and the universal cerebellar transform, which hold that the cerebellum maintains behavior around a homeostatic baseline, automatically, without conscious awareness, informed by implicit learning, and performed according to context. Functional topography within the cerebellum facilitates the modulation of distributed networks subserving multiple different functions. The sensorimotor cerebellum is represented in the anterior lobe with a second representation in lobule VIII, and lesions of these areas lead to the cerebellar motor syndrome of ataxia, dysmetria, dysarthria and impaired oculomotor control. The cognitive / limbic cerebellum is in the cerebellar posterior lobe, with current evidence pointing to three separate topographic representations, the nature of which remain to be determined. Posterior lobe lesions result in the cerebellar cognitive affective syndrome (CCAS), the hallmark features of which include deficits in executive function, visual spatial processing, linguistic skills and regulation of affect. The affective dyscontrol manifests in autism spectrum and psychosis spectrum disorders, and disorders of emotional control, attentional control, and social skill set. This report presents an overview of the rapidly growing field of the clinical cognitive neuroscience of the cerebellum. It commences with a brief historical background, then discusses tract tracing experiments in animal models and functional imaging observations in humans that subserve the cerebellar contribution to neurological function. Structure function correlation studies following focal cerebellar lesions in adults and children permit a finer appreciation of the functional topography and nature of the cerebellar motor syndrome, cerebellar vestibular syndrome, and the third cornerstone of clinical ataxiology - the cerebellar cognitive affective syndrome. The ability to detect the CCAS in real time in clinical neurology with a brief and validated scale should make it possible to develop a deeper understanding of the clinical consequences of cerebellar lesions in a wide range of neurological and neuropsychiatric disorders with a link to the cerebellum.
Topics: Animals; Cerebellar Diseases; Cerebellum; Cognition; Humans; Neural Pathways
PubMed: 29997061
DOI: 10.1016/j.neulet.2018.07.005 -
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 -
Cerebellum (London, England) Feb 2016Cerebellar dysfunction is evident in several developmental disorders, including autism, attention deficit-hyperactivity disorder (ADHD), and developmental dyslexia, and... (Review)
Review
Cerebellar dysfunction is evident in several developmental disorders, including autism, attention deficit-hyperactivity disorder (ADHD), and developmental dyslexia, and damage to the cerebellum early in development can have long-term effects on movement, cognition, and affective regulation. Early cerebellar damage is often associated with poorer outcomes than cerebellar damage in adulthood, suggesting that the cerebellum is particularly important during development. Differences in cerebellar development and/or early cerebellar damage could impact a wide range of behaviors via the closed-loop circuits connecting the cerebellum with multiple cerebral cortical regions. Based on these anatomical circuits, behavioral outcomes should depend on which cerebro-cerebellar circuits are affected. Here, we briefly review cerebellar structural and functional differences in autism, ADHD, and developmental dyslexia, and discuss clinical outcomes following pediatric cerebellar damage. These data confirm the prediction that abnormalities in different cerebellar subregions produce behavioral symptoms related to the functional disruption of specific cerebro-cerebellar circuits. These circuits might also be crucial to structural brain development, as peri-natal cerebellar lesions have been associated with impaired growth of the contralateral cerebral cortex. The specific contribution of the cerebellum to typical development may therefore involve the optimization of both the structure and function of cerebro-cerebellar circuits underlying skill acquisition in multiple domains; when this process is disrupted, particularly in early development, there could be long-term alterations of these neural circuits, with significant impacts on behavior.
Topics: Animals; Cerebellum; Humans; Neurodevelopmental Disorders
PubMed: 26298473
DOI: 10.1007/s12311-015-0715-3 -
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 -
Neurologic Clinics Nov 2014The cerebellum resides in the posterior cranial fossa dorsal to the brainstem and has diverse connections to the cerebrum, brain stem, and spinal cord. It is... (Review)
Review
The cerebellum resides in the posterior cranial fossa dorsal to the brainstem and has diverse connections to the cerebrum, brain stem, and spinal cord. It is anatomically and physiologically divided into distinct functional compartments and is composed of highly regular arrays of neuronal units, each sharing the same basic cerebellar microcircuitry. Its circuitry is critically involved in motor control and motor learning, and its role in nonmotor cognitive and affective functions is becoming increasingly recognized. This article describes the cerebellar gross and histologic neuroanatomy in relation to its function, and the relevance of cerebellar circuitry and firing patterns to motor learning.
Topics: Cerebellum; Humans; Neural Pathways; Neuroanatomy
PubMed: 25439284
DOI: 10.1016/j.ncl.2014.07.013 -
Cell Stem Cell Jan 2024Research on human cerebellar development and disease has been hampered by the need for a human cell-based system that recapitulates the human cerebellum's cellular...
Research on human cerebellar development and disease has been hampered by the need for a human cell-based system that recapitulates the human cerebellum's cellular diversity and functional features. Here, we report a human organoid model (human cerebellar organoids [hCerOs]) capable of developing the complex cellular diversity of the fetal cerebellum, including a human-specific rhombic lip progenitor population that have never been generated in vitro prior to this study. 2-month-old hCerOs form distinct cytoarchitectural features, including laminar organized layering, and create functional connections between inhibitory and excitatory neurons that display coordinated network activity. Long-term culture of hCerOs allows healthy survival and maturation of Purkinje cells that display molecular and electrophysiological hallmarks of their in vivo counterparts, addressing a long-standing challenge in the field. This study therefore provides a physiologically relevant, all-human model system to elucidate the cell-type-specific mechanisms governing cerebellar development and disease.
Topics: Humans; Infant; Purkinje Cells; Cerebellum; Metencephalon; Organoids
PubMed: 38181749
DOI: 10.1016/j.stem.2023.11.013 -
Handbook of Clinical Neurology 2018With the growing recognition of the extent and prevalence of human cerebellar disorders, an understanding of developmental programs that build the mature cerebellum is... (Review)
Review
With the growing recognition of the extent and prevalence of human cerebellar disorders, an understanding of developmental programs that build the mature cerebellum is necessary. In this chapter we present an overview of the basic epochs and key molecular regulators of the developmental programs of cerebellar development. These include early patterning of the cerebellar territory, the genesis of cerebellar cells from multiple spatially distinct germinal zones, and the extensive migration and coordinated cellular rearrangements that result in the formation of the exquisitely foliated and laminated mature cerebellum. This knowledge base is founded on extensive analysis of animal models, particularly mice, due in large part to the ease of genetic manipulation of this important model organism. Since cerebellar structure and function are largely conserved across species, mouse cerebellar development is highly relevant to humans and has led to important insights into the developmental pathogenesis of human cerebellar disorders. Human fetal cerebellar development remains largely undescribed; however, several human-specific developmental features are known which are relevant to human disease and underline the importance of ongoing human fetal research.
Topics: Animals; Cerebellum; Embryology; Humans; Neurons
PubMed: 29903446
DOI: 10.1016/B978-0-444-63956-1.00002-3 -
Nature Sep 2022Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to...
Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins. However, the anatomical and cellular complexity of developing human tissues-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development.
Topics: Animals; Cell Lineage; Cerebellar Neoplasms; Cerebellum; Humans; Medulloblastoma; Metencephalon; Mice; Neurons; Prospective Studies
PubMed: 36131015
DOI: 10.1038/s41586-022-05208-9 -
Handbook of Clinical Neurology 2018Conventional magnetic resonance imaging (MRI) allows for a detailed noninvasive visualization/examination of posterior fossa structures and represents a fundamental step... (Review)
Review
Conventional magnetic resonance imaging (MRI) allows for a detailed noninvasive visualization/examination of posterior fossa structures and represents a fundamental step in the diagnostic workup of many cerebellar disorders. In the first part of this chapter methodologic issues, like the correct choice of hardware (magnets, coils), pro and cons of the different MRI sequences, and patient management during the examination are discussed. In the second part, the MRI anatomy of the cerebellum, as noted on the various conventional MRI sequences, as well as a detailed description of cerebellar maturational processes from birth to childhood and into adulthood, are reported. Volumetric studies on the cerebellar growth based on three-dimensional MRI sequences are also presented. Moreover, we briefly discuss two main topics regarding conventional MRI of the cerebellum that have generated some debate in recent years: the differentiation between cerebellar atrophy, hypoplasia, and pontocerebellar hypoplasia, and signal changes of dentate nuclei after repetitive gadolinium-based contrast injections. The advantages and benefits of advanced neuroimaging techniques, including H magnetic resonance spectroscopy, diffusion-weighted imaging, diffusion tensor imaging, and perfusion-weighted imaging are discussed in the last section of the chapter.
Topics: Age Factors; Cerebellar Diseases; Cerebellum; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging
PubMed: 29903441
DOI: 10.1016/B978-0-444-63956-1.00013-8 -
Nature Sep 2022Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain....
Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMESKI67 unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.
Topics: Cell Differentiation; Cell Lineage; Cerebellar Neoplasms; Cerebellum; Core Binding Factor alpha Subunits; Hedgehog Proteins; Histone Demethylases; Humans; Ki-67 Antigen; Medulloblastoma; Metencephalon; Muscle Proteins; Mutation; Otx Transcription Factors; Repressor Proteins; T-Box Domain Proteins; Transcription Factors
PubMed: 36131014
DOI: 10.1038/s41586-022-05215-w