-
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 -
Revista de NeurologiaThe cerebellum is a neural structure, of a crystalline like organization, present in all vertebrates. Its progressive growth from fishes to mammals, and particularly in... (Review)
Review
INTRODUCTION
The cerebellum is a neural structure, of a crystalline like organization, present in all vertebrates. Its progressive growth from fishes to mammals, and particularly in primates, takes place following the repetition of a primitive cellular plan and connectivity.
DEVELOPMENT
The cerebellum is organized in folia located one behind the other in the rostrocaudal axis, and placed transversally on the brain stem. The cerebellar cortex has five types of neuron: Purkinje, stellate, basket, Golgi and granule cells. Apart from granule cells, the other cell types are inhibitory in nature. Afferent fibers to the cerebellar cortex are of two types (mossy and climbing) and carry information from somatosensory, vestibular, acoustic and visual origins, as well as from the cerebral cortex and other brain stem and spinal motor centers. The only neural output from the cerebellar cortex is represented by Purkinje axons that synapse on the underlying deep nuclei. Cerebellar nuclei send their axons towards many brain stem centers and, by thalamic relay nuclei, act on different cortical areas. Functionally, the cerebellum seems to be organized in small modules, similar in structure, but different in the origin and end of their afferent and efferent fibers. The cerebellum is involved in the coordination or integration of motor and cognitive processes.
CONCLUSION
Although cerebellar lesion does not produce severe motor paralysis, loss of sensory inputs or definite deficits in cognitive functions, its certainly affects motor performance and specific perceptive and cognitive phenomena.
Topics: Afferent Pathways; Animals; Cerebellum; Cognition; Efferent Pathways; Humans; Motor Activity; Neurons; Perception
PubMed: 11784952
DOI: No ID Found -
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 -
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 -
Neuron Oct 2005In this issue of Neuron, Wang et al. and Machold and Fishell present contrasting molecular fate maps of Math1, which redefine the derivatives of the embryonic rhombic...
In this issue of Neuron, Wang et al. and Machold and Fishell present contrasting molecular fate maps of Math1, which redefine the derivatives of the embryonic rhombic lip and offer a conceptual overhaul of cerebellar and precerebellar development. These fate maps identify a common developmental thread linking diverse, functionally associated neurons and reveal an exquisite temporal organization in cell production within a precise spatially defined region of neuroepithelium.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cerebellum; Embryonic Development; Gene Expression Regulation, Developmental; Neurons
PubMed: 16202701
DOI: 10.1016/j.neuron.2005.09.012 -
Development (Cambridge, England) Sep 2022The cerebellum has a simple cytoarchitecture consisting of a folded cortex with three cell layers that surrounds a nuclear structure housing the output neurons. The... (Review)
Review
The cerebellum has a simple cytoarchitecture consisting of a folded cortex with three cell layers that surrounds a nuclear structure housing the output neurons. The excitatory neurons are generated from a unique progenitor zone, the rhombic lip, whereas the inhibitory neurons and astrocytes are generated from the ventricular zone. The growth phase of the cerebellum is driven by lineage-restricted progenitor populations derived from each zone. Research during the past decade has uncovered the importance of cell-to-cell communication between the lineages through largely unknown signaling mechanisms for regulating the scaling of cell numbers and cell plasticity during mouse development and following injury in the neonatal (P0-P14) cerebellum. This Review focuses on how the interplay between cell types is key to morphogenesis, production of robust neural circuits and replenishment of cells after injury, and ends with a discussion of the implications of the greater complexity of the human cerebellar progenitor zones for development and disease.
Topics: Animals; Astrocytes; Cerebellum; Humans; Mice; Morphogenesis; Neurons; Purkinje Cells
PubMed: 36172987
DOI: 10.1242/dev.185587 -
Cerebellum (London, England) Aug 2022The first attempts at using electric stimulation to study human brain functions followed the experiments of Luigi Galvani and Giovanni Aldini on animal electricity... (Review)
Review
The first attempts at using electric stimulation to study human brain functions followed the experiments of Luigi Galvani and Giovanni Aldini on animal electricity during the eighteenth century. Since then, the cerebellum has been among the areas that have been studied by invasive and non-invasive forms of electrical and magnetic stimulation. During the nineteenth century, animal experiments were conducted to map the motor-related regions of cerebellar cortex by means of direct electric stimulation. As electric stimulation research on the cerebellum moved into the twentieth century, systematic research of electric cerebellar stimulation led to a better understanding of its effects and mechanism of action. In addition, the clinical potential of cerebellar stimulation in the treatment of motor diseases started to be explored. With the introduction of transcranial electric and magnetic stimulation, cerebellar research moved to non-invasive techniques. During the twenty-first century, following on groundbreaking research that linked the cerebellum to non-motor functions, non-invasive techniques have facilitated research into different aspects of cerebellar functioning. The present review provides a brief historical account of cerebellar neurostimulation and discusses current challenges and future direction in this field of research.
Topics: Animals; Cerebellar Cortex; Cerebellum; Electric Stimulation; Humans; Transcranial Direct Current Stimulation; Transcranial Magnetic Stimulation
PubMed: 34403075
DOI: 10.1007/s12311-021-01310-2