-
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 -
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 -
Human Molecular Genetics Sep 2023Neurons within the cerebellum form temporal-spatial connections through the cerebellum, and the entire brain. Organoid models provide an opportunity to model the early...
Neurons within the cerebellum form temporal-spatial connections through the cerebellum, and the entire brain. Organoid models provide an opportunity to model the early differentiation of the developing human cerebellum, which is difficult to study in vivo, and affords the opportunity to study neurodegenerative and neurodevelopmental diseases of the cerebellum. Previous cerebellar organoid models focused on early neuron generation and single cell activity. Here, we modify previous protocols to generate more mature cerebellar organoids that allow for the establishment of several classes of mature neurons during cerebellar differentiation and development, including the establishment of neural networks during whole-organoid maturation. This will provide a means to study the generation of several more mature cerebellar cell types, including Purkinje cells, granule cells and interneurons expression as well as neuronal communication for biomedical, clinical and pharmaceutical applications.
Topics: Humans; Cerebellum; Neurons; Purkinje Cells; Neurogenesis; Organoids
PubMed: 37387247
DOI: 10.1093/hmg/ddad110 -
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 -
ELife Nov 2023A new computational tool provides insights into the structure of the cerebellum in mammals.
A new computational tool provides insights into the structure of the cerebellum in mammals.
Topics: Animals; Cerebellum; Mammals
PubMed: 37943162
DOI: 10.7554/eLife.93122 -
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 -
The American Journal of Psychiatry Jan 2020
Topics: Cerebellum; Humans; Schizophrenia
PubMed: 31892299
DOI: 10.1176/appi.ajp.2019.19111124 -
Nature Neuroscience Feb 2021The past several years have brought revelations and paradigm shifts in research on the cerebellum. Historically viewed as a simple sensorimotor controller with... (Review)
Review
The past several years have brought revelations and paradigm shifts in research on the cerebellum. Historically viewed as a simple sensorimotor controller with homogeneous architecture, the cerebellum is increasingly implicated in cognitive functions. It possesses an impressive diversity of molecular, cellular and circuit mechanisms, embedded in a dynamic, recurrent circuit architecture. Recent insights about the diversity and dynamism of the cerebellum provide a roadmap for the next decade of cerebellar research, challenging some old concepts, reinvigorating others and defining major new research directions.
Topics: Animals; Cerebellum; Cognition; Humans; Learning; Models, Neurological; Nerve Net; Neuronal Plasticity
PubMed: 33288911
DOI: 10.1038/s41593-020-00754-9 -
Cells Sep 2022Despite their homogeneous appearance, Purkinje cells are remarkably diverse with respect to their molecular phenotypes, physiological properties, afferent and efferent... (Review)
Review
Despite their homogeneous appearance, Purkinje cells are remarkably diverse with respect to their molecular phenotypes, physiological properties, afferent and efferent connectivity, as well as their vulnerability to insults. Heterogeneity in Purkinje cells arises early in development, with molecularly distinct embryonic cell clusters present soon after Purkinje cell specification. Traditional methods have characterized cerebellar development and cell types, including Purkinje cell subtypes, based on knowledge of selected markers. However, recent single-cell RNA sequencing studies provide vastly increased resolution of the whole cerebellar transcriptome. Here we draw together the results of multiple single-cell transcriptomic studies in developing and adult cerebellum in both mouse and human. We describe how this detailed transcriptomic data has increased our understanding of the intricate development and function of Purkinje cells and provides first clues into features specific to human cerebellar development.
Topics: Animals; Biomarkers; Cerebellum; Humans; Mice; Nerve Tissue Proteins; Phenotype; Purkinje Cells
PubMed: 36139493
DOI: 10.3390/cells11182918 -
Experimental Neurology Dec 2021The dystonias are a group of disorders characterized by excessive muscle contractions leading to abnormal repetitive movements or postures. In blepharospasm, the face is...
BACKGROUND
The dystonias are a group of disorders characterized by excessive muscle contractions leading to abnormal repetitive movements or postures. In blepharospasm, the face is affected, leading to excessive eye blinking and spasms of muscles around the eyes. The pathogenesis of blepharospasm is not well understood, but several imaging studies have implied subtle structural defects in several brain regions, including the cerebellum.
OBJECTIVE
To delineate cerebellar pathology in brains collected at autopsy from 7 human subjects with blepharospasm and 9 matched controls.
METHODS
Sections from 3 cerebellar regions were sampled and processed using Nissl and silver impregnation stains. Purkinje neurons were the focus of the evaluation, along with as several other subtle pathological features of cerebellar dysfunction such as Purkinje neuron axonal swellings (torpedo bodies), proliferation of basket cell processes around Purkinje neurons (hairy baskets), empty baskets (missing Purkinje neurons), and displacement of cell soma from their usual location (ectopic Purkinje neurons).
RESULTS
The results revealed a significant reduction in Purkinje neuron and torpedo body density, but no changes in any of the other measures.
CONCLUSIONS
These findings demonstrate subtle neuropathological changes similar to those reported for subjects with cervical dystonia. These findings may underly some of the subtle imaging changes reported for blepharospasm.
Topics: Aged; Aged, 80 and over; Blepharospasm; Cerebellum; Female; Humans; Male; Middle Aged; Purkinje Cells
PubMed: 34464652
DOI: 10.1016/j.expneurol.2021.113855