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The Journal of Neuroscience : the... Nov 2023The cerebellum, traditionally associated with motor coordination and balance, also plays a crucial role in various aspects of higher-order function and dysfunction....
The cerebellum, traditionally associated with motor coordination and balance, also plays a crucial role in various aspects of higher-order function and dysfunction. Emerging research has shed light on the cerebellum's broader contributions to cognitive, emotional, and reward processes. The cerebellum's influence on autonomic function further highlights its significance in regulating motivational and emotional states. Perturbations in cerebellar development and function have been implicated in various neurodevelopmental disorders, including autism spectrum disorder and attention deficit hyperactivity disorder. An increasing appreciation for neuropsychiatric symptoms that arise from cerebellar dysfunction underscores the importance of elucidating the circuit mechanisms that underlie complex interactions between the cerebellum and other brain regions for a comprehensive understanding of complex behavior. By briefly discussing new advances in mapping cerebellar function in affective, cognitive, autonomic, and social processing and reviewing the role of the cerebellum in neuropathology beyond the motor domain, this Mini-Symposium review aims to provide a broad perspective of cerebellar intersections with the limbic brain in health and disease.
Topics: Humans; Autism Spectrum Disorder; Cognition; Cerebellum; Neurodevelopmental Disorders; Attention Deficit Disorder with Hyperactivity
PubMed: 37940582
DOI: 10.1523/JNEUROSCI.1451-23.2023 -
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 -
Science (New York, N.Y.) Sep 2023The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell...
The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell three-dimensional (3D) genome assay-diploid chromosome conformation capture, or Dip-C-into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we resolved the first 3D genome structures of single cerebellar cells, created life-spanning 3D genome atlases for both humans and mice, and jointly measured transcriptome and chromatin accessibility during development. We found that although the transcriptome and chromatin accessibility of cerebellar granule neurons mature in early postnatal life, 3D genome architecture gradually remodels throughout life, establishing ultra-long-range intrachromosomal contacts and specific interchromosomal contacts that are rarely seen in neurons. These results reveal unexpected evolutionarily conserved molecular processes that underlie distinctive features of neural development and aging across the mammalian life span.
Topics: Animals; Humans; Mice; Cerebellum; Neurons; Genome; Imaging, Three-Dimensional; Single-Cell Analysis; Chromatin Assembly and Disassembly; Cellular Senescence; Atlases as Topic
PubMed: 37676945
DOI: 10.1126/science.adh3253 -
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 -
Neuron Nov 2023Interleukin-4 (IL-4) is a type 2 cytokine with pleiotropic functions in adaptive immunity, allergies, and cognitive processes. Here, we show that low levels of IL-4 in...
Interleukin-4 (IL-4) is a type 2 cytokine with pleiotropic functions in adaptive immunity, allergies, and cognitive processes. Here, we show that low levels of IL-4 in the early postnatal stage delineate a critical period in which microglia extensively prune cerebellar neurons. Elevating the levels of this cytokine via peripheral injection, or using a mouse model of allergic asthma, leads to defective pruning, permanent increase in cerebellar granule cells, and circuit alterations. These animals also show a hyperkinetic and impulsive-like phenotype, reminiscent of attention-deficit hyperactivity disorder (ADHD). These alterations are blocked in Il4rα::Cx3cr1-CreER mice, which are deficient in IL-4 receptor signaling in microglia. These findings demonstrate a previously unknown role for IL-4 during a neuroimmune critical period of cerebellar maturation and provide a first putative mechanism for the comorbidity between allergic disease and ADHD observed in humans.
Topics: Animals; Humans; Interleukin-4; Microglia; Cerebellum; Brain; Cytokines
PubMed: 37918358
DOI: 10.1016/j.neuron.2023.09.031 -
Neuron Feb 2024Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To...
Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a deep learning method to predict disease state accurately and identified specific features that enable accurate distinction of wild-type and SCA1 cells. Together, this work reveals new roles for diverse cerebellar cell types in SCA1 and provides a generalizable analysis framework for studying neurodegeneration.
Topics: Animals; Mice; Humans; Ataxin-1; Mice, Transgenic; Spinocerebellar Ataxias; Cerebellum; Purkinje Cells; Disease Models, Animal
PubMed: 38016472
DOI: 10.1016/j.neuron.2023.10.039 -
Current Biology : CB Jan 2024The cerebellum, that stripey 'little brain', sits at the back of your head, under your visual cortex, and contains more than half of the neurons in your entire nervous...
The cerebellum, that stripey 'little brain', sits at the back of your head, under your visual cortex, and contains more than half of the neurons in your entire nervous system. The cerebellum is highly conserved across vertebrates, and its evolutionary expansion has tended to proceed in concert with expansion of cerebral cortex. The crystalline neuronal architecture of the cerebellar cortex was first described by Cajal a century ago, and its functional connectivity was elucidated in exquisite anatomical and physiological detail by the mid-20 century. The ability to clearly identify molecularly distinct cerebellar cell types that constitute discrete circuit elements is perhaps unparalleled among brain areas, even within the context of modern circuit neuroscience. Although traditionally thought of as primarily a motor structure, the cerebellum is highly interconnected with diverse brain areas and, as I will explain in this Primer, is well-poised to influence a wide range of motor and cognitive functions.
Topics: Animals; Cerebellum; Brain; Biological Evolution; Cerebral Cortex; Cognition
PubMed: 38194930
DOI: 10.1016/j.cub.2023.11.048 -
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 -
Cerebellum (London, England) Aug 2023The internist Hermann Nothnagel (1841-1905) took a special interest in the cerebellum. In an early experimental study on rabbits conducted in 1876, he demonstrated the...
The internist Hermann Nothnagel (1841-1905) took a special interest in the cerebellum. In an early experimental study on rabbits conducted in 1876, he demonstrated the involvement of the vermis in the pathophysiology of motor ataxia. Between 1879 and 1889, he reported four cases of tectal tumors that clinically manifested with bilateral ophthalmoplegia and unilateral gait ataxia, culminating in the Cerebellar Classic highlighted here. Nothnagel attributed this clinical syndrome to lesions of the colliculi ("quadrigeminal bodies") and compression of the nuclei of the third cranial nerves, but also left open the possibility of the involvement of neighboring structures, such as the cerebellar vermis. Today, the ataxic component of Nothnagel syndrome is explained by a dorsal midbrain abnormality of either neoplastic or vascular origin, involving the superior cerebellar peduncles, besides the oculomotor nerves.
Topics: Male; Animals; Rabbits; Cerebellar Ataxia; Ataxia; Ophthalmoplegia; Mesencephalon; Cerebellum
PubMed: 35817948
DOI: 10.1007/s12311-022-01437-w -
Science Translational Medicine Nov 2023Inflammation early in life is a clinically established risk factor for autism spectrum disorders and schizophrenia, yet the impact of inflammation on human brain...
Inflammation early in life is a clinically established risk factor for autism spectrum disorders and schizophrenia, yet the impact of inflammation on human brain development is poorly understood. The cerebellum undergoes protracted postnatal maturation, making it especially susceptible to perturbations contributing to the risk of developing neurodevelopmental disorders. Here, using single-cell genomics of postmortem cerebellar brain samples, we characterized the postnatal development of cerebellar neurons and glia in 1- to 5-year-old children, comparing individuals who had died while experiencing inflammation with those who had died as a result of an accident. Our analyses revealed that inflammation and postnatal cerebellar maturation are associated with extensive, overlapping transcriptional changes primarily in two subtypes of inhibitory neurons: Purkinje neurons and Golgi neurons. Immunohistochemical analysis of a subset of these postmortem cerebellar samples revealed no change to Purkinje neuron soma size but evidence for increased activation of microglia in those children who had experienced inflammation. Maturation-associated and inflammation-associated gene expression changes included genes implicated in neurodevelopmental disorders. A gene regulatory network model integrating cell type-specific gene expression and chromatin accessibility identified seven temporally specific gene networks in Purkinje neurons and suggested that inflammation may be associated with the premature down-regulation of developmental gene expression programs.
Topics: Child, Preschool; Humans; Cerebellum; Neurons; Purkinje Cells; Genomics; Inflammation
PubMed: 37824600
DOI: 10.1126/scitranslmed.ade1283