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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 -
Continuum (Minneapolis, Minn.) Aug 2018The migraine postdrome is the least studied and least understood phase of migraine. This article covers the salient features of the migraine postdrome and provides... (Review)
Review
PURPOSE OF REVIEW
The migraine postdrome is the least studied and least understood phase of migraine. This article covers the salient features of the migraine postdrome and provides insight into the history, clinical symptoms, and future implications of this phase of migraine.
RECENT FINDINGS
Prospective electronic diary studies have shown that patients are left disabled with various nonheadache symptoms in the migraine postdrome, and 81% of patients report at least one nonheadache symptom in the postdrome. Hence, it is important to understand this phase better and ensure that more effective treatments become available in the future to lessen the morbidity associated with this phase. Functional imaging shows widespread reduction in brain-blood flow in the postdrome, which explains the multitudes of symptoms experienced by patients.
SUMMARY
The disability related to migraine is not exclusive to the headache phase but extends into the postdrome phase and is associated with several nonheadache symptoms that prolong the symptoms experienced by patients with migraine. Further research into the postdrome is crucial to improve our overall understanding of migraine mechanisms. This knowledge may also help to treat the concurrent nonheadache symptoms better in the future. Novel neuroimaging techniques provide a valuable noninvasive tool to push the frontiers in the understanding of migraine pathophysiology. These methods may help shed further light onto the possible links between key brain structures and networks that could be implicated in the pathophysiology of the various migraine phases.
Topics: Adult; Female; Humans; Attention Deficit Disorder with Hyperactivity; Electronic Health Records; Fatigue; History, 19th Century; Migraine Disorders; Nausea; Rhombencephalon
PubMed: 30074547
DOI: 10.1212/CON.0000000000000626 -
World Neurosurgery Mar 2022Rhombencephalosynapsis is a rare congenital anomaly, characterized by partial or total agenesis of the cerebellar vermis with midline fusion of the cerebellar... (Review)
Review
Rhombencephalosynapsis is a rare congenital anomaly, characterized by partial or total agenesis of the cerebellar vermis with midline fusion of the cerebellar hemispheres, dentate nuclei, and the superior cerebellar peduncles, creating the distinctive keyhole appearance of the fourth ventricle. Rhombencephalosynapsis can be isolated or can occur in association with other congenital anomalies and syndromes such as Gómez-López-Hernández syndrome (GLHS) or VACTERL: vertebral anomalies (V), anal atresia (A), cardiovascular defects (C), esophageal atresia and/or tracheoesophageal fistula (TE), and renal (R) and limb/radial (L) anomalies. Recent advances in prenatal imaging have resulted in an increasing rate of prenatal diagnosis of abnormalities of the posterior fossa including rhombencephalosynapsis. Patients with rhombencephalosynapsis may present with motor developmental delay, ataxia, swallowing difficulties, muscular hypotonia, spastic quadriparesis, abnormal eye movements, and a characteristic "figure-of-eight" head shaking. Cognitive outcome varies from severe intellectual disability to normal intellectual function. Rhombencephalosynapsis with VACTERL is often associated with severe cognitive disabilities, whereas patients with GLHS may have better cognitive function. The most common associated findings with rhombencephalosynapsis include hydrocephalus, mesencephalosynapsis, holoprosencephaly, pontocerebellar hypoplasia, corpus callosum dysgenesis, and absence of septum pellucidum. Patients can be categorized into 4 groups: 1) rhombencephalosynapsis associated with GLHS; 2) rhombencephalosynapsis with VACTERL; 3) rhombencephalosynapsis with atypical holoprosencephaly, and 4) isolated rhomboencephalosynapsis. The etiology of rhombencephalosynapsis is unknown. Here, we discuss several hypotheses about its etiology.
Topics: Abnormalities, Multiple; Alopecia; Cerebellum; Craniofacial Abnormalities; Female; Growth Disorders; Holoprosencephaly; Humans; Neurocutaneous Syndromes; Pregnancy; Rhombencephalon
PubMed: 34954057
DOI: 10.1016/j.wneu.2021.12.062 -
Physiological Reports Jun 2018Fluid satiation, or quenching of thirst, is a critical homeostatic signal to stop drinking; however, its underlying neurocircuitry is not well characterized.... (Review)
Review
Fluid satiation, or quenching of thirst, is a critical homeostatic signal to stop drinking; however, its underlying neurocircuitry is not well characterized. Cutting-edge genetically encoded tools and techniques are now enabling researchers to pinpoint discrete neuronal populations that control fluid satiation, revealing that hindbrain regions, such as the nucleus of the solitary tract, area postrema, and parabrachial nucleus, primarily inhibit fluid intake. By contrast, forebrain regions such as the lamina terminalis, primarily stimulate thirst and fluid intake. One intriguing aspect of fluid satiation is that thirst is quenched tens of minutes before water reaches the circulation, and the amount of water ingested is accurately calibrated to match physiological needs. This suggests that 'preabsorptive' inputs from the oropharyngeal regions, esophagus or upper gastrointestinal tract anticipate the amount of fluid required to restore fluid homeostasis, and provide rapid signals to terminate drinking once this amount has been consumed. It is likely that preabsorptive signals are carried via the vagal nerve to the hindbrain. In this review, we explore our current understanding of the fluid satiation neurocircuitry, its inputs and outputs, and its interconnections within the brain, with a focus on recent studies of the hindbrain, particularly the parabrachial nucleus.
Topics: Brain; Brain Mapping; Drinking; Homeostasis; Humans; Neural Pathways; Prosencephalon; Rhombencephalon; Satiation; Thirst
PubMed: 29932494
DOI: 10.14814/phy2.13744 -
Development (Cambridge, England) Aug 2021During early development, the hindbrain is sub-divided into rhombomeres that underlie the organisation of neurons and adjacent craniofacial tissues. A gene regulatory... (Review)
Review
During early development, the hindbrain is sub-divided into rhombomeres that underlie the organisation of neurons and adjacent craniofacial tissues. A gene regulatory network of signals and transcription factors establish and pattern segments with a distinct anteroposterior identity. Initially, the borders of segmental gene expression are imprecise, but then become sharply defined, and specialised boundary cells form. In this Review, we summarise key aspects of the conserved regulatory cascade that underlies the formation of hindbrain segments. We describe how the pattern is sharpened and stabilised through the dynamic regulation of cell identity, acting in parallel with cell segregation. Finally, we discuss evidence that boundary cells have roles in local patterning, and act as a site of neurogenesis within the hindbrain.
Topics: Animals; Body Patterning; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Humans; Rhombencephalon; Vertebrates
PubMed: 34323269
DOI: 10.1242/dev.186460 -
Revista de Neurologia Apr 2018Brainstem dysgenesis designates all those patients with congenital dysfunction of cranial nerves and muscle tone due to prenatal lesions or malformations of the... (Review)
Review
Brainstem dysgenesis designates all those patients with congenital dysfunction of cranial nerves and muscle tone due to prenatal lesions or malformations of the brainstem. This generic term has the advantage over the eponyms Moebius 'expanded' or 'unrestricted', Robin, Cogan or Carey-Fineman-Ziter syndromes in that it has a less restrictive view and provides a frame work that enables a systematic approach to diagnosis and research of most developmental disorders involving the brainstem. The review of the literature and our experience shows that infants with a predominant rombencephalic involvement are due to brainstem prenatal disruptive vascular accidents, while cases with midbrain and cerebellar involvement and widespread malformative syndromes have most likely an underlying genetic cause. Due to phenotypic heterogeneity associated with brainstem dysgenesis, it is crucial to evaluate each case individually and to establish a specific therapeutic plan. Intervention programs should start soon after diagnosis and directed to improve functions needed for daily life activities. Even though the prognosis of patients with brainstem dysgenesis due to prenatal destructive lesions depends on the magnitude of the vascular territory involved, in most patients with brainstem dysgenesis, the prognosis is better than the initial clinical manifestations would indicate.
Topics: Abnormalities, Multiple; Brain Stem; Cerebral Cortex; Disease Progression; Early Diagnosis; Eponyms; Humans; Infant, Newborn; Mesencephalon; Phenotype; Precision Medicine; Prognosis; Rhombencephalon; Syndrome
PubMed: 29557550
DOI: No ID Found -
Nature Dec 2023The function of the mammalian brain relies upon the specification and spatial positioning of diversely specialized cell types. Yet, the molecular identities of the cell...
The function of the mammalian brain relies upon the specification and spatial positioning of diversely specialized cell types. Yet, the molecular identities of the cell types and their positions within individual anatomical structures remain incompletely known. To construct a comprehensive atlas of cell types in each brain structure, we paired high-throughput single-nucleus RNA sequencing with Slide-seq-a recently developed spatial transcriptomics method with near-cellular resolution-across the entire mouse brain. Integration of these datasets revealed the cell type composition of each neuroanatomical structure. Cell type diversity was found to be remarkably high in the midbrain, hindbrain and hypothalamus, with most clusters requiring a combination of at least three discrete gene expression markers to uniquely define them. Using these data, we developed a framework for genetically accessing each cell type, comprehensively characterized neuropeptide and neurotransmitter signalling, elucidated region-specific specializations in activity-regulated gene expression and ascertained the heritability enrichment of neurological and psychiatric phenotypes. These data, available as an online resource ( www.BrainCellData.org ), should find diverse applications across neuroscience, including the construction of new genetic tools and the prioritization of specific cell types and circuits in the study of brain diseases.
Topics: Animals; Mice; Brain; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Hypothalamus; Mesencephalon; Neuropeptides; Neurotransmitter Agents; Phenotype; Rhombencephalon; Single-Cell Gene Expression Analysis; Transcriptome
PubMed: 38092915
DOI: 10.1038/s41586-023-06818-7 -
American Journal of Medical Genetics.... Dec 2018Rhombencephalosynapsis (RES) is a unique cerebellar malformation characterized by fusion of the cerebellar hemispheres with partial or complete absence of a recognizable... (Review)
Review
Rhombencephalosynapsis (RES) is a unique cerebellar malformation characterized by fusion of the cerebellar hemispheres with partial or complete absence of a recognizable cerebellar vermis. Subsets of patients also have other brain malformations such as midbrain fusion with aqueductal stenosis, characteristic craniofacial features (prominent forehead, flat midface, hypertelorism, ear abnormalities), and somatic malformations (heart, kidney, spine, and limb defects). Similar to known genetic brain malformations, the RES cerebellar malformation is highly stereotyped, yet no genetic causes have been identified. Here, we outline our current understanding of the genetic basis for RES, discuss limitations, and outline future approaches to identifying the causes of this fascinating brain malformation.
Topics: Cerebellar Diseases; Cerebellum; Growth Disorders; Humans; Rhombencephalon
PubMed: 30580482
DOI: 10.1002/ajmg.c.31666 -
Cell Dec 2022To track and control self-location, animals integrate their movements through space. Representations of self-location are observed in the mammalian hippocampal...
To track and control self-location, animals integrate their movements through space. Representations of self-location are observed in the mammalian hippocampal formation, but it is unknown if positional representations exist in more ancient brain regions, how they arise from integrated self-motion, and by what pathways they control locomotion. Here, in a head-fixed, fictive-swimming, virtual-reality preparation, we exposed larval zebrafish to a variety of involuntary displacements. They tracked these displacements and, many seconds later, moved toward their earlier location through corrective swimming ("positional homeostasis"). Whole-brain functional imaging revealed a network in the medulla that stores a memory of location and induces an error signal in the inferior olive to drive future corrective swimming. Optogenetically manipulating medullary integrator cells evoked displacement-memory behavior. Ablating them, or downstream olivary neurons, abolished displacement corrections. These results reveal a multiregional hindbrain circuit in vertebrates that integrates self-motion and stores self-location to control locomotor behavior.
Topics: Animals; Zebrafish; Neurons; Rhombencephalon; Brain; Swimming; Homeostasis; Mammals
PubMed: 36563666
DOI: 10.1016/j.cell.2022.11.022 -
Neuroscience May 2021In the last 50 years, our vision of the cerebellum has vastly evolved starting with Voogd's (1967) description of extracerebellar projections' terminations and how the... (Review)
Review
In the last 50 years, our vision of the cerebellum has vastly evolved starting with Voogd's (1967) description of extracerebellar projections' terminations and how the projection maps transformed the presumptive homogeneity of the cerebellar cortex into a more complex center subdivided into transverse and longitudinal distinct functional zones. The picture became still more complex with Richard Hawkes and colleagues' (Gravel et al., 1987) discovery of the biochemical heterogeneity of Purkinje cells (PCs), by screening their molecular identities with monoclonal antibodies. Antigens were expressed in a parasagittal pattern with subsets of PCs either possessing or lacking the respective antigens, which divided the cerebellar cortex into precise longitudinal compartments that are congruent with the projection maps. The correlation of these two maps in adult cerebellum shows a perfect matching of developmental mechanisms. This review discusses a series of arguments in favor of the essential role played by PCs in organizing the microzonation of the cerebellum during development (the "matching" hypothesis).
Topics: Antibodies, Monoclonal; Antigens; Cerebellar Cortex; Cerebellum; Purkinje Cells
PubMed: 31982466
DOI: 10.1016/j.neuroscience.2020.01.019