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Developmental Dynamics : An Official... Jul 2019The cerebellum coordinates vestibular input into the hindbrain to control balance and movement, and its anatomical complexity is increasingly viewed as a high-throughput... (Review)
Review
The cerebellum coordinates vestibular input into the hindbrain to control balance and movement, and its anatomical complexity is increasingly viewed as a high-throughput processing center for sensory and cognitive functions. Cerebellum development however is relatively simple, and arises from a specialized structure in the anterior hindbrain called the rhombic lip, which along with the ventricular zone of the rostral-most dorsal hindbrain region, give rise to the distinct cell types that constitute the cerebellum. Granule cells, being the most numerous cell types, arise from the rhombic lip and form a dense and distinct layer of the cerebellar cortex. In this short review, we describe the various strategies used by amniotes and anamniotes to generate and diversify granule cell types during cerebellar development.
Topics: Animals; Cell Differentiation; Cerebellum; Humans; Neocortex; Rhombencephalon
PubMed: 31131952
DOI: 10.1002/dvdy.64 -
Nature Neuroscience Aug 2023The brain generates predictive motor commands to control the spatiotemporal precision of high-velocity movements. Yet, how the brain organizes automated internal...
The brain generates predictive motor commands to control the spatiotemporal precision of high-velocity movements. Yet, how the brain organizes automated internal feedback to coordinate the kinematics of such fast movements is unclear. Here we unveil a unique nucleo-olivary loop in the cerebellum and its involvement in coordinating high-velocity movements. Activating the excitatory nucleo-olivary pathway induces well-timed internal feedback complex spike signals in Purkinje cells to shape cerebellar outputs. Anatomical tracing reveals extensive axonal collaterals from the excitatory nucleo-olivary neurons to downstream motor regions, supporting integration of motor output and internal feedback signals within the cerebellum. This pathway directly drives saccades and head movements with a converging direction, while curtailing their amplitude and velocity via the powerful internal feedback mechanism. Our finding challenges the long-standing dogma that the cerebellum inhibits the inferior olivary pathway and provides a new circuit mechanism for the cerebellar control of high-velocity movements.
Topics: Olivary Nucleus; Cerebellum; Neurons; Purkinje Cells; Axons
PubMed: 37474638
DOI: 10.1038/s41593-023-01387-4 -
Methods in Molecular Biology (Clifton,... 2022Live imaging of zebrafish embryos that maintains normal development can be difficult to achieve due to a combination of sample mounting, immobilization, and...
Live imaging of zebrafish embryos that maintains normal development can be difficult to achieve due to a combination of sample mounting, immobilization, and phototoxicity issues that, once overcome, often still results in image quality sufficiently poor that computer-aided analysis or even manual analysis is not possible. Here, we describe our mounting strategy for imaging the zebrafish midbrain-hindbrain boundary (MHB) with light sheet fluorescence microscopy (LSFM) and pilot experiments to create a study-specific set of parameters for semiautomatically tracking cellular movements in the embryonic midbrain primordium during zebrafish segmentation.
Topics: Animals; Mesencephalon; Microscopy, Fluorescence; Rhombencephalon; Zebrafish; Zebrafish Proteins
PubMed: 35218540
DOI: 10.1007/978-1-0716-2051-9_11 -
ELife Apr 2023The cerebellum is involved in learning of fine motor skills, yet whether presynaptic plasticity contributes to such learning remains elusive. Here, we report that the...
The cerebellum is involved in learning of fine motor skills, yet whether presynaptic plasticity contributes to such learning remains elusive. Here, we report that the EPAC-PKCε module has a critical role in a presynaptic form of long-term potentiation in the cerebellum and motor behavior in mice. Presynaptic cAMP-EPAC-PKCε signaling cascade induces a previously unidentified threonine phosphorylation of RIM1α, and thereby initiates the assembly of the Rab3A-RIM1α-Munc13-1 tripartite complex that facilitates docking and release of synaptic vesicles. Granule cell-specific blocking of EPAC-PKCε signaling abolishes presynaptic long-term potentiation at the parallel fiber to Purkinje cell synapses and impairs basic performance and learning of cerebellar motor behavior. These results unveil a functional relevance of presynaptic plasticity that is regulated through a novel signaling cascade, thereby enriching the spectrum of cerebellar learning mechanisms.
Topics: Animals; Mice; Cerebellum; Guanine Nucleotide Exchange Factors; Long-Term Potentiation; Neurons; Purkinje Cells; Synapses
PubMed: 37159499
DOI: 10.7554/eLife.80875 -
Current Topics in Developmental Biology 2020In vertebrates, the hindbrain serves as a highly conserved complex coordination center for regulating many fundamental activities of the central nervous system, such as... (Review)
Review
In vertebrates, the hindbrain serves as a highly conserved complex coordination center for regulating many fundamental activities of the central nervous system, such as respiratory rhythms, sleep patterns and equilibrium, and it also plays an important role in craniofacial development. The basic ground plan that underlies the diverse functions of the hindbrain and its neural crest derivatives is established and patterned by a process of segmentation. Through a dynamic series of signaling and regulatory interactions the developing hindbrain is transiently compartmentalized into a set of seven segmental units, termed rhombomeres. The nested expression of the Hox family of transcription factors is tightly coupled to the process of segmentation and provides a molecular code for specifying the unique regional properties of the hindbrain and its neural crest derived craniofacial structures. The high degree of similarity in hindbrain architecture between diverse vertebrates has enabled cross-species regulatory analysis. This has facilitated the experimental assembly of the signaling and regulatory interactions, which underlie the process of segmentation, into a Hox-dependent gene regulatory network (GRN) model. This hindbrain GRN is a key regulatory feature of head patterning, conserved to the base of vertebrate evolution. This regulatory framework also serves as a basis for comparing and contrasting GRNs that govern cranial neural crest formation and axial patterning and provide insight into regulatory mechanisms associated with the evolution of novel vertebrate traits. The purpose of this review is to discuss the majorfeatures of the GRN for hindbrain segmentation and its relationship to the broader functional role of the hindbrain in patterning head development.
Topics: Animals; Body Patterning; Evolution, Molecular; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Genes, Homeobox; Humans; Neural Crest; Rhombencephalon; Vertebrates
PubMed: 32450960
DOI: 10.1016/bs.ctdb.2020.03.001 -
Nature Communications Sep 2023Social recognition memory (SRM) is a key determinant of social interactions. While the cerebellum emerges as an important region for social behavior, how cerebellar...
Social recognition memory (SRM) is a key determinant of social interactions. While the cerebellum emerges as an important region for social behavior, how cerebellar activity affects social functions remains unclear. We selectively increased the excitability of molecular layer interneurons (MLIs) to suppress Purkinje cell firing in the mouse cerebellar vermis. Chemogenetic perturbation of MLIs impaired SRM without affecting sociability, anxiety levels, motor coordination or object recognition. Optogenetic interference of MLIs during distinct phases of a social recognition test revealed the cerebellar engagement in the retrieval, but not encoding, of social information. c-Fos mapping after the social recognition test showed that cerebellar manipulation decreased brain-wide interregional correlations and altered network structure from medial prefrontal cortex and hippocampus-centered to amygdala-centered modules. Anatomical tracing demonstrated hierarchical projections from the central cerebellum to the social brain network integrating amygdalar connections. Our findings suggest that the cerebellum organizes the neural matrix necessary for SRM.
Topics: Mice; Animals; Cerebellar Vermis; Cerebellum; Purkinje Cells; Interneurons; Memory Disorders
PubMed: 37752149
DOI: 10.1038/s41467-023-41744-2 -
Biology Open Oct 2023Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely...
Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role of HNRNPU in cerebral cortical development, but the effects of HNRNPU deficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes of HNRNPU locus deficiency during in vitro neural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level HNRNPU downregulation leads to an increased fraction of neural progenitors in the maturing neuronal population. We conclude that the HNRNPU locus is involved in delayed commitment of neural progenitors to differentiate in cell types with hindbrain profile.
Topics: Humans; Chromatin; Heterogeneous-Nuclear Ribonucleoprotein U; Neurodevelopmental Disorders; Neurogenesis; Rhombencephalon
PubMed: 37815090
DOI: 10.1242/bio.060113 -
Child's Nervous System : ChNS :... Oct 2019Chiari malformations (CM) have been traditionally classified into four categories: I, II, III, and IV. In light of more recent understandings, variations of the CM have... (Review)
Review
PURPOSE
Chiari malformations (CM) have been traditionally classified into four categories: I, II, III, and IV. In light of more recent understandings, variations of the CM have required a modification of this classification.
METHODS
This article discusses the presentation, diagnostics, and treatment of the newer forms of hindbrain herniation associated with the CM type I.
RESULTS
The CM 1 is a spectrum that includes some patients who do not fall into the exact category of this entity.
CONCLUSIONS
While CM have been categorically recognized as discrete and individual conditions, newer classifications such as CM 0 and CM 1.5 exhibit some degree of continuity with CM 1; however, they require distinct and separate classification as symptoms and treatments can vary among these clinical subtypes.
Topics: Arnold-Chiari Malformation; Humans; Magnetic Resonance Imaging; Rhombencephalon; Syringomyelia
PubMed: 31049667
DOI: 10.1007/s00381-019-04172-6 -
The Journal of Physiology Jan 2024The whisker system is widely used as a model system for understanding sensorimotor integration. Purkinje cells in the crus regions of the cerebellum have been reported...
The whisker system is widely used as a model system for understanding sensorimotor integration. Purkinje cells in the crus regions of the cerebellum have been reported to linearly encode whisker midpoint, but it is unknown whether the paramedian and simplex lobules as well as their target neurons in the cerebellar nuclei also encode whisker kinematics and if so which ones. Elucidating how these kinematics are represented throughout the cerebellar hemisphere is essential for understanding how the cerebellum coordinates multiple sensorimotor modalities. Exploring the cerebellar hemisphere of mice using optogenetic stimulation, we found that whisker movements can be elicited by stimulation of Purkinje cells in not only crus1 and crus2, but also in the paramedian lobule and lobule simplex; activation of cells in the medial paramedian lobule had on average the shortest latency, whereas that of cells in lobule simplex elicited similar kinematics as those in crus1 and crus2. During spontaneous whisking behaviour, simple spike activity correlated in general better with velocity than position of the whiskers, but it varied between protraction and retraction as well as per lobule. The cerebellar nuclei neurons targeted by the Purkinje cells showed similar activity patterns characterized by a wide variety of kinematic signals, yet with a dominance for velocity. Taken together, our data indicate that whisker movements are much more prominently and diversely represented in the cerebellar cortex and nuclei than assumed, highlighting the rich repertoire of cerebellar control in the kinematics of movements that can be engaged during coordination. KEY POINTS: Excitation of Purkinje cells throughout the cerebellar hemispheres induces whisker movement, with the shortest latency and longest duration within the paramedian lobe. Purkinje cells have differential encoding for the fast and slow components of whisking. Purkinje cells encode not only the position but also the velocity of whiskers. Purkinje cells with high sensitivity for whisker velocity are preferentially located in the medial part of lobule simplex, crus1 and lateral paramedian. In the downstream cerebellar nuclei, neurons with high sensitivity for whisker velocity are located at the intersection between the medial and interposed nucleus.
Topics: Mice; Animals; Vibrissae; Biomechanical Phenomena; Cerebellum; Purkinje Cells; Cerebellar Cortex
PubMed: 37987552
DOI: 10.1113/JP284064 -
Development (Cambridge, England) Jul 2023Cerebellar granule neurons (CGNs) are the most abundant neurons in the human brain. Dysregulation of their development underlies movement disorders and medulloblastomas....
Cerebellar granule neurons (CGNs) are the most abundant neurons in the human brain. Dysregulation of their development underlies movement disorders and medulloblastomas. It is suspected that these disorders arise in progenitor states of the CGN lineage, for which human models are lacking. Here, we have differentiated human hindbrain neuroepithelial stem (hbNES) cells to CGNs in vitro using soluble growth factors, recapitulating key progenitor states in the lineage. We show that hbNES cells are not lineage committed and retain rhombomere 1 regional identity. Upon differentiation, hbNES cells transit through a rhombic lip (RL) progenitor state at day 7, demonstrating human specific sub-ventricular cell identities. This RL state is followed by an ATOH1+ CGN progenitor state at day 14. By the end of a 56-day differentiation procedure, we obtain functional neurons expressing CGN markers GABAARα6 and vGLUT2. We show that sonic hedgehog promotes GABAergic lineage specification and CGN progenitor proliferation. Our work presents a new model with which to study development and diseases of the CGN lineage in a human context.
Topics: Humans; Hedgehog Proteins; Cerebellum; Rhombencephalon; Cell Differentiation; Neurogenesis; Stem Cells
PubMed: 37381820
DOI: 10.1242/dev.201534