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シンポジウム 27 Organization and development of the cerebellar nuclei 座長：Uusisaari Marylka Yoe（沖縄科学技術大学院大学） 2022年7月2日　16:10～16:35　ラグナガーデンホテル 羽衣：東　第8会場 3S08e-01 Developmental history of the Cerebellar Nuclei : The Glutamatergic population *Daniel Goldowitz Goldowitz(1), GIACOMO CONSALEZ(2), KARL SCHILLING(3), RICHARD WINGATE(4), FILIPPO CASONI(5), Joshua Wu(6), Joanna Yeung(1) 1. CMMT, University of British Columbia, Vancouver, Canada, 2. Div of Neurosc, San Raffaele Scientific Institute, and San Raffaele University, Milan, Italy, 3. Dept Anatomy, Anatomy & Cell Biology, Rheinische Friedrich-Wilhelms-Universität, D-53115 Bonn, FRG, 4. MRC Centre for Neurodevelopmental Disorders, Inst of Psychiatry, Psychology and Neurosci, King's College, London, 5. Div Neurosci, San Raffaele Scientific Institute, and San Raffaele University, Milan, Italy, 6. MD/PhD Program, Brown University, Providence, Rhode Island, USA Keyword: Cerebellar nuclei in mice, Atoh1, migration, Developmental genetics In this presentation a review of what is know about the development of the cerebellar nuclei (CN) will be presented. This covers topics such as cell fate determination, the origins of the precursors to the CN, the timing of their final division, the initial migratory paths, and their settling of cells into the respective nuclei. Special attention will be paid to the molecules which are critical to the formation of the Glutamatergic portion of the CN. A final discussion of the pathogenesis of disorders that involve the CN will be explored. 2022年7月2日　16:35～17:00　ラグナガーデンホテル 羽衣：東　第8会場 3S08e-02 Brain region evolution by duplication-and-divergence --- Lessons from the cerebellar nuclei *Justus M Kebschull(1) 1. Johns Hopkins University Keyword: Cerebellum, scRNAseq, Evolution How have complex brain regions, circuits, and cell types evolved from simple origins? Here we investigate brain region evolution at cell-type resolution in the cerebellar nuclei, the output structures of the cerebellum. We applied single-nucleus RNA sequencing in chickens, mice, and humans, STARmap spatial transcriptomic analysis in chicken and mice, and whole-CNS projection mapping in mice. Our work revealed a conserved cell type set containing three classes of region-invariant inhibitory neurons and two classes of region-specific excitatory neurons. This cell type set forms an archetypal cerebellar nucleus that was repeatedly duplicated to create new regions, and thus cerebellar output channels. In excitatory neurons, duplication was accompanied by divergence in gene expression and shifts in projection patterns. By contrast, inhibitory neurons maintained their gene expression signatures. Interestingly, the excitatory cell class that preferentially funnels information to lateral frontal cortices in mice becomes predominant in the massively expanded human Lateral CN. Our data provide the first characterization of CN transcriptomic cell types in three species and suggest a model of brain region evolution by duplication and divergence of entire cell type sets. 2022年7月2日　17:00～17:25　ラグナガーデンホテル 羽衣：東　第8会場 3S08e-03 CEREBELLAR COMPARTMENTATION AND THE CEREBELLAR NUCLEI *Hawkes Richard(1) *Richard Hawkes(1) 1. University of Calgary Keyword: cerebellum, cerebellar nuclei, zone, stripe The cerebellum receives two primary sources of afferent inputs. One – the mossy fiber pathways - are usually considered to provide their primary innovation to the granular layer of the cerebellar cortex. Mossy fibers derive from dozens of sources. The second afferent pathway comprises the olivocerebellar projections - climbing fibers from the inferior olive to the cerebellar cortex, which terminate on the Purkinje cells, which are the sole efferent pathway – the corticonuclear projection - from the cerebellar cortex to the cerebellar nuclei. Both the climbing fiber and the mossy fiber pathways converge as the corticonuclear projection to the cerebellar nuclei. In addition, the mossy fibers and climbing fibers also send direct projections to the cerebellar nuclei, which are the sole cerebellar output. This apparently homogeneous cerebellar structure is actually highly compartmentalized. Recent studies of connectivity, function and gene expression, in both the inferior olive and the cerebellar nuclei, suggest a cerebellum comprising 10-20 parallel functional modules. In contrast, similar studies reveal that the cerebellar cortex has enormously more discrete compartments. These compartments can be identified as gene expression boundaries, restriction boundaries for both climbing and mossy fiber afferent projections, and mutant phenotypes. ⁃ First, it is divided by transverse boundaries into 5 transverse zones. ⁃ Next, each transverse zone is subdivided into about 20 parasagittal stripes ⁃ Finally, each stripe is further divided into dozens of granular layer patches (“quanta”) Thus, the architecture of the cerebellar cortex comprises more than a thousand discrete and reproducible compartments. The implication of this extreme compartmentation is that cerebellar cortical architecture reveals that each output unit in the cerebellar nuclei is innovated by >100 discrete cerebellar cortical units. Many explanations for such elaborate topography can be advanced. As one example, perhaps cerebellar nuclear targets are very small. Alternatively, multiple inputs – e.g., groups of granular layer patches coupled via parallel fibers - may facilitate learning in multiple contexts. In conclusion, this lecture reviews the evidence for this elaborate cerebellar architecture and asks why so many cerebellar cortical units apparently innovate the same cerebellar nuclear target. 2022年7月2日　17:25～17:50　ラグナガーデンホテル 羽衣：東　第8会場 3S08e-04 Anticipatory control of movement by the cerebellum *Person Abigail(1) *Abigail L Person(1) 1. University of Colorado Anschutz Medical Campus Keyword: cerebellum The cerebellum is critical for fast and accurate movements, but how it supports such behavioral improvement remains debated. Leading hypotheses propose that the cerebellar cortex computes forward models, predictions of sensory consequences of movements, that are used to enhance motor control. Alternatively, models of associative learning that link sensory events with anticipatory commands account for a variety of other cerebellum-dependent behaviors. In this talk I will present data that unify these disparate hypotheses, demonstrating anticipatory control signals in the cerebellar nuclei and how they may be generated by associative learning in upstream cerebellar cortical circuitry. We find that in mice performing a skilled reach task, many cerebellar nuclear neurons residing in the interposed nucleus, burst as the limb decelerates to a target. This bursting activity scales with the rate of deceleration, and optogenetic perturbation of these cells bidirectionally scales deceleration supporting causality. We hypothesized that this bursting activity is akin to a conditioned response in delay eyelid conditioning, which predicts that inputs to the cerebellum can be flexibly associated with anticipatory control to enhance reach endpoint accuracy. To test this, we performed optogenetic perturbations of cerebellar inputs, in closed loop with reaching movements. Light stimulation effectively skewed reach kinematics, however, kinematic effects were quickly adapted, restoring accurate endpoints. Removal of light led to opposing after-effects on reach kinematics, supporting a model wherein cues from cerebellar inputs are integrated into a control policy in Purkinje cells to achieve expert performance by bypassing slow sensory guidance of movement with learned anticipatory control. Overall, our work supports the view that the cerebellum enhances motor control and coordination by generating anticipatory control signals through learned associations of early phases of movement with appropriate late-phase commands.