THE OLIVO-CEREBELLAR SYSTEM EDITED BY : Egidio D’Angelo, Elisa Galliano and Chris I. De Zeeuw PUBLISHED IN : Frontiers in Neural Circuits 1 April 2016 | The Olivo-Cer ebellar System Frontiers in Neural Circuits Frontiers Copyright Statement © Copyright 2007-2016 Frontiers Media SA. All rights reserved. All content included on this site, such as text, graphics, logos, button icons, images, video/audio clips, downloads, data compilations and software, is the property of or is licensed to Frontiers Media SA (“Frontiers”) or its licensees and/or subcontractors. The copyright in the text of individual articles is the property of their respective authors, subject to a license granted to Frontiers. The compilation of articles constituting this e-book, wherever published, as well as the compilation of all other content on this site, is the exclusive property of Frontiers. For the conditions for downloading and copying of e-books from Frontiers’ website, please see the Terms for Website Use. 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ISSN 1664-8714 ISBN 978-2-88919-826-9 DOI 10.3389/978-2-88919-826-9 About Frontiers Frontiers is more than just an open-access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. Frontiers Journal Series The Frontiers Journal Series is a multi-tier and interdisciplinary set of open-access, online journals, promising a paradigm shift from the current review, selection and dissemination processes in academic publishing. All Frontiers journals are driven by researchers for researchers; therefore, they constitute a service to the scholarly community. 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What are Frontiers Research Topics? Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: researchtopics@frontiersin.org 2 April 2016 | The Olivo-Cer ebellar System Frontiers in Neural Circuits THE OLIVO-CEREBELLAR SYSTEM The figure captures the activity state of the granular layer in a realistic simulation, during which a cluster of granule cells is activated over a background noisy activity. The large elements are Golgi cells, the small elements are granule cells. The simulation, which involved about 400000 neurons, was run in the Human Brain Project framework on a blue-gene-II supercomputer (Casali S., VanGeit W., Masoli S., Rizza M., D’Angelo E., unpublished). Image by Elisa Galliano Topic Editors: Egidio D’Angelo, University of Pavia, Italy Elisa Galliano, King’s College London, UK Chris I. De Zeeuw, Erasmus Medical Center, Netherlands 3 April 2016 | The Olivo-Cer ebellar System Frontiers in Neural Circuits During the last decades, investigations on the olivo-cerebellar system have attained a high level of sophistication, which led to redefinitions of several structural and functional properties of neurons, synapses, connections and circuits. Research has expanded and deepened in so many directions and so many theories and models have been proposed that an ensemble review of the matter is now needed. Yet, hot topics remain open and scientific discussion is very lively at several fronts. One major question, here as well as in other major brain circuits, is how single neurons and synaptic properties emerge at the network level and contribute to behavioural regulation via neuronal plasticity. Other major aspects that this Research Topic covers and discusses include the development and circuit organization of the olivo-cerebellar network, the established and recent theories of learning and motor control, and the emerging role of the cerebellum in cognitive processing. By touching on such varied and encompassing subjects, this Frontiers Special Topic aims to highlight the state of the art and stimulate future research. We hope that this unique collection of high-quality articles from experts in the field will provide scientists with a powerful basis of knowledge and inspiration to enucleate the major issues deserving further attention. Citation: D’Angelo, E., Galliano, E., Zeeuw, C. I. D., eds. (2016). The Olivo-Cerebellar System. Lausanne: Frontiers Media. doi: 10.3389/978-2-88919-826-9 Cover Image: A forest of Purkinje cells, stained with an antibody against SMI-32. Image by Elisa Gallian 4 April 2016 | The Olivo-Cer ebellar System Frontiers in Neural Circuits Table of Contents 06 Editorial: The Olivo-Cerebellar System Egidio D’Angelo, Elisa Galliano,and Chris I. De Zeeuw Development, circuit organization and structural plasticity of the olivocerebellar system 09 Architecture and development of olivocerebellar circuit topography Stacey L. Reeber, Joshua J. White, Nicholas A. George-Jones and Roy V. Sillitoe 23 Branching patterns of olivocerebellar axons in relation to the compartmental organization of the cerebellum Hirofumi Fujita and Izumi Sugihara 32 Structural plasticity of climbing fibers and the growth-associated protein GAP-43 Giorgio Grasselli and Piergiorgio Strata 39 Molecular mechanism of parallel fiber-Purkinje cell synapse formation Masayoshi Mishina, Takeshi Uemura, Misato Yasumura and Tomoyuki Yoshida 48 The compartmental restriction of cerebellar interneurons G. Giacomo Consalez and Richard Hawkes 62 Anatomical investigation of potential contacts between climbing fibers and cerebellar Golgi cells in the mouse Elisa Galliano, Marco Baratella, Martina Sgritta, Tom J. H. Ruigrok, Elize D. Haasdijk, Freek E. Hoebeek, Egidio D’Angelo, Dick Jaarsma and Chris I. De Zeeuw Neuronal activity and synaptic plasticity 71 Theta-frequency resonance at the cerebellum input stage improves spike timing on the millisecond time-scale Daniela Gandolfi, Paola Lombardo, Jonathan Mapelli, Sergio Solinas and Egidio D’Angelo 87 The cerebellar Golgi cell and spatiotemporal organization of granular layer activity Egidio D’Angelo, Sergio Solinas, Jonathan Mapelli, Daniela Gandolfi, Lisa Mapelli and Francesca Prestori 108 High frequency burst firing of granule cells ensures transmission at the parallel fiber to Purkinje cell synapse at the cost of temporal coding Boeke J. van Beugen, Zhenyu Gao, Henk-Jan Boele, Freek Hoebeek and Chris I. De Zeeuw 120 Non-Hebbian spike-timing-dependent plasticity in cerebellar circuits Claire Piochon, Peter Kruskal, Jason MacLean and Christian Hansel 5 April 2016 | The Olivo-Cer ebellar System Frontiers in Neural Circuits 128 Olivary subthreshold oscillations and burst activity revisited Paolo Bazzigaluppi,Jornt R. De Gruijl,Ruben S. van der Giessen, Sara Khosrovani, Chris I. De Zeeuw, and Marcel T. G. de Jeu 141 Strength and timing of motor responses mediated by rebound firing in the cerebellar nuclei after Purkinje cell activation Laurens Witter, Cathrin B. Canto, Tycho M. Hoogland, Jornt R. de Gruijl and Chris I. De Zeeuw Network patterns 155 The olivo-cerebellar system: a key to understanding the functional significance of intrinsic oscillatory brain properties Rodolfo R. Llinás 168 Cerebellar cortical neuron responses evoked from the spinal border cell tract Pontus Geborek, Anton Spanne, Fredrik Bengtsson and Henrik Jörntell 178 Stimulation within the cuneate nucleus suppresses synaptic activation of climbing fibers Pontus Geborek, Henrik Jörntell and Fredrik Bengtsson 187 In and out of the loop: external and internal modulation of the olivo-cerebellar loop Avraham M. Libster and Yosef Yarom 202 Synchrony and neural coding in cerebellar circuits Abigail L. Person and Indira M. Raman 217 Linking oscillations in cerebellar circuits Richard Courtemanche, Jennifer C. Robinson and Daniel I. Aponte Theories of learning and control 233 Error detection and representation in the olivo-cerebellar system Masao Ito 241 Beyond “all-or-nothing” climbing fibers: graded representation of teaching signals in Purkinje cells Farzaneh Najafi and Javier F. Medina 249 How do climbing fibers teach? Thomas S. Otis, Paul J. Mathews, Ka Hung Lee, and Jaione Maiz 252 Role of the olivo-cerebellar complex in motor learning and control Nicolas Schweighofer, Eric J. Lang and Mitsuo Kawato 261 Distributed cerebellar plasticity implements adaptable gain control in a manipulation task: a closed-loop robotic simulation Jesús A. Garrido, Niceto R. Luque,Egidio D’Angelo, and Eduardo Ros Cerebellum as an integrated system for sensorimotor control and cognition 281 Seeking a unified framework for cerebellar function and dysfunction: from circuit operations to cognition Egidio D’Angelo and Stefano Casali 304 The olivo-cerebellar system and its relationship to survival circuits Thomas C. Watson, Stella Koutsikou, Nadia L. Cerminara, Charlotte R. Flavell, Jonathan J. Crook, Bridget M. Lumb and Richard Apps 311 The cerebellum: a new key structure in the navigation system Christelle Rochefort, Julie M. Lefort and Laure Rondi-Reig EDITORIAL published: 12 January 2016 doi: 10.3389/fncir.2015.00066 Frontiers in Neural Circuits | www.frontiersin.org January 2016 | Volume 9 | Article 66 Edited and reviewed by: Rodolfo R. Llinas, New York University School of Medicine, USA *Correspondence: Egidio D’Angelo dangelo@unipv.it; Chris I. De Zeeuw c.dezeeuw@erasmusmc.nl Received: 28 May 2015 Accepted: 12 October 2015 Published: 12 January 2016 Citation: D’Angelo E, Galliano E and De Zeeuw CI (2016) Editorial: The Olivo-Cerebellar System. Front. Neural Circuits 9:66. doi: 10.3389/fncir.2015.00066 Editorial: The Olivo-Cerebellar System Egidio D’Angelo 1, 2 *, Elisa Galliano 3, 4 and Chris I. De Zeeuw 4, 5 * 1 Neurophysiology Unit, Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy, 2 Brain Connectivity Center, Neurophysiology, IRCCS C. Mondino Neurological Institute, Pavia, Italy, 3 MRC Centre for Developmental Neurobiology, King’s College London, London, UK, 4 Department of Neuroscience, ErasmusMC, Rotterdam, Netherlands, 5 Department of Cerebellar Coordination and Cognition, Netherlands Institute for Neuroscience, Amsterdam, Netherlands Keywords: cerebellum, inferior olive, synaptic plasticity (LTP/LTD), purkinje cell, granular layer, deep cerebellar nucleus The Editorial on the Research Topic The Olivo-Cerebellar System Studies on the olivo-cerebellar system have rapidly advanced over the past decade, leading to new insight in the structural and functional properties of its synapses, neurons, intrinsic circuits, and connectivity with the rest of the brain. As in many other fields of neuroscience, it is becoming more and more appropriate to try to bring our understanding at the level of individual synapses and neurons to that of ensemble activity, circuits, and behavior. This Editorial aims to facilitate this process by ordering the 26 contributions of this special issue of Frontiers in Brain Microcircuits Series from studies on the development and structure of synaptic contacts to those on the function of local microcircuits and network plasticity as well as the olivo-cerebellar system as a whole. More specifically, we highlight here the main points of the chapters on development, circuit organization and structural plasticity of various types of neurons in the olivo-cerebellar system (A); the chapters on their basic activity and synaptic plasticity (B); the chapters on the relevance of the emerging network patterns in the olivo-cerebellar system (C); the chapters on current high-level theories of motor learning (D); and the chapters on the overall role of the olivo-cerebellar system in the integration of sensorimotor control and cognition (E). (A) DEVELOPMENT, CIRCUIT ORGANIZATION, AND STRUCTURAL PLASTICITY OF THE OLIVO-CEREBELLAR SYSTEM The development and architecture of the olivo-cerebellar afferents, the climbing fibers, are described in great detail by Reeber and colleagues and Fujita and Sugihara. Indeed, attempts to relate the climbing fiber branching patterns to the development of cerebellar compartmentalization and lobulation will help us to untangle the organization of the cerebellar cortex at the functional level. Interestingly, the climbing fiber system is not only highly plastic during development, but also following degeneration of Purkinje cells and/or their afferents. Grasselli and Strata highlight how this process depends on the growth-associated protein GAP-43 in olivary neurons, while Mishina and colleagues show how postsynaptic GluR δ 2 plays a pivotal role in territory control of the Purkinje cell spines by the parallel fibers versus that of the climbing fibers through trans- synaptic interaction with presynaptic neurexins (NRXNs) and cerebellin 1. The compartmental restriction in sagittal zones, which is evident in the climbing fiber system, apparently also provides a framework for both the excitatory and inhibitory interneurons in the cerebellar cortex in that 6 D’Angelo et al. Editorial: The Olivo-Cerebellar System their axons mostly remain within the same zonal boundaries (Consalez and Hawkes). However, in terms of direct appositions there is a clear distinction between the interneurons in the granular layer, which do not show direct contact with climbing fibers, and those in the molecular layer, which do show adjacent climbing fiber varicosities (Galliano et al.). (B) NEURONAL ACTIVITY AND SYNAPTIC PLASTICITY The activity at the input stage of cerebellum plays an important role in determining the spatiotemporal patterns of simple spike activity that are ultimately generated by Purkinje cells. Gandolfi and colleagues show how resonance in the granular layer can be sustained at the theta-frequency range by K slow (M-like), KA, and Na-persistent currents and thereby improve spike timing at the millisecond time-scale. In addition, the same lab illustrates how the Golgi cells can fine-tune the spatiotemporal organization of granular layer activity by generating dense center-surround clusters of granule cell activity and implementing combinatorial operations on multiple mossy fiber inputs (D’Angelo et al.), regulating transmission gain and cut-off frequency, controlling spike timing and burst transmission, and determining the intensity and duration of mossy fiber to granule cell plasticity. Importantly, van Beugen and colleagues were the first to show in awake behaving mammals that the high instantaneous firing frequency of mossy fiber bursts can be reliably transferred to individual granule cells (up to about 800 Hz) and from there via the parallel fibers to Purkinje cells, inducing a heterogeneous short-lived facilitation to ensure signaling within the first few spikes. To what extent the activity in the parallel fibers will be subsequently depressed or potentiated in the Purkinje cells depends on the temporal relation with the climbing fiber activity, implying a non-Hebbian form of spike-timing- dependent plasticity (Piochon et al.). If parallel fiber EPSPs are elicited in Purkinje cells before activation by the climbing fibers, long-term depression (LTD) will be induced; instead, when they are evoked after climbing fiber activity long-term potentiation (LTP) will occur. As all climbing fibers originate in the inferior olive, this means that the precise timing of activation of olivary neurons is critical. Bazzigaluppi and colleagues did whole-cell recordings of olivary neurons in vivo and showed that the number of wavelets riding on top of their action potentials is related to the amplitude of their subthreshold oscillations as well as the level of electronic coupling between them. The pattern of simple spikes and complex spikes that are generated in the Purkinje cells following various forms of plasticity ultimately converge onto a smaller set of neurons in the cerebellar and vestibular nuclei. Importantly, here these patterns can evoke rebound firing and trigger movements, especially when the timing with respect to the activity of mossy fiber and/or climbing fiber collaterals is optimal (Witter et al.). (C) NETWORK PATTERNS As discussed above, the olivo-cerebellar modules form a unique control system and their specific wiring allows fine temporal control and rhythmicity. Oscillatory and synchronous activities are generated, sustained, and modulated throughout the network, in order to create the appropriate spatiotemporal code necessary to drive behavior. In his review Rodolfo Llinas focuses on rhythmicity in the olive (Llinas) and he underlies that it is indeed the combination of strong and rather stereotyped intrinsic electrical properties with electrical coupling that allows the synchronous activation of clusters of olivary neurons. Feedback inhibition provides the dynamic variance of the membership of such coupled clusters, and the cluster’s activity phase can be resetted by an incoming stimulus or by inputs arising from outside the olivo-cerebellar system. Geborek and colleagues show that olivary excitability is suppressed during different phases of movement and a relay through the cuneate nucleus is a possible gateway (Geborek et al., Geborek et al.). Elaborating even further on the topic of external inputs providing modulation to system’s rhythmicity, Libster and Yarom provide a detailed review of neuromodulators acting on DCN, IO, and PCs and they advocate for the importance of cerebellar neuromodulation, which is necessary to produce a wide range of behavioral response appropriate in the context of the general behavioral state of the animal. Going back to internal source of rhythmic activity in the olivo-cerebellar system, Person and Ramon contribute with a very comprehensive review on PC-DCN convergence and coding. They underline that disruption to such finetuned code, both in terms of timing and rate, can lead to motor dysfunctions. Finally, rhythmic activity is not only essential at the input (IO) and output (DCN) stages of the system. Courtemanche and colleagues provide an overview on oscillatory activity of the cerebellar cortex. Slow oscillations (4–25 Hz) organize spatial patterns of synchronization and communication with and within the granular layer. Fast oscillations (150–300 Hz) in PCs have a more direct influence on DCN, neighboring modules and motor output, and are found to be more pronounced in pathological scenarios such as Angelman disease. (D) THEORIES OF LEARNING AND CONTROL Central to all theoretical models of cerebellar learning is the instructive role played by the IO signals carried via CF to PCs. One of the original proposers of such role, Masao Ito, here elaborates about the apparent dichotomy between sensory (feedforward control) and motor (feedback control) errors carried by CFs to PCs, and pinpoints that such an error dichotomy persists throughout vertebrate phylogeny (Ito). Najafi and Medina focus on the nature of such error signals, and argue that the all-or-nothing idea is being separated. They support this position by underlining that CF burst size has been shown to be tightly regulated and informative, but that it can modulate calcium channels on PC dendrites. A graded CF instructive signal activating PCs can thus be effectively encoded via pre- or post- synaptic modulation. The Otis laboratory confirmed that such Frontiers in Neural Circuits | www.frontiersin.org January 2016 | Volume 9 | Article 66 7 D’Angelo et al. Editorial: The Olivo-Cerebellar System signal not only is graded, but is also not univocally received by PCs, but also by MLIs via spillover mechanisms (Otis et al.). Schweighofer et al. discuss the implication of electrical coupling strength in the IO on the error signal effectiveness. They argue that intermediate coupling strength is best, because it leads to chaotic resonance and increase information transfer of the error signal. Beside the recognized role of supervised plasticity at the PF-CF-PC node, the impact of distributed cerebellar plasticity on cerebellar adaptive behaviors remains to be clarified. This problem would be hard to tackle unless distributed plasticity mechanisms are integrated into a fully interconnected sensory-motor control system operating in closed-loop during behavior. This challenge has been taken by the Ros’ and D’Angelo’s laboratories (Garrido et al.), who elaborated on a robotic controller, embedding a computational model of the whole olivo-cerebellar system. The model was endowed with multiple distributed forms of synaptic plasticity. During a closed-loop load manipulation task, parallel fiber— Purkinje cell LTP and LTD rapidly acquired sensory-motor contingencies under climbing fiber guidance but then plasticity was slowly transferred into the DCN. This two-rate process proved critical to allow the system to dynamically adjust its gain when the load was changed. Distributed plasticity beyond parallel fiber LTD was therefore required to efficiently generate rapid, stable and self-adapting behavioral learning and control. (E) CEREBELLUM AS AN INTEGRATED SYSTEM FOR SENSORIMOTOR CONTROL AND COGNITION After the fundamental recognition of its involvement in sensorimotor coordination and learning, the olivo-cerebellar system is now also believed to take part in cognition and emotion. D’Angelo and Casali have reviewed a broad spectrum of observations and argue that a similar circuit structure in all olivo-cerebellar sections may cope with the different cerebellar operations using a common underlying computational scheme. It is proposed that the different roles of the cerebellum depend on the specific connectivity of cerebellar modules and that motor, cognitive and emotional functions are (at least partially) segregated in different cerebro-cerebellar loops. In a multi- level conceptual framework, cellular/molecular and network mechanisms would generate computational primitives (timing, learning, and prediction) that could operate in high-level cognitive processing and finally control mental function and dysfunction. It is proposed that the cerebellum operates as a general-purpose co-processor, whose effects depend on the specific brain centers to which individual modules are connected. Abnormal functioning in these loops could eventually take part in the pathogenesis of major brain pathologies including not just ataxia but also dyslexia, autism, schizophrenia, and depression. The Apps laboratory highlights anatomical and physiological evidence gathered in monkeys, cats, and rats, indicates that survival circuits structures such as the peri-acquaductal gray are connected with cerebellum and olive (Watson et al.). Additionally, the Rondi-Reig laboratory calls for a key role of the cerebellum in spatial navigation (Rochefort et al.). They argue that the cerebellum is a necessary regulator of spatial representation and integrates multisource self-motion information, transforming such reference frame into vestibular signals and distinguishing between self and externally generated vestibular signals. OPEN QUESTIONS AND DEBATES While much progress has been made during the last decades in trying to elucidate how the olivo-cerebellar network might work, several questions still remain open. Some of the questions raised by the articles contributing to this special issue concern the genetic and molecular mechanisms during development that generate olivo-cerebellar compartmentalization and determine which behavior is encoded in each cerebellar zone. Another fundamental question is how spatio-temporal patterns elaborated in local microcircuits are integrated into meaningful engrams under the coordination of oscillation and resonance phenomena. At the front of synaptic plasticity there are several open issues. Do we know all existing forms of plasticity in the cerebellum? How do these plasticities contribute to cerebellar learning? How important is structural plasticity in adults and how does this interact with synaptic and intrinsic plasticity mechanisms? How are all the different forms of rhythmicity and plasticity affected by neuromodulators? Taken together, it is becoming clear that understanding how the cerebellum works eventually depends on how its activity is integrated into large-scale loops in the whole brain. A major challenge will be therefore to determine the precise anatomy and behavioral correlates of cerebellar-telencephalic connections in different species, as well as the impact of cerebellar temporally patterned activity onto the cerebral cortex. Tackling such important questions will be the challenge that the field will face in the years ahead of us. ACKNOWLEDGMENTS This work was supported by grants of European Union to ED (CEREBNET FP7-ITN238686 to ED and CDZ, REALNET FP7- ICT270434, Human Brain Project HBP-604102 to ED) and ERC- advanced and ERC-POC to CDZ. EG is supported by a Sir Henry Wellcome Fellowship. Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Copyright © 2016 D’Angelo, Galliano and De Zeeuw. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Neural Circuits | www.frontiersin.org January 2016 | Volume 9 | Article 66 8 REVIEW ARTICLE published: 02 January 2013 doi: 10.3389/fncir.2012.00115 Architecture and development of olivocerebellar circuit topography Stacey L. Reeber 1,2 , Joshua J. White 1,2 , Nicholas A. George-Jones 1,2 and Roy V. Sillitoe 1,2 * 1 Department of Pathology and Immunology, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital, Houston, TX, USA 2 Department of Neuroscience, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital, Houston, TX, USA Edited by: Chris I. De Zeeuw, Erasmus MC, Netherlands Reviewed by: Edward S. Ruthazer, Montreal Neurological Institute, Canada Iris Salecker, MRC National Institute for Medical Research, UK *Correspondence: Roy V. Sillitoe, Department of Pathology and Immunology, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA. e-mail: sillitoe@bcm.edu The cerebellum has a simple tri-laminar structure that is comprised of relatively few cell types. Yet, its internal micro-circuitry is anatomically, biochemically, and functionally complex. The most striking feature of cerebellar circuit complexity is its compartmentalized topography. Each cell type within the cerebellar cortex is organized into an exquisite map; molecular expression patterns, dendrite projections, and axon terminal fields divide the medial-lateral axis of the cerebellum into topographic sagittal zones. Here, we discuss the mechanisms that establish zones and highlight how gene expression and neural activity contribute to cerebellar pattern formation. We focus on the olivocerebellar system because its developmental mechanisms are becoming clear, its topographic termination patterns are very precise, and its contribution to zonal function is debated. This review deconstructs the architecture and development of the olivocerebellar pathway to provide an update on how brain circuit maps form and function. Keywords: inferior olive, circuitry, topography, climbing fibers, cerebellum, zones INTRODUCTION It is well established that brain circuits are organized into spatial maps that control behavior (Hubel and Wiesel, 1979; Johnston, 1989; Friedman and O’Leary, 1996; Logan et al., 1996; Bozza et al., 2002; Huffman and Cramer, 2007; Leergaard and Bjaalie, 2007; Li and Crair, 2011; Suzuki et al., 2012). Yet, we have a limited under- standing of how precise functional connections form during map development. Neural circuit connectivity is intensely studied in the cerebellum because its cellular networks are well understood and its developmental mechanisms are experimentally tractable. Cerebellar circuits have an established role in motor control and they are now also implicated in higher order functions such as cognition and emotion (Sacchetti et al., 2009; Strata et al., 2011). Two main types of afferents transmit information to the cerebel- lum: climbing fibers and mossy fibers. Climbing fibers arise only from neurons of the inferior olivary nucleus in the brainstem ( Figure 1 ) and monoinnervate adult Purkinje cells ( Figure 2A ) whereas mossy fibers originate from numerous brain and spinal cord nuclei to innervate granule cells. Each climbing fiber elicits powerful Purkinje cell responses that sculpt cerebellar function ( Figures 2C,D ). Here, we discuss the development, organiza- tion, and function of the olivocerebellar projection and highlight the mechanisms that make this pathway an attractive model for understanding topographic brain circuitry. CEREBELLAR SAGITTAL ZONES The adult cerebellum is anatomically divided into distinct folds called lobules ( Figure 3A ; Larsell, 1952). Mammals and birds have 10 lobules that are separated from one another by a series of fissures. Because each fissure extends to a specific depth in the cerebellum, each lobule develops with a unique shape ( Figure 3A ). The invariance of lobule structure and their con- servation across species support the idea that lobule/fissure formation is spatially and temporally controlled by complex morphogenetic programs (Sudarov and Joyner, 2007). Strikingly, each lobule in the cerebellum is further com- partmentalized along the medial-lateral axis into sagittal zones ( Figure 3 ). Each set of zones is clearly delineated by the pat- terned expression of genes and proteins (Apps and Hawkes, 2009). The most comprehensively studied zonal marker is zebrin II (Brochu et al., 1990; Figures 3B,C , 4D ), an antigen on the aldolase C protein (Ahn et al., 1994; Hawkes and Herrup, 1995). Zebrin II is expressed by alternating subsets of Purkinje cells (zebrin II + adjacent to zebrin II − ), thus forming complementary rows of biochemically distinct Purkinje cells ( Figures 3B,C , 4D ). The zonal organization of zebrin II is symmetrical about the cerebellar midline, highly reproducible between individuals, and conserved across species (Brochu et al., 1990; Sillitoe et al., 2005; Apps and Hawkes, 2009). The pattern of zebrin II has an intricate relationship to the expression of several other Purkinje cell pro- teins. For example, phospholipase C β 3 (PLC β 3), sphingosine kinase 1a (SPHK1a), and excitatory amino-acid transporter 4 (EAAT4; Hawkes et al., 1985; Hawkes and Leclerc, 1987; Dehnes et al., 1998; Terada et al., 2004; Sarna et al., 2006) are all co- expressed with zebrin II. In contrast, phospholipase C β 4 (PLC β 4; Armstrong and Hawkes, 2000; Sarna et al., 2006) is expressed selectively in zebrin II − zones. In addition to the complemen- tary and corresponding relationships between zones, proteins such as neurofilament heavy chain (NFH) divide individual zebrin II zones into smaller sagittal units (Demilly et al., 2011). Frontiers in Neural Circuits www.frontiersin.org January 2013 | Volume 6 | Article 115 | NEURAL CIRCUITS 9 Reeber et al. Olivocerebellar zones FIGURE 1 | (A) Wholemount image of an adult brain showing the cerebellum (Cb) from a dorsal view. The dotted line indicates the level of the tissue section schematic in (B) (B) Schematic of sagittal section cut through an adult cerebellum showing the cerebellum (red) and inferior olive (IO; blue). FIGURE 2 | (A) Schematic of a simplified cerebellar microcircuit illustrating the two major sensory afferent pathways that project to the cerebellum: climbing fibers and mossy fibers. Climbing fibers (blue projection) terminate directly onto Purkinje cells whereas mossy fibers (yellow projection) terminate on granule cell dendrites (green). Granule cell axons called parallel fibers contact Purkinje cells (purple). Purkinje cells are the sole output of the cerebellar cortex and transmit signals to the cerebellar nuclei (red). (B) High power image of a climbing fiber expressing cocaine-and amphetamine-regulated transcript (CART) peptide [arrow; staining was performed according to Reeber and Sillitoe (2011)]. The target Purkinje cell is weakly immunoreactive for CART. (C) Example Purkinje cell spike train recorded in vivo . Recordings were performed in Ketamine/Xylazine anesthetized mice using 2–5 M Ohm Tungsten electrodes (Thomas Recording, Germany). Signals were band-pass filtered at 300–5000 Hz, amplified with an ELC-03XS amplifier (NPI, Germany), and recorded with Spike2 (CED, England). (D) Higher power view of the recording trace illustrating the clear distinction between a climbing fiber complex spike (cs) and simple spike (ss) responses in Purkinje cells. Asterisk in panel (C) indicates a complex spike. The layers of the cerebellum are indicated as molecular layer (ml), Purkinje cell layer (pcl), granular layer (gl), and white matter (wm). The cerebellar nuclei are located in the white matter. Scale bar in (B) = 25 μ m. Cumulatively, molecularly defined zonal compartments divide the cerebellar cortex into hundreds of reproducible units with each one containing up to several hundred Purkinje cells (Apps and Hawkes, 2009). Purkinje cell zones may be used to divide the cerebellum into four transverse domains in the anterior–posterior axis (Ozol et al., 1999). For example, in the vermis zebrin II expression reveals a specific pattern in lobules I–V and VIII/IX ( Figures 3B,C , 4D ). In contrast, expression of the small 25 kDa heat shock protein HSP25 delineates distinct zonal patterns in lobules VI/VII and IX/X, which express zebrin II in all Purkinje cells (Armstrong et al., 2000). Afferent termination patterns mirror the topography Frontiers in Neural Circuits www.frontiersin.org January 2013 | Volume 6 | Article 115 | 10 Reeber et al. Olivocerebellar zones FIGURE 3 | (A) Schematic of a sagittal section cut through the cerebellar vermis revealing the stereotypical foliation pattern, which consists of 10 lobules [adapted with permission from White and Sillitoe (2013)]. The cerebellum can be further divided along the anterior–posterior axis into four transverse domains: anterior (blue; lobules I–V), central (green; lobules VI and VII), posterior (yellow; lobules VIII and anterior IX), and nodular (red; lobules posterior IX and X) (Ozol et al., 1999). (B) In the adult cerebellum, zebrin II/aldolase C expression, which is revealed using wholemount staining (Sillitoe and Hawkes, 2002; White et al., 2012), delineates zones of Purkinje cells. The transverse zones are color coded according to panel (A) (C) A schematic representation of an unfolded vermis illustrating the full pattern of zebrin II zones (adapted with permission from Sillitoe and Joyner, 2007). Lobule numbers are indicated by Roman numerals. Anterior and posterior axes are denoted by A and P of Purkinje cell zones ( Figures 4B,E ). As a result, each transverse domain is innervated by a specific combination of function- ally distinct afferent fibers. For instance, spinocerebellar mossy fibers project to lobules I–V and VIII/IX (Arsenio Nunes and Sotelo, 1985; Brochu et al., 1990; Sillitoe et al., 2010), whereas the vestibulocerellar mossy fibers project mainly to lobules IX and X (Jaarsma et al., 1997; Maklad and Fritzsch, 2003). In mouse, climbing fibers that express cocaine- and amphetamine-related transcript peptide (CART) terminate selectively in lobules VI/VII and IX/X (Reeber and Sillitoe, 2011), and corticotrophin releas- ing factor (CRF) expressing climbing fibers are expressed in a striking array of zones in lobules I–V and VIII/IX ( Figures 4C,E ) (Sawada et al., 2008). The efferent side of the cortical circuit also respects the zonal topography. Sugihara and collaborators have mapped the tra- jectories of Purkinje cell axons from specific cerebellar cortical compartments onto the three sets of cerebellar nuclei. They revealed a close correspondence between adolase C expressing Purkinje cell terminals with subdivisions of cerebellar nuclei (Sugihara and Shinoda, 2007). Together, Purkinje cell zones, afferent topography, and Purkinje cell efferent projections to the cerebellar nuclei define the cerebellar module, the func- tional unit of the cerebellum (Apps and Hawkes, 2009; Ruigrok, 2011). ANATOMICAL AND FUNCTIONAL ORGANIZATION OF OLIVOCEREBELLAR ZONES Fine topological mapping using anterograde tracers injected into specific sub-nuclei of the inferior olive and the tracing of climb- ing fiber collateral projections labeled from injections into the cerebellar cortex of birds, rodents, and primates have shown that there is a strict and precise association between climbing fiber topography and zebrin II Purkinje cell zones (Voogd et al., 2003; Sugihara and Shinoda, 2004; Voogd and Ruigrok, 2004; Sugihara and Quy, 2007; Pakan and Wylie, 2008; Sugihara et al., 2009; Fujita et al., 2010). In addition, several studies have used climbing fiber markers to link the architecture of chemically dis- tinct subsets of climbing fiber afferents to the adult pattern of Purkinje cell zones ( Table 1 ). For example, CRF, an amino acid peptide, is expressed in a subset of climbing fibers that cor- re