Modular organization of cerebellar climbing fiber inputs during goal-directed behavior

The cerebellum has a parasagittal modular architecture characterized by precisely organized climbing fiber (CF) projections that are congruent with alternating aldolase C/zebrin II expression. However, the behavioral relevance of CF inputs into individual modules remains poorly understood. Here, we used two-photon calcium imaging in the cerebellar hemisphere Crus II in mice performing an auditory go/no-go task to investigate the functional differences in CF inputs to modules. CF signals in medial modules show anticipatory decreases, early increases, secondary increases, and reward-related increases or decreases, which represent quick motor initiation, go cues, fast motor behavior, and positive reward outcomes. CF signals in lateral modules show early increases and reward-related decreases, which represent no-go and/or go cues and positive reward outcomes. The boundaries of CF functions broadly correspond to those of aldolase C patterning. These results indicate that spatially segregated CF inputs in different modules play distinct roles in the execution of goal-directed behavior.

[1]  Stefan R. Pulver,et al.  Ultra-sensitive fluorescent proteins for imaging neuronal activity , 2013, Nature.

[2]  Sergey L. Gratiy,et al.  Fully integrated silicon probes for high-density recording of neural activity , 2017, Nature.

[3]  Mark J. Schnitzer,et al.  Automated Analysis of Cellular Signals from Large-Scale Calcium Imaging Data , 2009, Neuron.

[4]  Julia A. Licholai,et al.  Dopamine D1 Receptor–Positive Neurons in the Lateral Nucleus of the Cerebellum Contribute to Cognitive Behavior , 2018, Biological Psychiatry.

[5]  Michael A. Gaffield,et al.  Movement Rate Is Encoded and Influenced by Widespread, Coherent Activity of Cerebellar Molecular Layer Interneurons , 2017, The Journal of Neuroscience.

[6]  Douglas R Wylie,et al.  Zebrin-Immunopositive and -Immunonegative Stripe Pairs Represent Functional Units in the Pigeon Vestibulocerebellum , 2012, The Journal of Neuroscience.

[7]  Javier F. Medina,et al.  Sensory-Driven Enhancement of Calcium Signals in Individual Purkinje Cell Dendrites of Awake Mice , 2014, Cell reports.

[8]  Timothy A. Blenkinsop,et al.  Complex spike synchrony dependent modulation of rat deep cerebellar nuclear activity , 2019, eLife.

[9]  M. Häusser,et al.  Predictive and reactive reward signals conveyed by climbing fiber inputs to cerebellar Purkinje cells , 2019, Nature Neuroscience.

[10]  P. Strick,et al.  An unfolded map of the cerebellar dentate nucleus and its projections to the cerebral cortex. , 2003, Journal of neurophysiology.

[11]  William R. Softky,et al.  Comparison of discharge variability in vitro and in vivo in cat visual cortex neurons. , 1996, Journal of neurophysiology.

[12]  Richard Apps,et al.  Cerebellar cortical organization: a one-map hypothesis , 2009, Nature Reviews Neuroscience.

[13]  R. Llinás,et al.  Dynamic organization of motor control within the olivocerebellar system , 1995, Nature.

[14]  Y. Isomura,et al.  Reward-Modulated Motor Information in Identified Striatum Neurons , 2013, The Journal of Neuroscience.

[15]  S. Palay,et al.  A study of afferent input to the inferior olivary complex in the rat by retrograde axonal transport of horseradish peroxidase , 1977, The Journal of comparative neurology.

[16]  S. L. Stuesse,et al.  Projections from the medial agranular cortex to brain stem visuomotor centers in rats , 2004, Experimental Brain Research.

[17]  J. Christie,et al.  Chronic imaging of movement-related Purkinje cell calcium activity in awake behaving mice. , 2016, Journal of neurophysiology.

[18]  Karel Svoboda,et al.  ScanImage: Flexible software for operating laser scanning microscopes , 2003, Biomedical engineering online.

[19]  Mati Joshua,et al.  Coordinated cerebellar climbing fiber activity signals learned sensorimotor predictions , 2018, bioRxiv.

[20]  D. Tank,et al.  Widespread State-Dependent Shifts in Cerebellar Activity in Locomoting Mice , 2012, PloS one.

[21]  Robin C. Ashmore,et al.  Delay activity of saccade-related neurons in the caudal dentate nucleus of the macaque cerebellum. , 2013, Journal of neurophysiology.

[22]  C. M. Severin,et al.  Afferent projections to the deep mesencephalic nucleus in the rat , 1982, The Journal of comparative neurology.

[23]  Martin Paukert,et al.  Zones of Enhanced Glutamate Release from Climbing Fibers in the Mammalian Cerebellum , 2010, The Journal of Neuroscience.

[24]  Michael N. Economo,et al.  A cortico-cerebellar loop for motor planning , 2018, Nature.

[25]  Izumi Sugihara,et al.  Identification of aldolase C compartments in the mouse cerebellar cortex by olivocerebellar labeling , 2007, The Journal of comparative neurology.

[26]  Tomoki Fukai,et al.  Microcircuitry coordination of cortical motor information in self-initiation of voluntary movements , 2009, Nature Neuroscience.

[27]  J. Voogd,et al.  Projections of the dorsal column nuclei and the spinal cord on the inferior olive in the cat , 1975, The Journal of comparative neurology.

[28]  E. J. Lang,et al.  Relationship of complex spike synchrony bands and climbing fiber projection determined by reference to aldolase C compartments in crus IIa of the rat cerebellar cortex , 2007, The Journal of comparative neurology.

[29]  Kouichi Hashimoto,et al.  The anatomical pathway from the mesodiencephalic junction to the inferior olive relays perioral sensory signals to the cerebellum in the mouse , 2018, The Journal of physiology.

[30]  M. Glickstein,et al.  The anatomy of the cerebellum , 1998, Trends in Neurosciences.

[31]  Y. Shinoda,et al.  Molecular, Topographic, and Functional Organization of the Cerebellar Cortex: A Study with Combined Aldolase C and Olivocerebellar Labeling , 2004, The Journal of Neuroscience.

[32]  J. Welsh Functional significance of climbing-fiber synchrony: a population coding and behavioral analysis. , 2002, Annals of the New York Academy of Sciences.

[33]  Jan Voogd,et al.  The organization of the corticonuclear and olivocerebellar climbing fiber projections to the rat cerebellar vermis: The congruence of projection zones and the zebrin pattern , 2004, Journal of neurocytology.

[34]  N. Mizuno,et al.  Dopaminergic and non-dopaminergic neurons in the ventral tegmental area of the rat project, respectively, to the cerebellar cortex and deep cerebellar nuclei , 1992, Neuroscience.

[35]  Abigail L. Person,et al.  Purkinje neuron synchrony elicits time-locked spiking in the cerebellar nuclei , 2011, Nature.

[36]  T. Akaike,et al.  The tectorecipient zone in the inferior olivary nucleus in the rat , 1992, The Journal of comparative neurology.

[37]  John P. Welsh,et al.  Functional Significance of Climbing‐Fiber Synchrony , 2002 .

[38]  P. Rousseeuw Silhouettes: a graphical aid to the interpretation and validation of cluster analysis , 1987 .

[39]  Masahiko Watanabe,et al.  Structure–Function Relationships between Aldolase C/Zebrin II Expression and Complex Spike Synchrony in the Cerebellum , 2015, The Journal of Neuroscience.

[40]  N. Strominger,et al.  Gracile, cuneate, and spinal trigeminal projections to inferior olive in rat and monkey , 1996, The Journal of comparative neurology.

[41]  D. Heck,et al.  Cerebellar cortical output encodes temporal aspects of rhythmic licking movements and is necessary for normal licking frequency , 2010, The European journal of neuroscience.

[42]  Zhanmin Lin,et al.  Cerebellar modules operate at different frequencies , 2014, eLife.

[43]  William Heffley,et al.  Classical conditioning drives learned reward prediction signals in climbing fibers across the lateral cerebellum , 2019, eLife.

[44]  Mario Dipoppa,et al.  Suite2p: beyond 10,000 neurons with standard two-photon microscopy , 2016, bioRxiv.

[45]  Richard Apps,et al.  Heterogeneity of Purkinje cell simple spike–complex spike interactions: zebrin‐ and non‐zebrin‐related variations , 2017, The Journal of physiology.

[46]  I. Sugihara,et al.  Electrophysiological Excitability and Parallel Fiber Synaptic Properties of Zebrin-Positive and -Negative Purkinje Cells in Lobule VIII of the Mouse Cerebellar Slice , 2019, Front. Cell. Neurosci..

[47]  O. Oscarsson Functional units of the cerebellum - sagittal zones and microzones , 1979, Trends in Neurosciences.

[48]  Rodolfo R. Llinás,et al.  Cerebellar motor learning versus cerebellar motor timing: the climbing fibre story , 2011, The Journal of physiology.

[49]  H. Jörntell,et al.  In Vivo Analysis of Inhibitory Synaptic Inputs and Rebounds in Deep Cerebellar Nuclear Neurons , 2011, PloS one.

[50]  I. Sugihara Compartmentalization of the Deep Cerebellar Nuclei Based on Afferent Projections and Aldolase C Expression , 2011, The Cerebellum.

[51]  Masaki Tanaka,et al.  Cerebellar Roles in Self-Timing for Sub- and Supra-Second Intervals , 2017, The Journal of Neuroscience.

[52]  R. Hawkes,et al.  Zebrin II: A polypeptide antigen expressed selectively by purkinje cells reveals compartments in rat and fish cerebellum , 1990, The Journal of comparative neurology.

[53]  Milton Pong,et al.  Functional Relations of Cerebellar Modules of the Cat , 2010, The Journal of Neuroscience.

[54]  R. Swenson,et al.  The afferent connections of the inferior olivary complex in rats: a study using the retrograde transport of horseradish peroxidase. , 1983, The American journal of anatomy.

[55]  Germund Hesslow Inhibition of inferior olivary transmission by mesencephalic stimulation in the cat , 1986, Neuroscience Letters.

[56]  Thomas D. Mrsic-Flogel,et al.  Cerebellar Contribution to Preparatory Activity in Motor Neocortex , 2018, Neuron.

[57]  R. Swenson,et al.  The afferent connections of the inferior olivary complex in rats. An anterograde study using autoradiographic and axonal degeneration techniques , 1983, Neuroscience.

[58]  Michael Häusser,et al.  Dendritic Calcium Signaling Triggered by Spontaneous and Sensory-Evoked Climbing Fiber Input to Cerebellar Purkinje Cells In Vivo , 2011, The Journal of Neuroscience.

[59]  Mario Negrello,et al.  Neurons of the inferior olive respond to broad classes of sensory input while subject to homeostatic control , 2018, bioRxiv.

[60]  Evan M. Gordon,et al.  Spatial and Temporal Organization of the Individual Human Cerebellum , 2018, Neuron.