Jussieu 1/12/2015 The cerebellum: what are the majority of brain cell good for? Clément Léna (lena@biologie.ens.fr) Institut de Biologie de l ‘École Normale Supérieure, Paris
The cerebellum 81.8% of brain mass 19.0% of brain neurons 7.8% of brain mass 10.3% of brain mass 0.8% of brain neurons 80.2% of brain neurons cerebellar cortex cerebellar nuclei
The cerebellum Herculano-Houzel Front Neuroanat 2010 cerebellar cortex cerebellar nuclei
Learning with the cerebellum • The cerebellum as an associative device • Plasticity in the cerebellum. • Prediction of sensory inputs with anti-Hebbian learning • Generating movement from the cerebellum : eyeblink conditioning. • Modulating movement with the cerebellum : gain control. • Programming movement?
>150.000 parallel fiber/PC stellate/ Purkinje Purkinje Purkinje basket cell cell cell cell 1 climbing fiber/PC cerebellar cerebellar cerebellar cortex cortex cortex 4 mossy fiber/granule cell nb PC ~ 300 x nb gc granule granule granule Golgi cell cell cell cell Pre-cerebellar Pre-cerebellar Pre-cerebellar Pre-cerebellar nuclei nuclei nuclei nuclei cerebellar cerebellar cerebellar cerebellar Post-cerebellar Post-cerebellar Post-cerebellar Post-cerebellar nuclei nuclei nuclei nuclei nuclei nuclei nuclei nuclei (mostly pre-motor) (mostly pre-motor) (mostly pre-motor) (mostly pre-motor) inferior inferior olive olive
Topology of the cerebellar cortex Coronal view Sagittal view
Pre- and post-cerebellar nuclei Input: Mossy fibers afferents Vestibular information • Inner ear • Vestibular nuclei Sensory-motor information: • spinal proprioceptive & sensory • Nucleus dorsalis (dorsal spino-cerebellar tract), • Cuneate nucleus • brainstem nuclei : trigeminal & Reticular nuclei (lateral, paramedian,reticulo-tegmental) Neocortical inputs: • Pontine nuclei Input: Climbing fibers afferents Inferior olive Output: Projections from cerebellar nuclei Mostly premotor regions in : • Vestibular nuclei • Reticular formation • Red nucleus • Thalamus (mostly to motor and premotor cortex)
Medio-lateral segmentation of the cerebellar cortex Differential expression of molecular markers in Purkinje cells: ANTERIOR ASPECT DORSAL ASPECT CAUDAL ASPECT Apps & Hawkes Nature Rev Neurosci 2009
Topography of PC afferents: mossy-fiber input types
Topography of PC afferents: mossy fiber receptive fields Fractured somatotopy of mossy fibers, conserved across individuals Parallel fibers extend over the whole lobule. Thus Purkinje cells receive multiple sensory input types. Voogd and Glickstein (1998) TINS 21(9):370-375
Topography of PC afferents: climbing fibers Cerebellar cortex Inferior olive
Topography of convergent Purkinje cells Cerebellar cortex Cerebellar nuclei
Summary of the cerebellar circuitry: a powerful associative device Cerebellar cortex Inferior olive Cerebellar nuclei
Summary • The topology of cerebellar connectivity maximizes the associative power of the cerebellum.
Plasticity sites in the cerebellum stellate/ Purkinje basket cell cell cerebellar cortex granule Golgi cell cell cerebellar nuclei Hansel et al. (2001) Nature Neurosci 4 , 467 - 475
Learning with the cerebellum: 2 inputs of Purkinje cells Contact fibre parallèle-cellule de Purkinje 20 m m Philippe Isope & Boris Barbour Kreitzer et al. Neuron 2000
Anti-Hebbian learning Before pairing Pairing After pairing
Learning with the cerebellum: inferior olive induce LTD in Purkinje cell Vestibular granule mossy inputs cells fibers Extracellular recordings in the Purkinje cells 3 min. pairing parallel Inferior olive + fibers Vestibular stim LTD Vestibular stim Vestibular stim Inferior Purkinje climbing olive cells fibers 5 cells Intracellular recordings in the Purkinje cells Spike counts Temps (min) Temps (min) Sakurai, J. Physiol. 1987 Ito et al. (1982) J Physiol. 324:113-34
Learning with the cerebellum: bidirectional plasticity at the synapse between parallel fiber and Purkinje cell Microcystin: PP inhibitor Chelerythrine: PKC inhibitor “Anti -Hebbian ” rule: PF -CF coincidence leads to reduced excitation Jörntell & Hansel (2006) Neuron. 52 (2):227-38
Learning with the cerebellum: hint of timing window from Ca2+ imaging PF: parallel fibers CF: climbing fibers Nature Neuroscience 3 , 1266 - 1273 (2000) Wang et al. (2000) Nature Neurosci 3 , 1266 - 1273
Summary • The topology of cerebellar connectivity maximizes the associative power of the cerebellum. • The cerebellum hosts anti-Hebbian learning rule(s) between the parallel fiber (encoding context) and the climbing fiber (encoding a learning signal).
Sensory prediction: lessons from cerebellum-like structures Bell et al. Annu Rev Neurosci 31:1-24
Adaptive filtering: the decorrelation algorithms (decorrelation by using anti-Hebbian rule) Adaptive interference cancellation Subtractions of expected sensory signal the output neuron should discharge only on unexpected inputs Decorrelation control Modification of motor command to reduce the error (the climbing fiber) Dean et al. (2002) Proc Biol Sci. 269 (1503):1895-904.
Cancellation of predictable sensory inputs by the cerebellum Vestibular Inner ear neurons Motor command Cerebellum of head mvt => The cerebellum predicts the sensory inputs and cancels the expected inputs
Summary • The topology of cerebellar connectivity maximizes the associative power of the cerebellum. • The cerebellum hosts anti-Hebbian learning rule(s) between the parallel fiber (encoding context) and the climbing fiber (encoding a learning signal). • The anti-Hebbian rule allows the cerebellum to implement adaptive filters (cancellation of expected input)
Learning with the cerebellum: eyeblink conditioning CS+US, saline in the interpositus CS+US, interpositus inactivated CS+US, no infusion Local infusion of GABA agonist Krupa, Thompson and Thompson (1993 ) Science. 260(5110):989-91.
Regions in the rabbit cerebellum involved in eyeblink control Eyelid Inferior Sensory neurons olive Eyelid Cerebellar muscles nuclei Hesslow J Physiol 1994
Purkinje cell firing changes in a longitudinal study of aversive conditioning => climbing fiber => mossy fiber Jirenhed, D.-A. et al. (2007) J. Neurosci. 27:2493-2502
Principle of eyeblink conditioning LTD
Cerebellum microzones: sensory receptive fields of climbing fibers Correspondence between single muscle nociceptive receptive fields and climbing fiber receptive fields Muscle EMG following noxious Quantitative comparison of the mecanichal stim. receptive fields of withdrawal reflex and climbing fibers Categories of CF receptive fields Receptive fields for single muscle withdrawal reflex Climbing Fiber/mossy fibers sensory receptive field Martin Garwicz (2002) Brain Research Reviews 40:152 – 165 Apps&Garwicz (2005) Nature Reviews Neuroscience 6, 297-311
Cerebellum microzones: relation between olivary inputs and controlled motor units Muscle group controlled by the target of Purkinje cells Climbing Fiber sensory receptive field Apps&Garwicz (2005) Nature Reviews Neuroscience 6, 297-311
Cerebellum microzones: sensory receptive fields of neurons Climbing fiber receptive fields Parallel fiber receptive fields Molecular layer interneuron receptive fields Apps&Garwicz (2005) Nature Reviews Neuroscience 6, 297-311
Purkinje cells receptive fields are defined by plasticity Jörntell & Hansel (2006) Neuron. 52 (2):227-38
Plasticity in interneurons : complementarity with LTD in Purkinje cells Few parallel fibers activate the interneurons PF + CF stim. Hebbian learning in interneurons: Parallel fibers and climbing fibers coincidence induce Many parallel LTP in interneuron (and fibers activate the anti-coincidence produce interneurons LTD). NB: The climbing fiber does not make direct synaptic contacts with the interneuron Jorntell & Ekerot J Neurosci (2003) 23(29):9620-9631
Learning with the cerebellum: a synthesis with microzonal organization
Summary • The topology of cerebellar connectivity maximizes the associative power of the cerebellum. • The cerebellum hosts anti-Hebbian learning rule(s) between the parallel fiber (encoding context) and the climbing fiber (encoding a learning signal). • The anti-Hebbian rule allows the cerebellum to implement adaptive filters ( cancellation of expected input). • The peripheral control of the climbing fiber is organized as for reflex loops. • The cerebellar learning leads to climbing fiber cancellation. Context Purkinje cell Learning Sensory neuron Motoneuron
Two main types of “internal models” “instructor” “controler” “effector” (what you want to do) (how to do it) (do it!) Knowing the context , “inverse” internal model you should do it a bit more this way “instructor” “controler” “effector” Knowing the “forward” internal model context , that's what you are about to get... “instructor” “controler” “effector”
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