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Home , Cerebellum, Climbing fiber, Deep cerebellar nuclei, Flocculus, Mossy fiber (cerebellum)

The : A Super-Resolution Predictor in the use of the automated ?

Eyal Cohen, PhD

(HUJI & BIU)

1 Cerebellum – The “Little Brain”

2 The Cerebellum takes ~10% of the Brain in Volume Small but Hefty…

Over 50% of the Brain’s are in the Cerebellum!! 3 The Convoluted Cerebellar consists of most Cerebellar Volume Results of Cerebellar Lesions or Volume reduction

• = loss of muscle tone • = loss of : 1. Postural instability, “drunken sailor” , sway, wide standing base 2. Walking: uncertain, asymmetric, irregular 3. Failure in execution of planned movements i.e. intentional , (lack of coordination) and (speech slurring) 4. Deficits in control

• Correlative Non-Motor Symptoms: 1. Lower Intelligence (Verbal) 2. Lower visuospatial abilities 3. problems (i.e. working, procedural) and Dementia 4. Emotional control problems, impulsiveness, aggression 5. Reduced ability of strategy formation 6. Psychosis, Schizophrenia (associated with reduced volume) 4 Cerebellar Role in Muscle Timing and Coordination

Position

Velocity

Biceps

Triceps

Cooling = Reducing Neuronal Firing Biceps Triceps

5 Villis and Hore 1977 Cerebellar is Central in Adaptation

6 General Structure of the Cerebellar Cortex

Ventral/Anterior View Dorsal/Posterior View

Nodulus Vermis Hemispheres 7 Lobes and Lobules of the Cerebellar Cortex

8 The Cerebellum is not Only Cortex…

Deep Cerebellar

9 Nuclei (DCN) The Deep Cerebellear Nuclei (DCN) are the Output Relays of the Cerebellum

Dentate Fastigial Interposed (Emboliform+ Globose) 10 Cerebellar Peduncles: Input / Output Highways

Superior

Medial Cerebellar Peduncle

Inferior Cerebellar Peduncle

Superior: / Inputs/Outputs Medial: Pontine Inputs and Commissure Inferior: Spinal/Medullary Inputs/Outputs

11 Two Major Input Pathways Serve the Cerebellum

Pontine Nuclei Inferior Olive

Inferior Olive CF = Climbing Fibers MF = Mossy Fibers

12 Pontine Nuclei Relay Cerebro-Coritcal Information

Non-Cortical Inputs: 1. Mamilary Body 2. Amygdala 3. Midbrain Nuclei (Brodal 1978) 4. Spinal Inputs

13 Cortical Areas That project to the Pontine Nuclei The IO receive motor and sensory inputs

Visual Inputs: SC = Superior Coliculus NOT = of Optic Tract

Vestibular Inputs: VN = Vestibular Nucleus

Motor Command: RN =

Somatosensory & Proprioceptive: DCN = Dorsal Column Nucleus Trigeminal & Spinal Chord

Inferior Olive (IO)

14 Additionally: Auditory Inputs Sugihara & Shinoda JNS 2004 Cerebellar Major Output Pathways

CTX = Cortex Motor CTX PM = Premotor PM PAR PAR = Parietal CTX CTX

PF = Prefrontal PF RN = Red Nucleus CTX VL = Ventrolateral DCN = Deep Cerebellar RN Nuclei VL RF = DCN

Other Outputs:

Inferior Olive RF Hippocampus Amygdala Septum

15 General Mapping of Cerebellar

16 Mapping of Cerebellar Cortex – Classic View

17 Cerebellar Cortex Mapping is Fragmented

18 Voogd and Glickstein 1998 Parasaggital Microzones of Cerebellar Cortex

Some Molecular Markers (i.e. Zebrin II) divide Purkinje Cells Populations 19 The 3 Layers of the Cerebellar Cortex

Molecular Layer

Purkinje cell Layer

Granule cell Layer

20 Cerebellar Cortex Consists of 5 types of Neurons

Inhibitory cells: • Purkinje • Golgi • Basket • Stelate

Excitatory Cells: • Granule cells

21 Apps & Garwicz NatRevNeu 2005 Purkinje Cells: The most Elaborate Neurons of the CNS

22 Purkinje Cells: The Beauty of Network Structure

23 PC: The Principal Cell of Cerebellar Cortex Cerebellar Cortex Parallel Fibers ~200,000

Climbing Fiber ~2000 Synapses

Deep Cerebellar Excitation Nuclei (DCN) Inhibition

Purkinje Cells are the only neurons Modified from Apps 24 projecting from the Cerebellar Cortex!! & Garwicz 2005 The Spatial Organization of Cerebellar Circuitry

Notice the perpendicular relationship between and enervations!!

25 No timed propagation on the parallel fibers

26 Yarom and Cohen AnnNYAc 2003 Closing the Loop: The Cerebellar Module

Cerebellar Cortex

Feedback Dysinhibition

Deep Cerebellar Excitation Nuclei (DCN) Inhibition

Feedback Inhibition

Inferior Olive (IO)

Modified from Apps 27 & Garwicz NatRevNeu 2005 The Numerics of Cerebellar Modules

40 Purkinje Cells Parallel Fibers: Div = 1:150-450 Con: 200,000:1

5-50x103 0.5-1 x106 Mossy Granule Cells Fibers Div = 1:450 Con = 4-5:1

Cortical Output Div = 1:20-50 Climbing Fibers Con = 1:20-50 Div = 1:10 Con = 1:1

28 40 Deep Nuclear Cells 4 Inferior Olivary Neurons The simplified Olivocerebellar Module

Cerebellar Cortex Parallel Fibers

Climbing Fibers Inferior Olive Pontine Nuclei Mossy Fibers Granular (IO) (PN) Layer

Sensory Feedback Sensorimotor + Efferent Copy Context () (DCN)

Cerebellar Outputs

Thalamus, Cerebellar Physiology

Infra Red Fluorescent Dye

Double Recording of Purkinje Cell in Slice

Hausser M.

30 Purkinje Cells exhibit Two distinct Spike Types

Simple Spike Complex Spike

Mossy Fiber Stimulation Inferior Olive Stimulation

Eccles, 1966

31 Cerebellar Learning Theories

Eccles, 1967

1971 32 Simple Spikes are Modulated by Inputs

Simple spikes of 2 Purkinje cells in awake monkey during hand movements

33 Roitman 2005 Complex Spikes are fired in Unexpected Events

34 Horn, Pong & Gibson 2002 Synchronous Population Coding by Purkinje Cells

35 Welsh 1995 attributes are encoded by a population of ~100 Purkinje cells

36 Tier-Barash 2000 Distinct Firing Regimes of Purkinje Cells

Complex Spikes & Simple Spikes (Up-State)

Complex Spikes Only (Down-State)

10mV 100ms

Simple Spikes: 0 - ~80Hz (Mostly 0Hz or 4-8Hz or 20-80Hz, with possible phasic >100Hz)

Complex Spikes : 1-3Hz (Phasic 10-15Hz)

37 Cohen and Lampl, unpublished Plasticity in the Cerebellar Cortex

38 Coesmans et al. 2004 Vestibulo - Ocular Adaptation

Synaptic Changes Complex VG = Spike VN =Vestibular Nucleus PA = Pontine Area AOS = Accessory Optic Climbing System Fiber OM = Oculomotor Activation Neurons Motor Synaptic Retinal Slip Changes Correction Reduced Retinal Slip

Visual Information

39 Ito 1984, Schonville et al. 2010 Eyelid Reflex Conditioning

40 Bracha and Bloedel 2009 Eyelid Reflex Conditioning

41 Medina et al. Nature 2002 Eyelid Reflex Conditioning

42 Rasmussen et al 2008 IO is crucial for Learning @350ms but not 700ms

43 Welsh 2002 Conditioning Memory Retention depends on Nucleo-Olivary Inhibition

44 Medina et al. Nature 2002 The Learning Transfer Hypothesis

Motor CTX

After 12 Hrs

VL After 6 Hrs

DCN

Cerebellar CTX Inferior Olive Fastest Learning~ Sec-Min

VL = Ventro-Lateral Nucleus DCN = Deep Cerebellar Nuclei CTX =45 Cortex CF = Climbing Fibers Cerebellar Involvement in Cognitive Processes Cognitive effects of focal damage were found when: 1. The damage involved the vermis 2. The damage was in an area which blood supply is from the posterior inferior cerebellar

Further research showed problems in and Children with Vermal damage show autistic-like features: 1. Irritability 2. impulsivity 3. Disinhibition 4. Emotional lability

Complex verbal dysfunction associated with right cerebellar damage Dysprosodia – associated with left cerebellar damage

46 Schmahmann J. FMRI Mapping pf Cerebellar Involvement in Various Processes

Somatosensory Processing

47 Stoodley and Schmahmann 2009 FMRI Mapping pf Cerebellar Involvement in Various Processes

Motor Processing

48 Stoodley and Schmahmann 2009 FMRI Mapping pf Cerebellar Involvement in Various Processes

Language Processing

49 Stoodley and Schmahmann 2009 FMRI Mapping pf Cerebellar Involvement in Various Processes

Working Memory

50 Stoodley and Schmahmann 2009 FMRI Mapping pf Cerebellar Involvement in Various Processes

Spatial Processing

51 Stoodley and Schmahmann 2009 FMRI Mapping pf Cerebellar Involvement in Various Processes

Executive Processing

52 Stoodley and Schmahmann 2009 FMRI Mapping pf Cerebellar Involvement in Various Processes

Emotional Processing

53 Stoodley and Schmahmann 2009 Cerebellar Involvement in Autism

Control Subject Autistic Subject

54 Levitt J. 1999 Autism candidate genes affects the Cerebellum

Autistic Control Control CASP2 -/-

Lose of Purkinje Cells in Autistic Developmental Problems in KO mice

Saskia 2004 Sadakata 2007

55 Cerebellar Involvement in

Control Subject Dyslexic Subject

56 Information Flow during On-Line Corrections

VL = Ventro-Lateral Nucleus Motor CTX DCN = Deep Cerebellar Nuclei PM PAR RN = Red Nucleus CTX Motor CTX (+ mid brain nuclei) Learning PF CTX Afferent Copy CTX = Cortex Of Motor Command

MF = Mossy Fibers RN CF = Climbing Fibers VL DCN

Pontine Nuclei Cerebellar CTX MF Inferior Olive

RF

Sensory & 57 Motor Command MotorVestibular To Spinal MNs CorrectionInformation The General Role of the Cerebellum

58 Complex Spikes as Purkinje Cell Switches

59 Loewenstein et al. NatNS 2005 The Inferior Olive as the Great Comparator

Feedback Inhibition from Deep Cerebellar Nuclei

Motor Intention

Inferior Olive

Sensory 60 feedback IO Neurons are Coupled by

Placantonakis et al. PNAS 2004

61 The Inferior Olive as the Great Comparator

Feedback Inhibition From the DCN

Motor Intention

Inferior Olive

Sensory 62 feedback IO Neurons are Natural Oscillators

Llinas and Yarom JPhysiol 1986 63 IO neurons are not Harmonious Oscillators in-vivo

Chorev, Yarom and Lampl JNS 2007

64 There are Various Oscillation Patterns

65 Oscillation as a Blocking Device for expected Inputs

Expected Inputs

How will The IO Differentiate Early vs. Late Inputs?

66 ISI vs. Oscillation phase “encoding”

67 Mathy, et al. 2009 CF activation Pattern sets the direction of plasticity

68 Mathy, et al. 2009 How does the Cerebellum compute?

69 Thank you for Thinking!!

70 Cerebellar Hemispheres have evolved Later in Evolution

Elephantnose Fish Porpoise

71 Voogd and Glickstein 1998 The Cerebellum has Evolved in Evolution

72 Cerebellum Complexity has also Evolved

Rat

Monkey

Human

73 Cerebellar evolution did not stop in …

74 Of course size is not the only thing that counts… Remember the ’s Cerebellum?

Big Cerebellum does not necessarily mean more cells… 75 Intelligence may lay in the power of Integration…

76 Of course size is not the only thing that counts…