The Cerebellum and Classical Conditioning€¦ · Classical Conditioning Acknowledgement: Dominic...
16
1 The Cerebellum and Classical Conditioning Acknowledgement: Dominic T. Cheng, Ph.D. Auburn University Classical Conditioning in Popular Culture • A model for a fundamental form of memory • One of the most studied forms memory • Tight experimental control • Clinical relevance Why Classical Conditioning? Outline • Classical Conditioning Terminology • CS, US, CR, UR • Animal Evidence • basic neural circuitry • mice, rats, rabbits, cats, dogs • lesion, recordings, stimulation • Human Evidence • taxonomy of memory • patient, neuroimaging, stimulation
Transcript of The Cerebellum and Classical Conditioning€¦ · Classical Conditioning Acknowledgement: Dominic...
1
The Cerebellum andClassical Conditioning
Acknowledgement:Dominic T. Cheng, Ph.D.
Auburn University
Classical Conditioning in Popular Culture
• A model for a fundamental form of memory
• One of the most studied forms memory
• Tight experimental control
• Clinical relevance
Why Classical Conditioning? Outline
• Classical Conditioning Terminology
• CS, US, CR, UR
• Animal Evidence
• basic neural circuitry• mice, rats, rabbits, cats, dogs• lesion, recordings, stimulation
• Human Evidence
• taxonomy of memory• patient, neuroimaging, stimulation
2
Basics of Eyeblink Classical Conditioning
time
Ivan Pavlov
CS
Conditioned stimulus (CS)(tone)
Trial 1
URs
Unconditioned response (UR)(eyeblink)
US
Unconditioned stimulus (US)(corneal airpuff)
MaximalEyelid
Closure
Trial n+1
CRs URs
time
Ivan Pavlov
Conditioned stimulus (CS)(tone)
CS
Unconditioned response (UR)(eyeblink)
Unconditioned stimulus (US)(corneal airpuff)
US
Conditioned response (CR)(eyeblink)
Basics of Eyeblink Classical Conditioning
MaximalEyelid
Closure
Basics of Eyeblink Classical Conditioning
Characteristics of an adaptive CRAmplitude
Gormezano (1966) Experimental Methods and Instrumentation in Psychology (ed. Sidowski)
CS
US
CRs
eyelid not completely closed
Basics of Eyeblink Classical Conditioning
Characteristics of an adaptive CRDuration
Gormezano (1966) Experimental Methods and Instrumentation in Psychology (ed. Sidowski)
CS
US
CRs
voluntary
3
Basics of Eyeblink Classical Conditioning
Characteristics of an adaptive CRLatency (timing)
Gormezano (1966) Experimental Methods and Instrumentation in Psychology (ed. Sidowski)
CS
US
CRs
poorly timed
Basics of Eyeblink Classical Conditioning
Characteristics of an adaptive CRAmplitude (eye must be fully closed)Duration (non-voluntary)Latency (appropriately timed)
Gormezano (1966) Experimental Methods and Instrumentation in Psychology (ed. Sidowski)
CS
US
CRs
Delay Conditioning
TraceConditioning
CS
US
CS
US
Delay and Trace Conditioning
time
In trace conditioning there is a gap between CS offset andUS onset. In delay conditioning there is no gap and CS Typically coterminates with US
Requires cerebellum
Requires cerebellum
Requires hippocampus
Basics of Eyeblink Classical Conditioning
Am
ou
nt
of L
ea
rnin
g(C
Rs)
Time
4
Basics of Eyeblink Classical Conditioning
Common Controls used in Classical Conditioning
PseudoconditioningUnpaired CS and US presentation
Differential ConditioningCS+ and CS- presentations
CS alone US alone
CS- CS+ CS- CS+
CS
US
A Little History…..
The first eyeblink conditioning studies were performed in humans (Cason, 1922).
Problems with humans:
measurement difficultiesresponse variabilityvoluntary respondingcannot do invasive neuroscience research
Isidore Gormezano developed the rabbit preparation “to remedy long-term deficiencies and difficulties in the study of classical conditioning (Gormezano et al., 1983, p. 202).”
Gormezano (1962)
• Tolerate restraint well (60-90 min)• Show low spontaneous blink rates• Gradual acquisition• Few alpha (orienting) responses• Eyes can be conditioned independently
From Humans to Rabbits
• Measurement difficulties• Response variability• Voluntary responses• Lack of physiological manipulations
• Mid 70’s: CR had never been eliminated without affecting UR
• Engram = The hypothetical place where learned associations occurred
• Lashley: Memory is diffuse
• Scoville and Milner (1957): Hippocampus & memory (patient HM)
• Thompson: Engram likely to be in hippocampus
5
A Little History…..
Berger et al. (1976) Science
Recording in the hippocampus during rabbit eyeblink conditioningNeuronal activity appears to mirror development of CRs, however for delay conditioning, lesions of hippocampus do notaffect conditioning
CS US
First Reports of CR Disruption
Desmond et al. (1981) Eastern Psych Assoc Abstracts, p. 171 Desmond and Moore (1982) Physiol Behav
Light CS
Tone CS
CR Eliminated, UR Intact
CR and UR Intact
-Lesion -Lesion
Desmond and Moore (1982) Physiol Behav
Lesions of Nuc Interpositus Disrupt Conditioning
Recordings from Nuc Interpositus Show Conditioning-Related Activity
6
Lincoln et al., (1982) Brain Res and McCormick and Thompson (1984) J Neurosci
Interpositus lesion prevents CR acquisition in eye ipsilateral to lesionContralateral eye can still learn and make CRs
Nuc Interpositus Lesion Prevents CR Acquisition
P: Eye ipsilateral to lesionR: Eye contralateral to lesion
Note: UCR = UR
Cerebellar Cortex (H VI)
Yeo et al. (1985) Exp Brain Res
Lesions to the Lobule H VI in cerebellar cortexDisrupt CRs to ipsilateral but not contralateral eyeURs are intact
x
URCRW.Noise CSLight CS
Contralateral eye
CR timing and the cerebellar cortex
Perrett et al. (1993) J Neurosci
Cerebellar cortex (anterior lobes) is important for timing of the CR
Anterior DamageTiming Deficits
Posterior DamageTiming Normal
Pre
Pre
Post
Post
7
Essential Circuitry for Eyeblink Classical Conditioning
Thompson & Steinmetz (2009) Neuroscience
ToneCS
AuditoryNuclei
PontineNuclei
mossyfibers
Cerebellar Cortex
InterpositusNucleus
climbingfibers
InferiorOlive
TrigeminalNucleus
CornealAirpuff
US
All other targets of the superiorcerebellar peduncle
RedNucleus
CranialMotorNerve
ReticularFormation
EyeblinkUR & CR
Thompson & Steinmetz (2009) Neuroscience
ToneCS
AuditoryNuclei
PontineNuclei
mossyfibers
Cerebellar Cortex
InterpositusNucleus
climbingfibers
InferiorOlive
TrigeminalNucleus
CornealAirpuff
US
All other targets of the superiorcerebellar peduncle
RedNucleus
CranialMotorNerve
ReticularFormation
EyeblinkUR & CR
Essential Circuitry for Eyeblink Classical Conditioning
Steinmetz et al. (1987) PNAS
Electrophysiological recordings from the pons
Pons and Mossy Fibers Pons and Mossy Fibers
Lesions to the auditory-responsive pontine nucleiEliminates CRs to auditory CS but not to light CS
Steinmetz et al. (1987) PNAS
8
Pons and Mossy Fibers
Pontine and mossy fiber stimulationCan be used as a CS to support conditioning
Steinmetz et al. (1986) Beh Neuro
% CRsAmplitude
This denotesLesion of deepCerebellar nuclei
Thompson & Steinmetz (2009) Neuroscience
ToneCS
AuditoryNuclei
PontineNuclei
mossyfibers
Cerebellar Cortex
InterpositusNucleus
climbingfibers
InferiorOlive
TrigeminalNucleus
CornealAirpuff
US
All other targets of the superiorcerebellar peduncle
RedNucleus
CranialMotorNerve
ReticularFormation
EyeblinkUR & CR
Essential Circuitry for Eyeblink Classical Conditioning
Thompson & Steinmetz (2009) Neuroscience
ToneCS
AuditoryNuclei
PontineNuclei
mossyfibers
Cerebellar Cortex
InterpositusNucleus
climbingfibers
InferiorOlive
TrigeminalNucleus
CornealAirpuff
US
All other targets of the superiorcerebellar peduncle
RedNucleus
CranialMotorNerve
ReticularFormation
EyeblinkUR & CR
Essential Circuitry for Eyeblink Classical Conditioning
Electrophysiological recordings from the inferior olive
The inferior olive respondsTo airpuff to the eye
Sears and Steinmetz (1991) Brain Res
Inferior Olive and Climbing Fibers
9
Inferior Olive and Climbing Fibers
McCormick et al. (1985) Brain Res
Lesions to the inferior oliveCause extinction of CRs(URs were not affected)
Control group: US turned offLesion group: US stays on, IO lesioned
Inferior olive and climbing fiber stimulationCan be used as a US to support conditioning
Mauk et al. (1986) PNAS
Inferior Olive and Climbing Fibers
CS US(IO stim)
CS US(air puff)
This is an EMG response(Another way to record eyeblinks)
Thompson & Steinmetz (2009) Neuroscience
ToneCS
AuditoryNuclei
PontineNuclei
mossyfibers
Cerebellar Cortex
InterpositusNucleus
climbingfibers
InferiorOlive
TrigeminalNucleus
CornealAirpuff
US
All other targets of the superiorcerebellar peduncle
RedNucleus
CranialMotorNerve
ReticularFormation
EyeblinkUR & CR
Essential Circuitry for Eyeblink Classical Conditioning
Thompson & Steinmetz (2009) Neuroscience
ToneCS
PontineNuclei
mossyfibers
Cerebellar Cortex
InterpositusNucleus
climbingfibers
InferiorOlive
TrigeminalNucleus
CornealAirpuff
US
All other targets of the superiorcerebellar peduncle
RedNucleus
CranialMotorNerve
ReticularFormation
EyeblinkUR & CR
Essential Circuitry for Eyeblink Classical Conditioning
AuditoryNuclei
10
Thompson & Steinmetz (2009) Neuroscience
ToneCS
PontineNuclei
mossyfibers
Cerebellar Cortex
InterpositusNucleus
climbingfibers
InferiorOlive
TrigeminalNucleus
CornealAirpuff
US
All other targets of the superiorcerebellar peduncle
RedNucleus
CranialMotorNerve
ReticularFormation
EyeblinkUR & CR
Essential Circuitry for Eyeblink Classical Conditioning
AuditoryNuclei
Desmond and Moore (1991) Neurosci Res
Red Nucleus
Electrophysiological recordings from red nucleus
Clark & Lavond (1993) Behav Neurosci
Red Nucleus
Cooling the red nucleus during conditioning does not prevent learningbut does prevent the expression of the CR
CS US CS USNeural CR inCerebellum
Cooling of RNprevents neural CR hereand preventsBehavioral CR
Essential Circuitry for Eyeblink Classical Conditioning
Thompson & Steinmetz (2009) Neuroscience
ToneCS
AuditoryNuclei
PontineNuclei
mossyfibers
Cerebellar Cortex
InterpositusNucleus
climbingfibers
InferiorOlive
TrigeminalNucleus
CornealAirpuff
US
All other targets of the superiorcerebellar peduncle
RedNucleus
CranialMotorNerve
ReticularFormation
EyeblinkUR & CR
11
Human Memory Classification
Memory
Declarative Nondeclarative
Procedural(Skills and
Habits)
Primingand
PerceptualLearning
SimpleClassical
Conditioning
NonassociativeLearning
Striatum Neocortex
EmotionalResponses
Amygdala
SkeletalResponses
Cerebellum ReflexPathways
Squire (2004) Neurobiology of Learning and Memory
Medial Temporal LobeDiencephalon
Facts Events
Memory
Declarative Nondeclarative
Procedural(Skills and
Habits)
Primingand
PerceptualLearning
SimpleClassical
Conditioning
NonassociativeLearning
Striatum Neocortex
EmotionalResponses
Amygdala
SkeletalResponses
Cerebellum ReflexPathways
Squire (2004) Neurobiology of Learning and Memory
Medial Temporal LobeDiencephalon
Facts Events
Human Memory Classification
Memory
Declarative Nondeclarative
Procedural(Skills and
Habits)
Primingand
PerceptualLearning
SimpleClassical
Conditioning
NonassociativeLearning
Striatum Neocortex
EmotionalResponses
Amygdala
SkeletalResponses
Cerebellum ReflexPathways
Squire (2004) Neurobiology of Learning and Memory
Medial Temporal LobeDiencephalon
Facts Events
Human Memory Classification Human Eyeblink Classical Conditioning
Behavioral Studies
Cason (1922)
Patient Studies (MTL and Cerebellar Lesions)
Daum et al. (1989, 1991, 1992, 1993)Woodruff-Pak et al. (1990, 1993, 1996)Gabrieli et al. (1995)Bracha et al. (1997)Clark and Squire (1998)Gerwig et al. (2003, 2005, 2006, 2008, 2010)
Neuroimaging Studies (PET and fMRI)
Molchan et al. (1994); Logan & Grafton, (1995); Blaxton et al. (1996)Schreurs et al. (1997, 2001); Parker et al. (2012)
Ramnani et al. (2000); Knuttinen et al. (2002); Cheng et al. (2008, 2014)
Neurostimulation Studies (TMS and tDCS)
Hoffland et al. (2012)Kaski et al. (2012)Zuchowski et al. (in press)
12
Patient Studies of Human Eyeblink Conditioning
Gerwig et al. (2003) Brain Gerwig et al. (2003) Brain
Patient Studies of Human Eyeblink Conditioning
CR incidence
Affected=the affected eye, ie, the one ipsilateral to the lesion
Patient Studies of Human Eyeblink Conditioning
CR timing
Gerwig et al. (2005) J Neurosci
Measuring Neural Activity Related to Learning
13
PET Studies of Human Eyeblink Conditioning
Molchan et al. (1994) PNAS
Logan and Grafton (1995) PNAS
Learning-related cerebellar cortical activation during EBC
Eyeblink Classical Conditioning in the MRI Scanner
Cheng et al. (2008) PNAS
Eyeblink Classical Conditioning Today
Unconditioned Responses
Eyeblink Classical Conditioning Today
Conditioned Responses
14
Topography of Eyeblinks in the MRI Scanner General Eyeblink Conditioning Methodology
Cheng et al. (2008) PNAS
The Gold Rush
Delay Conditioning
TraceConditioning
CS
US
CS
US
Delay and Trace Conditioning
time
What are some common and unique brain regions?
Hippocampal Lesions Disrupt Trace but not Delay Conditioning
Cingulate and retrosplenial cortex receive outputs of hippocampus
(A)(B)
(C)(D)
C+D
C+D
DelayConditioning
Hippocampus
Trace Conditioning
15
General Experimental Design
CS
US
CS
US
Delay Conditioning Trace Conditioning
CSUS
Delay Block Trace Block
Delay CS alone Trace CS alone Airpuff alone
Pseudoconditioning
Acquisition
Cheng et al. (2008) PNAS
Behavioral Results
Trace ConditioningDelay ConditioningCheng et al. (2008) PNAS
* * *
n.s.n.s.
Pseudo-conditioning
Early Acquisition
LateAcquisition
% C
R
20
25
30
35
40
45
Subjects were able to learn both delay and trace paradigms in parallel
Imaging Results
Both delay and trace trials elicited significant activity in the left cerebellar cortex (Lobule HVI)
L R-57 -24 -23
Cheng et al. (2008) PNAS
Delay Trace
Ce
reb
ella
r Act
ivity
**
0.0
0.1
0.2
0.3
0.4
Greater hippocampal responding was measured during trace conditioning relative to delay conditioning
L R-29 +23 -4
Cheng et al. (2008) PNAS
*
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Hip
poc
am
pa
l Act
ivity
Delay Trace
Imaging Results
16
Sparing & Mottaghy (2008) Methods
Transcranial Direct Current Stimulation (tDCS) Transcranial Direct Current Stimulation (tDCS)
Zuchowski et al., (2014) Brain Stimulation
Transcranial Direct Current Stimulation (tDCS)
Zuchowski et al., (2014) Brain Stimulation
