Creating Lasting Memories
James L. McGaugh
Center for the Neurobiology of
Learning and Memory
And
Department of Neurobiology and Behavior
University of California, Irvine
Good
Retrograde Enhancement
GABAergic antagonists: picrotoxin,
bicuculline
D-amphetamine, strychnine
No Treatment
Memory
Retrograde Amnesia
Poor
1
10
100
Time of Posttraining Treatment (log min)
Stress-Released Hormones
Arousal/Stress
Brain Activation

Anterior Pituitary

Adrenal Cortex

Cortisol (corticosterone)

Autonomic Nervous System

Adrenal Medulla

Epinephrine (Adrenaline)
“The usefulness of all of the passions consists
in their strengthening and prolonging in the soul
thoughts which are good for it to conserve…
Descartes, The Passions of the Soul, 1650
Inhibitory
Avoidance
Epinephrine Administered
After Training Enhances Memory of
Inhibitory Avoidance Training
250
200
Retention Latencies
150
100
50
0
0
10
30
120
Time of Posttraining Injection (min)
Saline
Gold and van Buskirk, 1975
Controls
Epinephrine
β-blocker in amygdala prevents
Saline i.p.
Epinephrine i.p.
epinephrine enhancement of
memory consolidation
600
500
Inhibitory Avoidance
Retention Latencies
400
300
200
100
0
Propranolol
Infused into Amygdala
Liang, Juler and McGaugh, 1986
Vehicle-control
NE (0.3 µg)
20
NE (1.0 µg)
250
% freezing
Latency (s)
300
200
150
100
16
12
8
4
50
0
shock training
No-shock controls
LaLumiere, Buen &
McGaugh 2003
Latency – freezing
200
shock training
No-shock controls
160
Contextual Fear
Conditioning
120
Posttraining Intra-BLA NE
80
40
shock training
No-shock controls
Posttraining NE BLA infusions enhance extinction
60
Saline
Norepinephrine
50
NE No Extinction
Freezing (s)
40
30
*
20
10
0
Saline
Berlau and McGaugh 2006
0.3 mg
1.0 mg
1.0 mg
Object recognition test in rats
Training trial
A1
Retention trial
A2
A3
B
?
Interval
Object Recognition Memory
Roozendaal et al., 2008
BLA β-Adrenoceptors mediate corticosterone
effects on
object recognition memory
No prior habituation
Discrimination index (%)
50
40
**
30
**
20
10
Vehicle
0
-10
-20
Cort 0.3 mg/kg
Saline
Propranolol (0.5 µg)
Intra-BLA infusion
Okuda , Roozendaal and McGaugh PNAS 2006
Cort 1 mg/kg
Cort 3 mg/kg
Norepinephrine Activation in the Amygdala
Influences Memory Consolidation
in vivo microdialysis
HPLC
Norepinephrine Release in the Amygdala After
Inhibitory Avoidance Training
Retention Latencies
800
600 SEC
600 SEC
600 SEC
600 SEC
342 SEC
227 SEC
10 SEC
% of Baseline NE
700
600
500
400
300
200
100
0
1
2
3
4
5
McIntyre, Hatfield and McGaugh, 2000
8
9
IA 7
15 min sample
10
11
12
13
14
BASOLATERAL AMYGDALA
GABAergic agonists and
antagonists
a- and b-adrenoceptor
(-)
agonists and antagonists
NTS
(-)
Vagus nerve
stria
terminalis
GABA
NE
OP
GR agonists and
antagonists
projections to other
brain structures
(+)
ACh
Opioid agonists
and antagonists
BLOOD-BRAIN BARRIER
Corticosterone
Adrenal Cortex
Epinephrine
Adrenal Medulla
McGaugh & Roozendaal
Other
Cortical
Regions
Caudate
Nucleus
Nucleus
HIPPOCAMPUS
Accumbens
NBM
Basolateral
Amygdala
Entorhinal
Cortex
ARC PROTEIN (Band Density) in
Dorsal Hippocampus
*
RATIO ACROSS HEMISPHERES
2
McIntyre et al. PNAS 2005
Vehicle
Vehicle
Clenbuterol
Vehicle
Clenbuterol
Vehicle
Clenbuterol
Vehicle
ARC PROTEIN (Band Density)
1.5
1
*
0.5
0
Vehicle
Vehicle
Clenbuterol
Vehicle
Lidocaine
Vehicle
Posttraining Intra-BLA treatment
Amygdala Activity (PET)
During Encoding and LongTerm Explicit Memory
r = + 0.93
12
10
8
Number of Films Recalled
6
4
2
0.03
0.04
0.05
0.06
0.07
Right Amygdala Glucose
Cahill, et al
1996
0.08
Enhanced memory of emotianal material in human
subjects with deletion of of alpha-2b adrenoceptor
de Quervain et al. 2007
Initiation of Memory Consolidation
Learning
Experience
Cortex
Hippocampus
Basolateral
Amygdala
Caudate Nucleus
NE
Other Brain Regions
Modulating Influences
Epinephrine
Adrenal Gland
Glucocorticoid
“The usefulness of all of the passions consists
in their strengthening and prolonging in the soul
thoughts which are good for it to conserve…
And all the harm they can do consists in their
strengthening and conserving these thoughts
more than is necessary.”
Descartes, The Passions of the Soul, 1650
Stress Hormones and Development of
Posttraumatic Stress Disorder
Pitman, Sanders, Zusman, Healy, Cheema, Lasko, Cahill and
Orr, Pilot Study of Secondary Prevention of Posttraumatic
Stress Disorder with propranolol, Biological Psychiatry, 2002.
Viava, Ducrocq, Jezequel, Averland, Levestal, Brunet and
Marmer, Immediate treatment with propranolol decreases
posttraumatic stress two months after trauma. Biological
Psychiatry, 2003.
Holbrook et al. Morphine used after combant injury in Iraq and
postraumatic stress disorder. New England Journal of
Medicine, 2010.
But … What about superior
autobiographical memory?
Other subjects with
highly superior
autobiographical
memory…..
The end