Visuo-spatial Memory in APP Transgenic Mice Mark Good School of Psychology Cardiff University
Dec 28, 2015
• 90-95% are sporadic late-onset forms of AD• 5% are early onset - Mendelian inheritance: Mutations APP, PS1 & PS2
Early- & Late-onset Forms of AD: Amyloid hypothesis
Amyloid Cascade HypothesisHardy & Allsop (1991)
APPswe Tg2676 model
From : Kawarabayashi et al., 2001
K670N/M671L “Swedish” mutation
No cell lossNo Tangles
Within-subject Longitudinal Assessment of T-maze Performance
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4 8 12
Age (Months)
% Correct
Tg2576
WT
Tg2576 Mice Show Age-dependent Impairment in Spatial Memory
Consistent: Spatial MemoryWatermazeRadial Arm MazeT-Maze
Arendash et al., 2001Kotilinek et al., 2002King & Arendash, 2002Westerman et al., 2002Ho et al., 2004Lesne et al., 2006
Hippocampus
Room A Room B
F F
Context/Room Discrimination II
Aged Tg2576 do not show a global non-specific learning deficit
Barnes, Hale & Good, Behav Neurosci, (2004)
Intra-maze Visual Discrimination
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Day
Percent Accuracy
Tg2576WT
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1 2 3 4 5 6 7
2 Day Blocks
Percent Correct
Tg2576WT
What aspect(s) of spatial memory is impaired in Tg2576 mice?
Navigation theories specify different strategies.
O’Keefe & Nadel (1978) - allocentric vs egocentric
Hippocampus Striatum
Location
Response
F
Hale & Good, 2008
Impaired Allocentric Learning but Spared Egocentric Learning in aged Tg2576 mice
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Session
Mean % Correct
WTResp Tg2576Resp WTPL Tg2576PL
How does the APP mutation influence spatial memory in Tg2576 mice?
Object Exploration Paradigm
Exploration reflects a mismatch between current sensory experience and a stored representation(memory) or a prior event.
1. Object Memory?
2. Object-Location Memory?
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Novel Familiar Novel Familiar Novel Familiar
2 Minutes 30 Minutes 24 hr
Mean Contact Time (s)
WT
Tg2576
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2 Minutes 30 Minutes 24 hr
Mean Pref Ratio
WT
Tg2576
Intact Object Memory in Aged Tg2576 Mice
Hale & Good, Behav Neurosci, (2005)
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Different Same
Mean Contact Time (s)
WT
Tg2576
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WT Tg2576
Mean Pref Ratio
Hale & Good, Behav Neurosci 2005
Impaired Object Location Memory
Dissociable components of object location memory
Object-in-place
Object-location
(Dix & Aggleton, 1999)
?Independent of object identity
a b
c d
a c
b d
Sample Test
Experiment 1
a b
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a b
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Experiment 2
a b
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Experiment 3b a
d c
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a e
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b d
Novelty
Familiar object ->
familiar location
Familiar object-> novel location
Novel objectand a novel location
a b
c d
Familiar object-> novel location
Familiar object-> familiar location
Good & Hale, Behav Neurosci. 2007
0.4
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Object Novelty Familiar Object &Location
Familiar Object &Novel Location
Novel Object &Location
Mean Preference Ratio
WT Tg2576
a ef d
a cb d
Novelty Detection
Experiment 1
Good & Hale, Behav Neurosci. 2007
0.4
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Object Novelty Familiar Object &Location
Familiar Object &Novel Location
Novel Object &Location
Mean Preference Ratio
WT Tg2576
a ef d
a cb d
a bc d
a cb d
Objects moved to familiar location
Experiment 1
Good & Hale, Behav Neurosci. 2007
0.4
0.5
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Object Novelty Familiar Object &Location
Familiar Object &Novel Location
Novel Object &Location
Mean Preference Ratio
WT Tg2576
a bc d
a
d
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c
a d
f
e
Objects moved to a novel location
Experiment 1 Experiment 2
Good & Hale, Behav Neurosci. 2007
0.4
0.5
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Object Novelty Familiar Object &Location
Familiar Object &Novel Location
Novel Object &Location
Mean Preference Ratio
WT Tg2576
a bc d
a
d
b
c
a d
f
e
Objects moved to a novel location
Experiment 1 Experiment 2Good & Hale, Behav Neurosci. 2007
0.4
0.5
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0.8
0.9
Object Novelty Familiar Object &Location
Familiar Object &Novel Location
Novel Object &Location
Mean Preference Ratio
WT Tg2576
a bc d
a
d
b
c
a d
f
e
Objects moved to a novel location
Experiment 1 Experiment 2Good & Hale, Behav Neurosci. 2007
Objects moved to novel locations
Experiment 3Good & Hale, Behav Neurosci. 2007
A B
C D
AB
CD
Sample Test
A B
C D A
B
C
D
Objects moved to familiar locations
Experiment 3Good & Hale, Behav Neurosci. 2007
Sample Test
Prediction: Tg2576 < WT: Object-> Familiar Locations Tg2576 = WT: Object -> Novel Locations
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Novel Location Familiar Location
Mean Preference Ratio
WTTg2576
Specific impairment in object-in-place memory in Tg2576 mice
Experiment 3
a b
c d
b a
d c
d b
c a
a b
c d
Good & Hale, Behav Neurosci. 2007
Novel Familiar
Spared Spatial MemoryMemory for object-locations(independent of object identity)
Impaired Spatial MemoryMemory for object-in-place associations(conjunctive representation of object and place)
Computational/Anatomical Locus?
Characteristics of Object Spatial Memory in Tg2576 mice
Impairments in entorhinal/dentate gyrus inputs to the hippocampus may underlie the deficits in spatial memory in Tg2576 mice
Impairments in dentate gyrus spine density observed early during development in Tg2576 mice
Jacobsen et al., 2006, PNAS,103 (13), 5161-6
WT Tg2576
Hernandez-Rabaza, et al., , 2007
Dentate Gyrus Lesions in RatsImpairs T-maze but SparesObject Recognition andObject Location Memory
Dentate Gyrus Lesions Disrupt T-Maze but not Recognition Memory
ConclusionsProfile of learning processes in Tg2576 mice
1. Impaired place learning/navigation in Tg2576.2. Not a global cognitive impairment.3. Integration of object/landmark identity and location
information is impaired in Tg2576 mice.
SpeculationDisruption of entorhinal/dentate gyrus synaptic
connections/plasticity supporting pattern separation may be amongst the early pathological changes underlying memory impairments in AD.
ConclusionImpaired spatial memory despite intactlandmark recognition
deIpolyi, et al., 2007: Neurology, 69,986-997
Characteristics of Spatial Memory in early AD patients
MCI & Mild AD patients >70 yo
Hallway Navigation Task