ASSESSMENT OF MEMORY IN NEURODEGENERATIVE MICE MODELS J.M. LASSALLE

11th ISN-IBRO AFRICAN NEUROSCIENCE SCHOOL

ASSESSMENT OF MEMORY IN ASSESSMENT OF MEMORY IN NEURODEGENERATIVE MICE MODELSNEURODEGENERATIVE MICE MODELS

J.M. LASSALLE J.M. LASSALLE

Outline of presentationOutline of presentation

• Memory systemsMemory systems• What kinds of memory are impaired in What kinds of memory are impaired in

neurodegenerative diseases neurodegenerative diseases • Mouse models for Alzheimer's diseaseMouse models for Alzheimer's disease• A recent mouse model of TauopathyA recent mouse model of Tauopathy• Some experimental paradigms for the study Some experimental paradigms for the study

of cognitive impairmentsof cognitive impairments• Examples of results with Tg2576 (Examples of results with Tg2576 (-amyloid -amyloid

pathology, P301L, a model of Tauopathy, pathology, P301L, a model of Tauopathy, and R6/2 mice expressing the Human and R6/2 mice expressing the Human Huntington's disease mutationHuntington's disease mutation

LONG-TERM

REFERENCE

Min to hours

MEMORY

SHORT-TERM

(Working-Memory)

FRONTAL CORTEX

DECLARATIVE

EXPLICIT

(Representational)

NON-DECLARATIVE

IMPLICIT

(Procedural)

SEMANTIC

(Facts)

EPISODIC

(Events)

ASSOCIATIVE

(Conditioning)

EMOTIONAL

RESPONSES

(Fear)

PROCEDURAL

(Skills & Habits)

PRIMING

(Influence of unconscious

presentation of elements)

MUSCULAR

RESPONSES

(Eye blink)

NON-ASSOCIATIVE

LEARNING

- habituation

- sensitization

TEMPORAL LOBE STRIATUM

CORTEX & NEOCORTEX AMYGDALA CEREBELLUM

Taxonomy of memory: adapted from Tülving and from Squire and Knowlton

REFLEX

PATHWAYS

Cortex & neocortex

Limbic sytem

Hindbrain

Neurodegenerative Neurodegenerative diseases with cognitive diseases with cognitive

impairmentsimpairments

• AlzheimerAlzheimer

• ParkinsonParkinson

• HuntingtonHuntington

• Lewy bodiesLewy bodies

• Vascular dementia Vascular dementia

• Prion pathologiesPrion pathologies

What kinds of memory impaired ?What kinds of memory impaired ?

DiseaseDisease System SStructuretructure Cognitive Cognitive impairmentsimpairments

AlzheimerAlzheimer CholinergicCholinergic neocortexneocortex Working memoryWorking memory

HippocampusHippocampus Episodic memoryEpisodic memory

AmygdalaAmygdala Spatial memorySpatial memory

Executive functionsExecutive functions

ParkinsonParkinson DopaminergicDopaminergic StriatumStriatum Working memoryWorking memory

Executive functionsExecutive functions

HuntingtonHuntington GabaergicGabaergic StriatumStriatum Spatial & temporal Spatial & temporal memorymemory

AttentionAttention

LanguageLanguage

ReasoningReasoning

RecognitionRecognition

MoodMood

BehaviorBehavior

Distribution of Amyloid Distribution of Amyloid deposits deposits

in Alzheimer's brainin Alzheimer's brain

Mouse models for Alzheimer's Mouse models for Alzheimer's diseasedisease

• No spontaneous model (except microcebus), No spontaneous model (except microcebus), no comprehensive modelno comprehensive model

• Experimental models: ICV or Hippocampal Experimental models: ICV or Hippocampal -amyloid A-amyloid A1-40 and A1-40 and A1-42 1-42 injections in rats. injections in rats. (See Stéphan & Phillips, 2005, G2B, (See Stéphan & Phillips, 2005, G2B, 44, 157-172 for a review), 157-172 for a review)

• Transgenic mice carrying a single or double mutations of the APP, PS1, Transgenic mice carrying a single or double mutations of the APP, PS1, PS2, APOE4, PS2, APOE4, -secretase, -secretase, -secretase and Tau human genes-secretase and Tau human genes

• APP APP PS1/PS2 PS1/PS2 Double mutantsDouble mutants APOE APOE (Chr 21)(Chr 21) (Chr 14/1)(Chr 14/1) (Chr 19)(Chr 19)

– APP-V717FAPP-V717F - PS1 cKO - PS1 cKO - APP+PS1 (S-W, B6D2F1) - APP-V717F:apoE( - APP+PS1 (S-W, B6D2F1) - APP-V717F:apoE(+/++/+))– PDAPP (D2, B6, S-W) PDAPP (D2, B6, S-W) - hPS1 Tg - hPS1 Tg - PSAPP (C3H/B6) - PSAPP (C3H/B6)– Tg 2576 (B6, SJL) Tg 2576 (B6, SJL) - hPS1 Tg (FVB/N) - hPS1 Tg (FVB/N) - APPxPS1(-/-)(FVB/N) - APPxPS1(-/-)(FVB/N)– APP23 (D2, B6) APP23 (D2, B6) - hPS2 Tg (BDF1) - hPS2 Tg (BDF1) - PS2APP (B6xD2) - PS2APP (B6xD2)– TgCRND8 (C3H/B6)TgCRND8 (C3H/B6)– J20 (D2, B6)J20 (D2, B6)– APP KO (B6)APP KO (B6)

-Secretase-Secretase -Secretase-Secretase TauTau (Chr 17)(Chr 17)

- BACE1 KOBACE1 KO - APP/RK (FVB/N) - APP/RK (FVB/N)- hBACE1 TghBACE1 Tg - ADAM KO - ADAM KO - P301L- P301L- BACE1BACE1-/--/- Tg2576 Tg2576++ (B6, SJL) (B6, SJL) - ADAM10xAPP (FVB/N) - ADAM10xAPP (FVB/N)

(For a review, see Kobayashi & Chen, 2005, G2B, (For a review, see Kobayashi & Chen, 2005, G2B, 44, 173-, 173-196)196)

A mouse model of TauopathyA mouse model of Tauopathy- Rtg (tau301L)4510 mouse expresses the P301

mutation in Tau, associated with fronto-parietal dementia and parkinsonism linked to Chr 17

- Transgene expression driven by a forebrain specific Ca2+ Calmoduline Kinase II promoter resulting in high levels of expression in the neocortex and hippocampus

- Expression induced via the tetracycline-operon responsive element and suppressed after treatment by doxycycline

- NFT pathology is first observed in the neocortex and progresses into the hippocampus and limbic structures with increasing age

- Cognitive impairments from 4 months of age- Forebrain atrophy, prominent loss of neurons

mainly in CA1- 129/FVB1 background

Ramsden et al. A novel mouse model of human Tauopathy. J. Neurosci. 2005, 25, 10637-10647Ramsden et al. A novel mouse model of human Tauopathy. J. Neurosci. 2005, 25, 10637-10647

Age-dependant forebrain Age-dependant forebrain degeneration in rTg (Tau p301L) degeneration in rTg (Tau p301L)

4510 mice4510 mice


Massive neuronal loss in the Massive neuronal loss in the hippocampus (and pre-frontal cortex), hippocampus (and pre-frontal cortex),

Neuro Fibrillary Tangles and GFAP-Neuro Fibrillary Tangles and GFAP-positive reactive astrocytespositive reactive astrocytes


Progression of Neuro Fibrillary Tangle Progression of Neuro Fibrillary Tangle Pathology in rTg(Taup301L)4510 brainPathology in rTg(Taup301L)4510 brain


Progression of NFT pathology in rTg(tauProgression of NFT pathology in rTg(taup301Lp301L)4510 brain. Formation of )4510 brain. Formation of Bielschowsky silver positive NFTs in the cortex and CA1 area is age Bielschowsky silver positive NFTs in the cortex and CA1 area is age dependant and consistant with cortical and hippocampal atrophydependant and consistant with cortical and hippocampal atrophy

INFERRING COGNITIVE IMPAIRMENTS INFERRING COGNITIVE IMPAIRMENTS FROM BEHAVIORAL PERFORMANCE IMPAIRMENTSFROM BEHAVIORAL PERFORMANCE IMPAIRMENTS

Studying cognition: MEASUREMENT VALIDITY

• Cognitive processes cannot be directly measured, they can only be inferred from the analysis of behavioral performances, expressed in experimental situations.These measures can be biased by uncontrolled factors

• The way these experimental paradigms are chosen and designed is crucial for the validity of these inferences

• To be valid, these paradigms must be based :- on extensive knowledge of the ethology and the ecology of model organisms- on accurate hypotheses upon the cognitive and neural processes that support behavior- on the certitude that there is no bias due to locomotion or emotionality or whatever

Forms of memory impaired Forms of memory impaired in neurodegenerative in neurodegenerative

diseasesdiseases

• Working MemoryWorking Memory

• Reference MemoryReference Memory

• Spatial memorySpatial memory

• Memory for familiar placesMemory for familiar places

• Configural vs Associative MemoryConfigural vs Associative Memory

The functions of spatial The functions of spatial memory are essentialmemory are essential

• Navigating towards a remote place (homing, using transports)

• Remembering a set of remote places (daily life places)

• Recognizing familiar places and detecting (spatial) changes

• Planning a route (shortcut, detour)

Some Experimental Paradigms Some Experimental Paradigms For The Study of Cognitive For The Study of Cognitive

impairmentsimpairmentsWorking Memory Working Memory - Delayed (Non-) Matching to Sample (D(N)MS)- Delayed (Non-) Matching to Sample (D(N)MS)Executive functions : Executive functions : - T-maze Continuous Alternation Task- T-maze Continuous Alternation Task

Spatial memory:Spatial memory: - Morris navigation task (location in LTM)- Morris navigation task (location in LTM)- Olton radial maze (list of places in WM)- Olton radial maze (list of places in WM)- Open-field with objects (spatial novelty)- Open-field with objects (spatial novelty)

Configural (Episodic-like)Configural (Episodic-like) memory:memory: - Contextual-fear conditioning- Contextual-fear conditioning

Non hippocampo-dependant versions of these tasks:Non hippocampo-dependant versions of these tasks:- Cued navigation task (associative)- Cued navigation task (associative)- Open-field with objects (object novelty)- Open-field with objects (object novelty)- Associative Tone-fear conditioning- Associative Tone-fear conditioning

T- maze continuous alternation T- maze continuous alternation tasktask

• Prefrontal cortex / alternation

• Hippocampus / memory delay

Access to certain compartments of the maze (black areas) can be blocked by lowering guillotine doors. Exploratory paths and direction of locomotion are indicated by the lines and arrow-heads inside the maze. The sequence of test-phases are indicated by letters.

T-maze alternation in mice expressing T-maze alternation in mice expressing the Human Huntington's disease the Human Huntington's disease

mutationmutation

R6/2 mice are R6/2 mice are impaired in T-maze impaired in T-maze spontaneous spontaneous alternationalternation

Lione et al., Progressive learning deficits in R6/2 mice. J. Neurosci., 1999, 19, 10428-10437Lione et al., Progressive learning deficits in R6/2 mice. J. Neurosci., 1999, 19, 10428-10437

T-maze alternation in mice expressing T-maze alternation in mice expressing the Human sweedish Alzheimer's the Human sweedish Alzheimer's

disease mutationdisease mutation

Percentage of Percentage of spontaneous alternatiojn spontaneous alternatiojn in the Y-mazein the Y-maze

(Mean (Mean ± S.E.M.)± S.E.M.)

Ognibene et al., Behav. Brain Res. ,2005, 156, 225-232Ognibene et al., Behav. Brain Res. ,2005, 156, 225-232

*

MORRIS NAVIGATION TASKMORRIS NAVIGATION TASK

The Morris navigation paradigm uses a circular swimming pool, 120 cm in The Morris navigation paradigm uses a circular swimming pool, 120 cm in diameter, filled with water made opaque with an opacifier diameter, filled with water made opaque with an opacifier

Mice are dropped into the water from a different point at each trial, and Mice are dropped into the water from a different point at each trial, and they are trained to locate and climb onto a platform which is hidden they are trained to locate and climb onto a platform which is hidden beneath the surface of the waterbeneath the surface of the water

In the In the spatial version of the taskspatial version of the task, mice need to learn to navigate towards the , mice need to learn to navigate towards the platform, using distal cues available in the room around the swimming-platform, using distal cues available in the room around the swimming-poolpool

In the In the cued version of the taskcued version of the task, the platform is either visible, or when , the platform is either visible, or when submerged, its position is indicated by a proximal cue (a flag attached to submerged, its position is indicated by a proximal cue (a flag attached to the platform or a signal hanging above the platform)the platform or a signal hanging above the platform)

There are two different learning (memory) components in the spatial task.

- To learn to find the platform, the mouse needs to learn the procedural and sensory motor components of the task : “there is a platform where I can rest on, somewhere in the pool, at a certain distance from the wall, and I have to swim efficiently to find it”And that may be enough, for the mouse to improve its latency to find the platform

- But to swim straight to the platform, whatever its starting point, the mouse has to learn also the spatial component of the task : i. e. the spatial location of the platform, using distal cues to build a cognitive map of the place.

To ensure that mice have built and stored in their memory a spatial representation to locate the platform, the experimenter needs to use a spatial probe test :

- After training, the platform is removed from the pool and the mouse is allowed to swim for one minute. The swimming path of the mouse is videotaped and it is then fairly easy to verify if the mouse searches at the right place

For that, one needs, for instance, to count the number of times the mouse crosses an annulus surrounding the place where the platform used to be, and to compare with the mean crossings of three other control annuli placed in the other three quadrants of the pool

LEARNING COMPONENTS OF THE NAVIGATION TASK

SPATIAL PROBE TESTSPATIAL PROBE TEST

Morris navigation task in Morris navigation task in mice expressing the Human mice expressing the Human

Huntington's disease Huntington's disease mutationmutation

Escape latencies in the visible, hidden Escape latencies in the visible, hidden and platform reversal tasksand platform reversal tasks


Impairments of Morris water maze learning in R6/2 mice Impairments of Morris water maze learning in R6/2 mice (Escape latency (A), path length (B) and Swimming speed (C)) (Escape latency (A), path length (B) and Swimming speed (C)) during acquisition of visible, hidden and reversal learningduring acquisition of visible, hidden and reversal learning

-R6/2 Tg mice were unimpaired in the visible platform taskR6/2 Tg mice were unimpaired in the visible platform task

- On the other hand, they were severely impaired in the spatial On the other hand, they were severely impaired in the spatial task task

-Their initial performance did not differ, indicating that R6/2 mice Their initial performance did not differ, indicating that R6/2 mice did not show any nonspecific sensory impairmentdid not show any nonspecific sensory impairment

-R6/2 mice were also impaired in reversal place learning of a R6/2 mice were also impaired in reversal place learning of a hidden platformhidden platform

- Although swimming speed was only slightly decreased in R6/2 Although swimming speed was only slightly decreased in R6/2 mice, during reversal trials, the difference became significantmice, during reversal trials, the difference became significant

Morris navigation task in Morris navigation task in mice expressing the Human mice expressing the Human

Huntington's disease Huntington's disease mutationmutation

Spatial probe testSpatial probe testImpairment of probe trial performance in Impairment of probe trial performance in R6/2 miceR6/2 mice

A - During the probe trials, R6/2 and A - During the probe trials, R6/2 and control groups spent significantly > 25% control groups spent significantly > 25% of their time in platform quadrant, of their time in platform quadrant, suggesting that all mice had learned le suggesting that all mice had learned le location of the platform location of the platform

B – However, R6/2 mice crossed less B – However, R6/2 mice crossed less frequently the exact location of the frequently the exact location of the platform, indicating impaired precision of platform, indicating impaired precision of spatial memoryspatial memory

C – R6/2 mice spent significantly more C – R6/2 mice spent significantly more time in the external outer zone and time in the external outer zone and significantly less time in the middle pool significantly less time in the middle pool zone than control micezone than control miceLione et al., Progressive learning deficits in R6/2 mice. J. Lione et al., Progressive learning deficits in R6/2 mice. J. Neurosci., 1999, 19, 10428-10437Neurosci., 1999, 19, 10428-10437

http://www.jneurosci.org.gate1.inist.fr/content/vol19/issue23/images/large/ns2393655002.jpeg

Chen et al., Nature, 2000, 408, 975-979Chen et al., Nature, 2000, 408, 975-979

A new water maze protocol: the platform is moved to a new location as soon as A new water maze protocol: the platform is moved to a new location as soon as the mouse quickly and reliably reaches the platform. Numerous locations are the mouse quickly and reliably reaches the platform. Numerous locations are used successivelyused successively

-Earlier locations of the platform are encoded in LT memory, potentially causing Earlier locations of the platform are encoded in LT memory, potentially causing interferenceinterference

-Memory retrieval must therefore be selective to the most recently encoded Memory retrieval must therefore be selective to the most recently encoded location, an "episodic-like" component of the tasklocation, an "episodic-like" component of the task

Age related and age-Age related and age-independent deficits independent deficits in spatial learning in in spatial learning in

PDAPP micePDAPP mice


(a) (a) PDAPP Tg mice show a significant PDAPP Tg mice show a significant age-related impairment of learning age-related impairment of learning performance (trials to criterion for performance (trials to criterion for five successive platform locations), five successive platform locations), compared to non-Tg control mice (b)compared to non-Tg control mice (b)

(c) PDAPP mice show lower (c) PDAPP mice show lower performance in learning the first performance in learning the first location (that is not age dependant)location (that is not age dependant)

(d) Whereas there is age dependant (d) Whereas there is age dependant deficit in learning as the number of deficit in learning as the number of reversals increasedreversals increased

Path taken by representative Path taken by representative animals in learning the 5th animals in learning the 5th location at each of the three ageslocation at each of the three ages

Note similar Note similar patterns in PDAPP patterns in PDAPP and non-Tg mice at and non-Tg mice at 6-9 months, but 6-9 months, but circuitous path circuitous path taken by PDAPP taken by PDAPP mice on some trials mice on some trials at 13-15 and 18-21 at 13-15 and 18-21 monthsmonthsChen et al., Nature, 2000, 408, Chen et al., Nature, 2000, 408,

975-979975-979

The relationship between performance The relationship between performance and and -amyloid plaque deposition-amyloid plaque deposition


RADIAL MAZERADIAL MAZE

The radial maze exploits the ability of rodents to memorize a The radial maze exploits the ability of rodents to memorize a list of feeding places (Olton) in spatial Working Memorylist of feeding places (Olton) in spatial Working Memory

At the beginning of the session, the eight arms are baited with At the beginning of the session, the eight arms are baited with little pieces of food. When the food has been eaten from a little pieces of food. When the food has been eaten from a place, it is not baited again. Rats and mice can learn rapidly to place, it is not baited again. Rats and mice can learn rapidly to avoid to return to these arms (which would be considered an avoid to return to these arms (which would be considered an error)error)

Working Memory and Reference Working Memory and Reference Memory errors on the Radial maze Memory errors on the Radial maze

TaskTask

• Working Memory ErrorWorking Memory Error: returning to a : returning to a place already visited during the same place already visited during the same training sessiontraining session(The subject has to memorize the list of (The subject has to memorize the list of already visited places, that has to be reset already visited places, that has to be reset at the beginning of each new learning at the beginning of each new learning session)session)

• Reference Memory ErrorReference Memory Error: If some : If some particular arms are never baited from particular arms are never baited from session to session, visiting those arms session to session, visiting those arms constitutes a reference (long term) memory constitutes a reference (long term) memory errorerror

Non spatial strategiesNon spatial strategiesand measurement validityand measurement validity

• Mice can develop strategies to avoid Mice can develop strategies to avoid returning to an already visited placereturning to an already visited place– Algorithmic strategies ( clockwise strategy)Algorithmic strategies ( clockwise strategy)– Use of odor trails Use of odor trails

• Non spatial (palliative) strategies may Non spatial (palliative) strategies may appear in mice that are unable to use appear in mice that are unable to use spatial representations to orientate, or spatial representations to orientate, or when such an ability is impaired during when such an ability is impaired during aging or in neurodegenerative diseasesaging or in neurodegenerative diseases

LEARNING PERFORMANCES

IN THE RADIAL MAZE NON- CONFI NEMENT PROCEDURE

0

2

4

6

8

10

12

1 2 3 4 5

LEARNING SESSIONS

ERRO

RS

CBA NC

NZB NC

C3H/He NC

BALB/c NC

CB6F1 NC

C57BL/6 NC

DBA/2 NC

B6D2F1 NC

Roullet & Lassalle, 1992, Behav. Brain Res., 48, 77-85

Roullet & Lassalle, 1995, Physiol. Behav., 88, 1189-1195

LEARNING PERFORMANCES

IN THE RADIAL MAZE

CONFI NEMENT + RANDOM ROTATI ON

PROCEDURE

0

2

4

6

8

10

12

TRIAL 1 TRIAL 2 TRIAL 3 TRIAL 4 TRIAL 5

LEARNI NG SESSI ONS

ERRO

RS

CBA

NZB

C3H/He

BALB/c

CB6F1

C57BL/6

DBA/2

B6D2F1

AA (A (A 1-40 and A 1-40 and A 1-43) infusion 1-43) infusion model of Alzheimer's disease in model of Alzheimer's disease in

the ratthe ratWorking memory Working memory deficit in a spatial deficit in a spatial learning task in the learning task in the RAM, and inhibited LTP RAM, and inhibited LTP induced by HFS in the induced by HFS in the dentate gyrus in vivodentate gyrus in vivo

In contrast, rats who In contrast, rats who received the amyloid received the amyloid injection injection andand a daily a daily treatment of non-treatment of non-steroidal anti-steroidal anti-inflammatory drug inflammatory drug showed similar showed similar performances as performances as controls and a rescue controls and a rescue of the decrement in of the decrement in LTPLTP

Stéphan & Phillips, G2B, 2005, 4, 157-Stéphan & Phillips, G2B, 2005, 4, 157-172172

SPATIAL NOVELTY SPATIAL NOVELTY

OPEN-FIELD WITH 3 IDENTICAL OBJECTSOPEN-FIELD WITH 3 IDENTICAL OBJECTS

Mice are exposed to 3 unknown Mice are exposed to 3 unknown object introduced in a familiar object introduced in a familiar environment, and allowed to explore environment, and allowed to explore them across different sessions. The them across different sessions. The objects have either a linear or objects have either a linear or triangular arrangement. Exploratory triangular arrangement. Exploratory contacts of the objects decrease as contacts of the objects decrease as the mouse habituates to themthe mouse habituates to them

After habituation has occurred, the After habituation has occurred, the objects are moved to the other objects are moved to the other spatial arrangement and mice are spatial arrangement and mice are checked for their reactions to checked for their reactions to spatial spatial noveltynovelty (exploration renewal) (exploration renewal)

OBJECT NOVELTYOBJECT NOVELTY

OPEN-FIELD WITH 3 IDENTICAL OBJECTSOPEN-FIELD WITH 3 IDENTICAL OBJECTS

Later on, one object is replaced by an unfamiliar object and reactions ofLater on, one object is replaced by an unfamiliar object and reactions of

mice to object novelty are assessed.mice to object novelty are assessed.

Spatial novelty reactions are hippocampus dependent, whereas Spatial novelty reactions are hippocampus dependent, whereas objectobject

noveltynovelty reactions do not need a functional hippocampus. reactions do not need a functional hippocampus.

SPATIAL OPEN-FIELD SPATIAL OPEN-FIELD Version WITH 5 DIFFERENT Version WITH 5 DIFFERENT

OBJECTSOBJECTS

OPEN-FIELD + ObjectsOPEN-FIELD + ObjectsMean Mean ± s.e.m. time spent in ± s.e.m. time spent in contact with objects by wild-type contact with objects by wild-type and Tg2576 miceand Tg2576 mice

Upper panel: Reaction to object Upper panel: Reaction to object displacement is measured as displacement is measured as time spent in contact with either time spent in contact with either displaced (DO) or non-displaced displaced (DO) or non-displaced (NDO) objects in session 5 minus (NDO) objects in session 5 minus session 4session 4

Lower panel: Reaction to object Lower panel: Reaction to object substitution is measured as time substitution is measured as time spent in contact with either spent in contact with either substituted (SO) or Non-substituted (SO) or Non-substituted (NSO) objects in substituted (NSO) objects in session 6 minus session 5session 6 minus session 5

Ognibene et al., Behav. Brain Res. ,2005, Ognibene et al., Behav. Brain Res. ,2005, 156, 225-232156, 225-232

The contextual fear The contextual fear conditioning paradigmconditioning paradigm

Tone (CS)Tone (CS)Foot shock (US)Foot shock (US)

ENDENDCS + USCS + US

CSCS

ENDEND

USUS

End End CS + ISCS + IS

t0 (min)t0 (min) 2 min2 min 2.5 min2.5 min 4.5 min4.5 min 5 min5 min 5.5 min5.5 min

t0 (min)t0 (min) t4t4

Freezing scanned every 5 sec

24 h laterTest to the context

t0 (min)t0 (min) t2 t2 t4 t4

Freezing scanned every 5 sec

Tone

2h laterTest to the tone

The fear conditioning response The fear conditioning response ::

freezing freezing

Freezing scores of - naïve (Stayed in their home cage, no Freezing scores of - naïve (Stayed in their home cage, no sound, No footshock), and sound, No footshock), and

- conditioned mice- conditioned miceDaumas et al, 2004, PhD ThesisDaumas et al, 2004, PhD Thesis

Contextual fear Contextual fear conditioningconditioning

in APP Tg2576 micein APP Tg2576 miceCONTEXTUAL FEAR CONDITIONING

Tg 2576 Wild-typeGENOTYPE

0

20

40

60

80

100

120

% F

reez

ing

TONEMODCONTCONTEXT

FREEZING TO:

***

Lassalle et al. in Lassalle et al. in preparationpreparation

Mean Mean ± S.E.M. freezing ± S.E.M. freezing frequencyfrequency

Freezing level to the Freezing level to the context is decreased in context is decreased in Tg 2576 mice Tg 2576 mice

whereas they do not whereas they do not differ from wild-type differ from wild-type controls for freezing to controls for freezing to the modified context the modified context and to the toneand to the tone

The elevated plus-mazeThe elevated plus-maze

Panel A: Percentage amount Panel A: Percentage amount of time (mean of time (mean ± S.E.M.) ± S.E.M.) spent by Tg 2576 transgenic spent by Tg 2576 transgenic and control mice in the and control mice in the open-arms as a function of open-arms as a function of total time (3 min x 3 total time (3 min x 3 repeated measures)repeated measures)

Panel B: Number of crossings Panel B: Number of crossings (mean ± S.E.M.) between (mean ± S.E.M.) between open arms during 3 min open arms during 3 min repeated measures in a 9 repeated measures in a 9 min. sessionmin. session

Elevated plus-maze: Behavioral Elevated plus-maze: Behavioral desinhibitiondesinhibition

Ognibene et al., Behav. Brain Res. ,2005, 156, 225-232 Ognibene et al., Behav. Brain Res. ,2005, 156, 225-232

Geno: p< 0.05

Geno X Time: p= 0.06

Schematic representation of the earliest age of Schematic representation of the earliest age of onset of impairment in spatial, visual, reversal and onset of impairment in spatial, visual, reversal and

alternation learning in R6/2 (Huntington) micealternation learning in R6/2 (Huntington) mice


NEUROBIOLOGIC AND NEUROGENETIC BASES NEUROBIOLOGIC AND NEUROGENETIC BASES

OF SPATIAL AND CONTEXTUAL COGNITIONOF SPATIAL AND CONTEXTUAL COGNITION

http://cognition.ups-tlse.frhttp://cognition.ups-tlse.fr

Pr. J.M. LassallePr. J.M. Lassalle

Pr. B. FrancèsPr. B. Francès

Dr. C. RamponDr. C. Rampon

Dr. P. RoulletDr. P. Roullet

H. Halley (IE)H. Halley (IE)

I. Massou (IE)I. Massou (IE)

G. Latil (Tech)G. Latil (Tech)

L. Verret (Post-doc)L. Verret (Post-doc)

S. Daumas (Doct)S. Daumas (Doct)

A. Bétourne (Doct)A. Bétourne (Doct)

UMR 5169

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ASSESSMENT OF MEMORY IN NEURODEGENERATIVE MICE MODELS J.M. LASSALLE