1 / 30

Visuo-spatial Memory in APP Transgenic Mice

Visuo-spatial Memory in APP Transgenic Mice. Mark Good School of Psychology Cardiff University. Early- & Late-onset Forms of AD: Amyloid hypothesis. 90-95% are sporadic late-onset forms of AD 5% are early onset - Mendelian inheritance: Mutations b APP, PS1 & PS2.

damon
Download Presentation

Visuo-spatial Memory in APP Transgenic Mice

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Visuo-spatial Memory in APP Transgenic Mice Mark Good School of Psychology Cardiff University

  2. Early- & Late-onset Forms of AD: Amyloid hypothesis • 90-95% are sporadic late-onset forms of AD • 5% are early onset - Mendelian inheritance: Mutations b APP, PS1 & PS2 Amyloid Cascade Hypothesis Hardy & Allsop (1991)

  3. APPswe Tg2676 model K670N/M671L “Swedish” mutation No cell loss No Tangles From : Kawarabayashi et al., 2001

  4. Tg2576 Mice Show Age-dependent Impairment in Spatial Memory Hippocampus Consistent: Spatial Memory Watermaze Radial Arm Maze T-Maze Arendash et al., 2001 Kotilinek et al., 2002 King & Arendash, 2002 Westerman et al., 2002 Ho et al., 2004 Lesne et al., 2006

  5. Room A Room B F F Aged Tg2576 do not show a global non-specific learning deficit Intra-maze Visual Discrimination Context/Room Discrimination II Barnes, Hale & Good, Behav Neurosci, (2004)

  6. 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

  7. Impaired Allocentric Learning but Spared Egocentric Learning in aged Tg2576 mice Location F Response Hale & Good, 2008

  8. 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?

  9. Testing Object and Location Memory in Mice Exposure Test ? D 10 min 10 min

  10. Intact Object Memory in Aged Tg2576 Mice Hale & Good, Behav Neurosci, (2005)

  11. Object Location Memory Sample Test

  12. Impaired Object Location Memory Hale & Good, Behav Neurosci 2005

  13. Dissociable components of object location memory Object-in-place Object-location Independent of object identity ? (Dix & Aggleton, 1999)

  14. Sample Test a e a c b d f d Experiment 1 Novelty Familiar object -> familiar location a b a c c d b d Experiment 2 b Familiar object -> novel location Novel object and a novel location a a b c d d c f a a b d c d e Experiment 3 a b b a Familiar object -> novel location Familiar object -> familiar location c d d c a b d b c d c a Good & Hale, Behav Neurosci. 2007

  15. a c b d Novelty Detection a e f d Experiment 1 Good & Hale, Behav Neurosci. 2007

  16. a c b d a b a c c d b d Objects moved to familiar location a e f d Experiment 1 Good & Hale, Behav Neurosci. 2007

  17. b f a a a b d c d d c e Objects moved to a novel location Experiment 1 Experiment 2 Good & Hale, Behav Neurosci. 2007

  18. b f a a a b d c d d c e Objects moved to a novel location Experiment 1 Experiment 2 Good & Hale, Behav Neurosci. 2007

  19. b f a a a b d c d d c e Objects moved to a novel location Experiment 1 Experiment 2 Good & Hale, Behav Neurosci. 2007

  20. A B C D Objects moved to novel locations Sample Test B A D C Experiment 3 Good & Hale, Behav Neurosci. 2007

  21. A B C D Objects moved to familiar locations Sample Test D B C A Prediction: Tg2576 < WT: Object-> Familiar Locations Tg2576 = WT: Object -> Novel Locations Experiment 3 Good & Hale, Behav Neurosci. 2007

  22. a b b a a b d b c d c a c d d c Specific impairment in object-in-place memory in Tg2576 mice Novel Familiar Experiment 3 Good & Hale, Behav Neurosci. 2007

  23. Characteristics of Object Spatial Memory in Tg2576 mice Spared Spatial Memory Memory for object-locations (independent of object identity) Impaired Spatial Memory Memory for object-in-place associations (conjunctive representation of object and place) Computational/Anatomical Locus?

  24. Impairments in entorhinal/dentate gyrus inputs to the hippocampus may underlie the deficits in spatial memory in Tg2576 mice

  25. Impairments in dentate gyrus spine density observed early during development in Tg2576 mice WT Tg2576 Jacobsen et al., 2006, PNAS,103 (13), 5161-6

  26. Dentate Gyrus Lesions Disrupt T-Maze but not Recognition Memory Dentate Gyrus Lesions in Rats Impairs T-maze but Spares Object Recognition and Object Location Memory Hernandez-Rabaza, et al., , 2007

  27. Conclusions • Profile of learning processes in Tg2576 mice • Impaired place learning/navigation in Tg2576. • Not a global cognitive impairment. • Integration of object/landmark identity and location information is impaired in Tg2576 mice. • Speculation • Disruption of entorhinal/dentate gyrus synaptic connections/plasticity supporting pattern separation may be amongst the early pathological changes underlying memory impairments in AD.

  28. Thanks to: Karen Ashe Paul Chapman (GSK?) Philip Barnes Gemma Hale

  29. Characteristics of Spatial Memory in early AD patients Hallway Navigation Task MCI & Mild AD patients >70 yo Conclusion Impaired spatial memory despite intact landmark recognition deIpolyi, et al., 2007: Neurology, 69,986-997

  30. Episodic-like Memory is impaired in aged Tg2576 Mice A B D B Place & Order C D C A Deficit reflects impaired spatial (object-location) memory Good, Hale & Staal,Behav Neurosci (2007)

More Related