Hippocampus & Medial Temporal Lobe Functional Neuroanatomy

1. Hippocampus & Medial Temporal LobeFunctional Neuroanatomy

2. LIMBIC SYSTEM(cingulate gyrus, PHG, hypothalamus, septal area, nucleus acumbens, orbitofrontal ctx, amygdala) Broca Maclean Cingulate Gyrus Fornix Ant. Nucleus of Thal Mamillary Bodies Septal Nuclei Subcallosal Gyrus HC Olfactory bulb PHG Amygdala

3. The Medial Temporal Lobeand Hippocampus

4. What is amnesia? • Loss of memory function • Two types • Retrograde amnesia • Loss of previously-acquired (”premorbid”) memories • Anterograde amnesia • Inability to form new (”postmorbid”) memories Injury Time

5. Patient H.M. and the Human MTL • Suffered head injury @age 9 • Developed severe epilepsy • Surgeon surgically removed the medial temporal lobe bilaterally • HM suffered severe anterograde and temporally graded retrograde amnesia • Spared skill learning (Corkin, Amaral, Gonzalez, Johnson and Hyman J. Neuro, 1997) (Scoville and Milner, 1957)

6. INTRODUCTIONMedial Temporal Circuitry Sub CA 1 PRC ERC PHC DG CA 3 Fornix Hippocampus (HC) proper : Dentate Gyrus (DG), CA3, CA1, and Subiculum (Sub) Adjacent MTL cortices : Entorhinal (ERC), Perirhinal (PRC) Parahippocampal (PHC)

7. Hippocampal Molecular Mechanisms • Place cells, head direction cells, grid cells • Long-term potentiation • Neurogenesis • Microcircuitry

8. Hippocampal Place Cells (O’Keefe & Conway,1978; Wilson & McNaughton, 1993, Ekstrom et al., 2003) Reproduced from Wilson and McNaughton, 1993, Science

9. Sub CA 1 PRC ERC PHC DG CA 3 Fornix Place Cells, Head Direction Cells,Grid Cells (Hafting et al., 2005; Moser & Moser, 2007)

10. Hippocampal Molecular Mechanisms • Place cells, head direction cells, grid cells • Long-term potentiation • Neurogenesis • Microcircuitry

11. Long-Term Potentiation (Kandel et al., 2000, Principles of Neural Science)

12. Long-term potentiation • Bliss & Lomo (1973) discovered that high-frequency stimulation of neurons in the hippocampus results in lasting increase in synapse strength (known as long-term potentiation, or LTP) • LTP relies upon a kind of glutamate receptor (NMDA) • Block LTP – Block Learning

13. Hippocampal Molecular Mechanisms • Place cells, head direction cells, grid cells • Long-term potentiation • Neurogenesis • Microcircuitry

14. Hippocampal Neurogenesis (Li et al., 2000)

15. Exercise-induced increases in Dentate Gyrus CBV correlate with Neurogenesis Pereira A C et al. PNAS 2007

16. Blocking Neurogenesis produces Learning Deficits • (Clelland et al., Science, 2009)

17. Taxonomy of Long-term Memory Systems Squire L, Zola S PNAS 1996;93:13515-13522 Adapted from Squire, Knowlton 1994

18. Episodic Learning & Memory Personally experienced events within a spatio-temporal Context (Tulving, 1983, 2002)

19. INTRODUCTIONMedial Temporal Circuitry Sub CA 1 PRC ERC PHC DG CA 3 Fornix Hippocampus (HC) proper : Dentate Gyrus (DG), CA3, CA1, and Subiculum (Sub) Adjacent MTL cortices : Entorhinal (ERC), Perirhinal (PRC) Parahippocampal (PHC)

20. Imaging the Human Hippocampus is Challenging

21. High-Resolution Hippocampal Imaging HHR Structural (voxel size = .4 x .4 x 3mm) HHR Functional EPI (voxel size = 1.6 x 1.6 x 3 mm)

22. High-resolution MRI of the MTL (Zeineh, Engel, Thompson, Bookheimer Neuroimage, 2001) (Ekstrom, Bazih, Suthana, Al-Hakim, Ogura, Zeineh, Burggren, Bookheimer. Neuroimag, 2009)

23. Current Research Directions • Encoding vs. Retrieval • Match/Mismatch or Updated Encoding • Allocentric Spatial Encoding • Recollection vs. Familiarity • Pattern Separation / Pattern Completion

24. Novelty Encoding Paradigm Alternating Blocks of Novel and Repeat Pictures New New New Rest Repeat Repeat Rest Outdoor Indoor

25. Time Series for Subregions Sustained Late Activation No Activation CA 2, 3, DG CA 1 Parahippocampal Fusiform Subiculum Entorhinal

26. Face-Name Association Zeineh et al, Science, 2003 Distractor Learn Face-Name Pair Covert Name Recall Learn Recall Learn Recall Learn Recall Learn Recall D Rest D D D Rest Time 7 minutes

27. Results

28. Performance Used as a regression model for learning and retrieval.

29. Results

30. Time Courses Learn Recall

31. Encoding/Retrieval of Spatial Associations (Suthana, Ekstrom, Moshirvaziri, Knowlton, Bookheimer in preparation)

32. Recollection versus Familiarity • (R) Recollection - re-experiencing the encoding event at the time of recall, true episodic memory • (K) - Know - the feeling of familiarity that you’ve seen something before, but not remembering the exact encoding event • Not implicit because it is conscious

33. Eldridge et al 2001, 2005: Remember- Know Distinction in HC

34. R vs. K • Eldridge et al have shown the HC is selectively involved in R, not with K.

35. Current Research Directions • Encoding vs. Retrieval • Match/Mismatch or Updated Encoding • Allocentric Spatial Encoding • Recollection vs. Familiarity • Pattern Separation / Pattern Completion

36. CA1 region? • Bilateral CA1 damage results in memory impairments • (Zola-Morgan et al., 1986; Sass et al., 1995; Rausch & Babb, 1993) • Place cells & computational models • (McNaughton & Morris 1987; Lee et al. 2004; Levy 1989; Hasselmo & Schnell, 1994; Blum & Abbot, 1996) Sub CA 1 PRC ERC PHC DG CA 3 Fornix

37. CA1 region? • Bilateral CA1 damage results in memory impairments • (Zola-Morgan et al., 1986; Sass et al., 1995; Rausch & Babb, 1993) • Place cells & computational models • (McNaughton & Morris 1987; Lee et al. 2004; Levy 1989; Hasselmo & Schnell, 1994; Blum & Abbot, 1996) = comparator (match/mismatch detector) CA 1 ERC DG CA 3

38. Learning a Cognitive Map (Allocentric Spatial Encoding) EGOCENTRIC (SSP): “Learn store locations relative to starting point” ALLOCENTRIC (MSP): “Learn store locations relative to other stores” Suthana et al., Journal of Neuroscience, 2009

39. Allocentric Egocentric (Spearman’s ρ = 0.53, p = 0.02, N=18) Suthana et al., Journal of Neuroscience, 2009

40. Current Research Directions • Encoding vs. Retrieval • Match/Mismatch or Updated Encoding • Allocentric Spatial Encoding • Recollection vs. Familiarity • Pattern Separation / Pattern Completion

41. Recollection versus Familiarity • (R) Recollection - re-experiencing the encoding event at the time of recall, true episodic memory • (K) - Know - the feeling of familiarity that you’ve seen something before, but not remembering the exact encoding event • Not implicit because it is conscious

42. R vs. K • Eldridge et al have shown the HC is selectively involved in R, not with K. (Eldridge et al., Nature Neuroscience 2000)

43. Current Research Directions • Encoding vs. Retrieval • Match/Mismatch or Updated Encoding • Allocentric Spatial Encoding • Recollection vs. Familiarity • Pattern Separation / Completion

44. Pattern separation & the Hippocampus • Separation of item/episodic representations • Orthogonolization of sensory input & reduction of interference (Rolls, 1996; Norman & O’Reilly, 2003)

45. Felleman & Van Essen (1991)

46. Hippocampal CA3/DG and Pattern Separation High-res fMRI of Human CA3/DG (Bakker, Kirwan, Miller, and Stark, Science 2008)

47. Pattern Separation (CA3/DG) • (Clelland et al., Science, 2009) (Leutgeb et al., Science, 2008)

48. Conclusions • Proposed Model (Encoding) BOLD PRC Neuronal Firing ERC DG CA 3 PHC

49. Conclusions • Proposed Model (Retrieval) BOLD CA 1 Sub PRC Neuronal Firing ERC Fornix DG CA 3 PHC

50. Conclusions • Proposed Model (Allocentric / Mismatch Encoding) BOLD CA 1 Sub PRC Neuronal Firing ERC DG CA 3 PHC