1. Associative Learning and the Monkey Medial Temporal Lobe Wendy A. Suzuki Center for Neural Science New York University

2. Ventral View of Macaque Monkey Brain rs PR ER PH

3. RL AP 14.5 HPC EC PR

4. 24/25/32 Pi Ia Id Ig Frontal LobeTemporal LobeInsular Cortex Cingulate Gyrus Parietal Lobe V4 23/29/30 7a/LIP STSdSTG TE STSv TEO 11/1246 13 DG Sub HPC 30-60% 18-29% 5-17% <5% Entorhinal Parahippocampal Perirhinal Suzuki and Amaral, 1994

5. Experimental Question: What are the neural correlates of associative memory formation in the medial temporal lobe?

6. Location-Scene Association Task Gaffan (1994) Murray and Wise (1996) Murray et. al., (1998)

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11. Location-scene association task + + + New Scenes (n = 2-4) + + + Reference Scenes n = 4 Fixation/ Baseline (300 ms) Scene/Target Presentation (500 ms) Delay (700 ms) Eye Movement Response

12. Working Hypothesis Selective changes in the patterns of activity in hippocampal neurons underlie the formation of new location-scene associations.

13. -30005001200 0 5 10 15 20 25 30 35 40 45 + Response to 3 New Scenes Baseline + + Scene/Target EM Delay Time from Scene Onset (ms) Spikes/Sec C110600

14. Probability Correct 01020304050 0 0.2 0.4 0.6 0.8 1 Behavioral Learning Curve and Delay Activity Over Time to Scene 653 Response (Spikes/Sec ) -10 0 10 20 30 40 50 Baseline Activity Trials C110600.4

15. Behavioral Learning Curve and Delay Activity Over Time for Reference Scene 67 C110600.4 02141 Response (Spikes/Sec) Trials Probability Correct -10 0 10 20 30 40 50 0 0.2 0.4 0.6 0.8 1

16. Are There Different Categories of Changing Cells?

17. 2 Categories of Changing Cells A. Sustained Changing cells: 56% of all changing cells B. Baseline Sustained Changing cells: 44% of all changing cells

18. Probability Correct 01020304050 0 0.2 0.4 0.6 0.8 1 Behavioral Learning Curve and Delay Activity Over Time to Scene 653 Response (Spikes/Sec ) -10 0 10 20 30 40 50 Baseline Activity Trials C110600.4

19. Categories of Changing Cells A. Sustained Changing cells: 56% of all changing cells B. Baseline Sustained Changing cells: 44% of all changing cells

20. Probability Correct Behavioral Learning Curve and Delay Activity Over Time to Scene 386 Response (Spikes/Sec ) Trials 0 0.2 0.4 0.6 0.8 1 14710131619222528313437 0 2 4 6 8 10 12 14 16

21. Categories of Changing Cells A. Sustained Changing cells: 56% of all changing cells B. Baseline Sustained Changing cells: 44% of all changing cells

22. What Does the Change in Neural Activity Represent?

23. Degree of selectivity was measured Using a selectivity Index (Moody et al., 1989) λ i is response to ith scene λ max is maximal response for a cell n is the total number of scenes

24. Measures of Selectivity: Sustained Changing Cells Selectivity Index BeforeAfter Learning 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 *

25. Response of a changing cell to all scenes 0 2 4 6 8 10 12 14 1112131415161718191101111 Response (Spikes/Sec ) Trials Ref 1 Ref 2 Ref 3 Ref 4 New 1 New 2 0 0.2 0.4 0.6 0.8 1 Probability Correct Learning Curve

26. Measures of Selectivity: Baseline Sustained Changing Cells Selectivity Index BeforeAfter Learning 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 *

27. What is The Time Course of the Changing Cells relative to Learning?

28. Behavioral Learning Curve and Delay Activity Over Time to Scene 653

29. Neurons that change after learning Neurons that change before learning Behavioral Change 01020304050 Neuronal Change 0 10 20 30 40 50 Neural Change vs. Learning

30. Ratio Index Before – After Before + After Ratio Index =

31. Trials to Learn -1.5 -0.5 0 0.5 1 1.5 1 - 1011 - 2021 - 30> 31 Ratio Index: Hippocampus Ratio Index

32. Where are the changing cells located?

33. Anteroposterior 2018161412108 Dorsoventral -18 -16 -14 -12 -10 -8 -6 AP 14.0 Hippocampal Recording Sites Monkey 1 Sustained Baseline Sustained Nonresponsive/nonselective Selective

34. Summary Hippocampal Changing Cells: 1.Signal new learning with changes in their stimulus- selective response properties 2. Participate throughout the early learning process 3. Are located throughout the hippocampal region

35. 2. Comparison with the Perirhinal Cortex

36. 24/25/32 Pi Ia Id Ig Frontal LobeTemporal LobeInsular Cortex Cingulate Gyrus Parietal Lobe V4 23/29/30 7a/LIP STSdSTG TE STSv TEO 11/1246 13 DG Sub HPC 30-60% 18-29% 5-17% <5% Entorhinal Parahippocampal Perirhinal (Suzuki and Amaral, 1994)

37. Selective PR Cortex (n = 2 monkeys) Hippocampus (n = 2 monkeys) 89/145 (61 %)67/104 (64 %) Changing Cells 25/89 (28%) 19/67 (28%) Sustained Baseline Sustained 4/19 (21%) 15/19 (79%) 14/25 (56%) 11/25 (44%)

38. Learning-related cells in the Perirhinal Cortex Sustained Changing Cell Probability Correct Response (Spikes/Sec) Trial Number 10203040 30 40 50 60 0.0 0.2 0.4 0.6 0.8 1.0 102030 0.0 0.2 0.4 0.6 0.8 1.0 10 15 20 25 r= -0.62 r= 0.58 Trial Number Baseline Sustained Changing Cell 40

39. What is The Time Course of the Changing Cells relative to Learning?

40. HippocampusPerirhinal Cortex Behavioral Change

41. Trials to Learn -1.5 -0.5 0 0.5 1 1.5 1 - 1011 - 2021 - 30> 31 Ratio Index: Hippocampus Ratio Index

42. -1.5 -0.5 0 0.5 1 1.5 1 - 1011 - 2021 - 30> 31 Trials to Learn Ratio Index Perirhinal Hippocampus Ratio Index: Hippocampus vs. PR

43. HippocampusPerirhinal Cortex Behavioral Change

44. Location-scene association task: + + + New Scenes FixationScene/TargetDelay Response Within Trial Analysis

45. Normalized Response Time (ms) + + FixationSceneDelayResponse Within-Trial Analysis: Sustained Cells Perirhinal Hippocampus 020040060080010001200140016001800 -0.2 0.0 0.2 0.4 0.6 0.8

46. Normalized Response Perirhinal Hippocampus Within-Trial Analysis: Baseline Sustained Cells + + FixationSceneDelayResponse 020040060080010001200140016001800 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 Time (ms)

47. HippocampusPerirhinal Cortex Behavioral Change

48. Learning Signals Across the Brain Hippocampus Cahusac et al., 1993 Wirth et al., 2003 SEF & FEF Chen and Wise, 1995a,b Premotor Cortex Mitz et al, 1991 Brasted and Wise, 2004 Striatum Brasted and Wise, 2004 Prefrontal Cortex Asaad et al., 1998 Perirhinal Cortex Yanike et al. 2005

49. Neurons that change after learning Neurons that change before learning Behavioral Change 01020304050 Neuronal Change 0 10 20 30 40 50 Neural Change vs. Learning

50. 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 LeadSame Time Lag Proportion PM Putamen SEF 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 LeadSame Time Lag HPC (Wirth) HPC (Cahusac) HPC (Wirth/Wise) Population Response: Sustained cells Neural activity relative to behavior

51. 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 LeadSame Time Lag Proportion PM Putamen SEF 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 LeadSame Time Lag HPC (Wirth) HPC (Cahusac) HPC (Wirth/Wise) Population Response: Sustained cells Neural activity relative to behavior 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 LeadSame Time Lag Perirhinal

52. 24/25/32 Pi Ia Id Ig Frontal LobeTemporal LobeInsular Cortex Cingulate Gyrus Parietal Lobe V4 23/29/30 7a/LIP STSdSTG TE STSv TEO 11/1246 13 DG Sub HPC 30-60% 18-29% 5-17% <5% Entorhinal Parahippocampal Perirhinal (Suzuki and Amaral, 1994)

53. Summary HPC and PR exhibit similar proportions and categories of changing cells. HPC and PR exhibit a similar temporal relationship between learning and neural activity PR signals learning during the scene period of the task while the HPC signals learning during the delay

54. Sylvia Wirth Marianna Yanike

55. Suzuki Laboratory Sylvia Wirth Stephen Leonard Postdoctoral Fellows Students Technicians Marianna Yanike Nilda Nystrom Cindy Chiu Collaborators Emery N. Brown Loren M. Frank Anne C. Smith Eric Hargreaves Emin Avsar

56. 24/25/32 Pi Ia Id Ig Frontal LobeTemporal LobeInsular Cortex Cingulate Gyrus Parietal Lobe V4 23/29/30 7a/LIP STSdSTG TE STSv TEO 11/1246 13 DG Sub HPC 30-60% 18-29% 5-17% <5% Entorhinal Parahippocampal Perirhinal Suzuki and Amaral, 1994