Spatial relational learning persists following neonatal hippocampal lesions in macaque monkeys

1. Spatial relational learning persists following neonatal hippocampal lesions in macaque monkeys Pierre Lavenex, Pamela Banta Lavenex, and David G Amaral Volume 10|Number 2| February 2007| Nature Neuroscience

2. Background

3. 1. Procedural learning: The unconscious learning of a skill, such as a series of actions or perceptual processing functions (for example, learning to ride a bike), which typically results in increased speed or accuracy with repetition. 2. Primining: A behavioral change that is manifested in the speed or accuracy with which a stimulus is processed following prior exposure to the same stimulus 3. Classical conditioning: If the CS and the US are repeatedly paired, eventually the two stimuli become associated and the organism begins to produce a behavioral response to the CS. Nat Rev Neurosci. 9:182-94. 2008

4. 1. Episodic memory is the memory of unique personal experiences (events, times, places, and associated emotions) that can be put in language. 2. Semantic memory refers to the memory of meaning, understandings, and other concept-based knowledge unrelated to specific experiences. Nat Rev Neurosci. 9:182-94. 2008

5. Spatial memory 1. Spatial memory involves allocentric (spatial relational) and egocentric coding of space. 2. Spatial memory has often been considered in the context of episodic memory, and has also been considered in the context of semantic memory. Nat Rev Neurosci. 9:182-94. 2008

6. Objective • Previously, they showed that selective hippocampal damage prevented spatial relational learning in freely moving adult monkey. • Here, they test the ability of juvenile monkeys with neonatal hippocampal lesions to learn new spatial relational information.

7. Materials and methods • 16 infant macaque monkeys (8 controls, 8 lesions). • Hippocampal-lesion surgeries performed 12-16 d after birth. • Reared in a cohort consisting of six mother-infant pairs and one adult female, and they met >3 h/day, 5 d/week. • Weaned when the youngest one reached at 6 months, and then housed in a cohort with one adult male and a new adult female. • Tested each day (5 d/week), between 7:30-11am (Monkeys were about 18.6 years old).

8. Pre-training 5d Each, 61X66X81cm 1. Pre-training: Monkeys were pre-trained in temporary holding cages for 5 d (20 trials per day until they successfully retrieved grapes in <30 s on all trials) to displace a cup to retrieve grapes.

9. Pre-training 5d Acclimation 5d 2. Acclimation: Monkeys were free to explore the open-field arena for 5 d, 5 min each day (no cups, no grapes). Monkeys randomly entered and exited the arena from one of the four entrances.

10. Poster Pre-training 5d Acclimation 5d 12 11 1 Local cue conditioning Mainly egocentric 13 3 trials/day, 2 w 10 2 18 14 3 9 17 15 4 8 16 5 7 6 3. Local cue conditioning: To test the ability to find food at fixed locations, blue cups (4, 8, 12) marked potentially-baited locations on the outer array, red cups (13, 15, 17) on the inner array. Others were covered with neutral cups.

11. Poster Pre-training 5d Acclimation 5d 12 Only allocentric 11 1 Local cue conditioning 3 trials/day, 2 w 13 10 2 18 14 3 9 Spatial relational conditioning 17 15 3 trials/day, 2 w 4 8 16 5 7 6 5. Spatial relational condition: To assess monkeys’ reliance on a spatial relational memory to discriminate these locations in relation to distal environmental cues, (such as posters). Neutral cups covered all locations.

12. Pre-training 5d Acclimation 5d 12 11 1 Local cue conditioning 3 trials/day, 2 w 13 10 2 18 14 Probe trial 1 trial 3 9 Spatial relational conditioning 17 15 4 8 16 5 7 Local cue conditioning 6 3 trials/day, 2 w 6. Two steps repeated Spatial relational conditioning 3 trials/day, 2 w

13. Poster Pre-training 5d Allocentric Acclimation 5d 12 11 1 Local cue conditioning Egocentric 3 trials/day, 2 w 13 10 2 18 14 3 9 17 15 4 8 16 5 7 Local cue conditioning 6 3 trials/day, 2 w Probe trial 1 trial 4. Probe trial (no grapes): To assess monkeys’ reliance on the local cues (colored cups) versus spatial relational information (surrounding environment). Colored cups were shifted 60º from the usual locations. Blue (2,6,10); Red(14,16,18). Spatial relational conditioning 3 trials/day, 2 w

14. Analysis (I) 12 PO 11 1 O 13 O 10 2 PI EO EO 18 14 EI EI 3 9 O O 17 15 PI PI 4 8 16 PO PO EI 5 7 O O 6 (I) local cue and relational conditions (II) Probe trial EO Space in (SI) Pot in (PI)--three inner baited locations (13,15,17) . Pot out(PO)--three outer baited locations (4,8,12). Space out (SO) Equ in (EI)--three inner never-baited corner locations (14,16,18). Color in (CI) Equ out (EO)--three outer never-baited corner locations (2,6,10). Color out (CO) Other (O) Other (O)--six never-baited side locations (1,3,5,7,9,11).

15. Analysis (II) • To identify strategies monkey used--The first four choice for the local cue and spatial relational trial, and all choice made during the probe trial. • To assess activity level--The number of cups being open in the each trial. • To examine lesion size and placement -Magnetic resonance images (MRI).

16. How to get this?

17. All choices 1.0 1.0 First four choices 0.8 0.8 Number of choices Number of choices 0.6 0.6 0.4 0.4 0.2 0.2 PI PO EI EO O PI PO EI EO O Analysis (III) 12 III PO 11 1 O 13 O 10 2 I PI VIII EO EO 18 14 II EI EI 3 9 O VI O 17 VII 15 IV PI PI 4 8 16 V PO PO EI 5 7 O O 6 EO

18. Results

19. Hyperactivity caused by hippocampal lesions Number of the monkey’s position among eight zones every 5s during the 5-min session ? Local cue and spatial relational conditioning Acclimation

20. 12 PO 11 1 O 13 O 10 2 PI EO EO 18 14 EI EI 3 9 O O 17 15 PI 4 PI 8 16 PO PO EI 5 7 O O 6 EO No difference in the local cue conditioning Neonatal hippocampal lesions Adult hippocampal lesions 10~13 year old ~ 18.6 months First Four Choices

21. 12 PO 11 1 O 13 O 10 2 PI EO EO 18 14 EI EI 3 9 O O 17 15 PI 4 PI 8 16 PO PO EI 5 7 O O 6 EO No difference in the spatial relational conditioning Neonatal hippocampal lesions Adult hippocampal lesions ~ 18.6 months 10~13 year old First Four Choices

22. 12 SO 11 1 13 O O 10 2 SI CO CO 18 14 CI CI 3 9 O O 17 15 SI 4 SI 8 16 SO SO CI 5 7 O O 6 CO No difference in the probe trial Neonatal hippocampal lesions Adult hippocampal lesions ~ 18.6 months 10~13 year old ?? All Choices

23. Lesion regions shown by MRI Coronal Horizontal Sagittal Control Hippocampal

24. Conclusions Local cue conditioning Relational conditioning Probe trial Egocentric Allocentric Allo- & Egocentric • Selective hippocampal prevented allocentric spatial relational learning in freely moving adult monkeys. However, new allocentric spatial relational information were unimpaired in monkeys that received lesions shortly after birth.

25. Discussion 1.Spatial memory--episodic memory The adult hippocampus is critical for the acquisition of new allocentric representations of space. 2. Spatial memory--episode-free semantic memory The adult hippocampal lesion showed impaired episode-free semantic memory. 3. However, juvenile monkey brain with hippocampal lesions shortly after birth will undergo a functional reorganization to enable the acquisition of these memories. They propose that the extra-hippocampal cortical regions, which are specialized for the maintenance and retrieval of long-term, episode-free memories will take over it.

26. Thank you!