1. Learning, memory & amnesia
Chapter 11

2. The case of H.M. Intractable epilepsy
one generalized convulsion each week
Several partial convulsions each day
1953 surgery: Bilateral medial temporal lobectomy
temporal pole
amygdala
entorhinal cortex
hippocampus

3. Corkin et al. (1997)

4. Corkin et al. (1997)

5. Effects of Bilateral Medial Temporal Lobectomy
Convulsions were dramatically reduced
IQ increased from 104 to 118
Short-term memory (STM) intact
Temporally-graded retrograde amnesia
Severe anterograde amnesia

6. Amnesia Retrograde (backward-acting) – unable to remember the past
Anterograde (forward-acting) – unable to form new memories
While H.M. was unable to form most types of new long-term memories, his STM was intact

7. Mirror-drawing task
H.M.’s performance improved over 3 days (10 trials/day) despite the fact that he could not consciously remember the task on days 2 and 3.

8. Rotary-Pursuit Test
H.M.’s performance improved over 9 daily practice sessions; again, with no recognition of the experience

9. Explicit vs Implicit Memories
Explicit memories – conscious memories
Implicit memories – unconscious memories
Repetition priming tests were developed to assess implicit memory performance;

10. Incomplete pictures test

11. Implications of H.M.’s amnesia
Medial temporal lobes are involved in memory formation.
STM and LTM are dissociable – H.M. is unable to consolidate certain kinds of explicit memory.
the fact that he could form some memories suggests that there are multiple memory systems in the brain.

12. Medial Temporal Lobe Amnesia
Not all patients with this form of amnesia are unable form new explicit long-term memories, as was the case with H.M.
Two kinds of explicit memory:
Semantic memory (general information) may function normally while episodic memory (events that one has experienced) does not – they are able to learn facts, but do not remember doing so (the episode when it occurred)

13. Vargha-Khadem et al., (1997)
Studied three children that had bilateral temporal lobe damage early in life.
Like H.M., the children could not form episodic memory, however they did acquire reasonable levels of factual knowledge and language ability in mainstream school.

14. Effects of Cerebral Ischemia on the Hippocampus and Memory
R.B. suffered damage to just one part of the hippocampus (CA1 pyramidal cell layer) and developed amnesia
R.B.’s case suggests that hippocampal damage alone can produce amnesia
H.M.’s damage and amnesia was more severe than R.B.’s

16. Object-Recognition Memory
Early animal models of amnesia involved implicit memory and assumed the hippocampus was key
1970’s – monkeys with bilateral medial temporal lobectomies showed LTM deficits in the delayed nonmatching-to-sample test
Like H.M., performance was normal when memory needed to be held for only a few seconds (within the duration of STM)

17. Delayed nonmatching-to-sample task pretend you’re the monkey
Sample stimulus
touch it and get a yummy treat

18. 10 min delay during which other sample stimuli are presented

19. Choice phase: pick the image that is new
Another
yummy treat
Darn, no food

20. Testing object-recognition memory

21. Medial temporal lobe (MTL)

22. Delayed non-match to sample results

23. The Mumby Box

24. Object recognition in rats

25. Comparison of lesions in monkeys and rats

26. Neuroanatomy of object recognition
Bilateral removal of the rhinal cortex consistently results in object-recognition deficits.
Bilateral removal of the hippocampus produces moderate deficits or none at all.
Bilateral removal of the amygdala has no effect on object-recognition.

27. Is the hippocampus involved in object recognition memory?
The Case of R.B. suggests that the lesions of the CA1 region of the hippocampus (due to ischemia) can produce severe memory deficits
Ischemia in animal models also produces deficits in object recognition
Yet deficits in object recognition are only moderate to non-existent in other animal lesion models
Why?

28. Mumby et al. (1996)
Bilateral hippocampectomy actually blocks the damage produced by ischemia!
Explanation:
Ischemia causes hippocampal neurons to release glutamate, which produces damage outside of the hippocampus (particularly in rhinal cortex), although standard histological techniques do not show the damage follow-up functional imaging studies have confirmed the dysfunction.

29. The Hippocampus
Rhinal cortex plays an important role in object recognition.
Hippocampus plays a key role in memory for spatial location.
Hippocampectomy produces deficits on Morris maze and radial arm maze (Chapter 5)
Many hippocampal cells are place cells – responding when a subject is in a particular place

30. Theories of Hippocampal Function
O’Keefe & Nadel (1978) Cognitive map theory – constructs and stores allocentric maps of the world
Rudy & Sutherland (1992) Configural association theory – involved in retaining the behavioral significance of combinations of stimuli
Brown & Aggleton (1999) is involved in recognizing the spatial arrangements of objects

31. Synaptic Mechanisms of Learning and Memory
What is happening within the brain structures involved in memory?
Hebb – changes in synaptic efficiency are the basis of LTM
Long-term potentiation (LTP) – synapses are effectively made stronger by repeated stimulation

32. Long Term Potentiation (LTP)
You have two kinds of glutamate receptors. AMPA receptors (green) are responsible for typical activation or fast neurotransmission. This causes a depolarization of the membrane potential. NMDA receptors (orange) are not typically activated first. In fact, NMDA receptor activation is dependent on prior depolarization of the membrane via AMPA receptor activation. This is because magnesium ions (light green) block the NMDA channel and depolarization of the membrane is the only thing that can release the block. So high frequency stimulation first depolarizes the postsynaptic membrane through AMPA receptor activation and then activates NMDA receptors. NMDA receptor activation causes an influx of calcium, which in turn activates calcium calmodulin kinase and other second- messengers. This completes the induction of LTP. What happens next during expression and maintenance is still debated, with evidence supporting three possibilities. 1) the potentiation is caused by increased release of glutamate, 2) new AMPA receptors are recruited to synapses to increase the amplitude of the postsynaptic response to glutamate, or 3) some evidence suggest that structural changes may occur including new synapse formation.

33. Cross-section of the NMDA receptor complex
This cross-section through the NMDA receptor shows that there are different sites (left) that recognize different substrates. On the right are some drugs that alter NMDA receptor function by interacting with different modulatory sites on the NMDA receptor complex. Green labels are agonists and Red labels are antagonists. Note that there are actually two glutamate sites, one that binds NMDA (an agonist site) and another close by site that binds AP-5, which is referred to as a competitive antagonist even though we now now that it doesn’t compete for same binding site as glutamate and NMDA. Noncompetitive antagonists, such as MK-801, act at the PCP site within the ion channel and are called channel blockers. Other sites, e.g., glycine and polyamine, are located on the receptor surface.