L2: Animal Models of Medial Temporal Lobe Amnesia

After discovery of memory deficits in HM, what did attention turn to

• trying to identify the particular regions within the medial temporal lobe that were critical for memory function

What is needed to study the specific parts?

Animals models

• with lesions of different brain regions

Why are animal models useful

1. Have similar neuroanatomy and neurophysiology to humans

2. Allows us to conduct experimental manipulations not possible on humans

   1. Specific lesions

   2. control over when lesions occur

   3. control over the stimuli to be remembered and when they occur relative to lesions

      • we know what we presented them, so know what they should be able to remember

   4. single-unit recordings

   5. pharmacological manipulations

What deficits do we need to model to model patient HM

1. Imparied in declarative/explicit memory

2. Intact short-term memory

3. Normal intellectual function

4. Preserved capcity for some forms of learning (e.g procedural learning)

Where did initial animal model studies has lesions in

Hippocampus

How to measure memory if animals cannot talk? (and affects on Hippocampal lesions)

1. Association task

2. Delayed non-matching to sample task

1. Association task procedure

1. Acquisition trial

   • present with object

   • some get a reward and some do not

   • acquire the memory of the objects that are associated with reward

2. Test trial

   • test with multiple objects

   • animals should pick the object that was preivously associated with the reward

1. Results of association trials in hippocmapal lesion models

• association was unimpaired

• basically like controls

1. Why did hippocompal lesions leave performance on the association task unimpaired

Associative memory

• memory of what went together with an item

• exists to e.g associate a stimulus and reward

• Assoiciative memory is more to do with the amygdala?

• Hippocampus is needed for recognition memory instead?

Solution to these results

• need to test instead for recognition memory:

  • Ability to judge familiarity of an item

  • exists to discriminate familiar vs novel items

2. Delayed non-matching to sample test: testing recognition memory

Developed by Gaffan and Mishkin and Delacour

Sample

1. presented with sample object

2. gets reward hidden in the well if displaces the object

Test

3. Screen lowered between monkey and test tray

4. variable delay (minute or seconds)

5. presented with original object and another object

Food found under the non-matching object

5. learns that food is present under the object that differs from the sample

Therefore is recognising the known object and choosing a new one

2. How is this test not pavlovian conditioning?

• a novel stimulus is used on each trial

2. After the DNMS rule has been mastered, recognition memory abilities typically are evaluated by what

1. Increasing the delay intervals interposed between the sample presentation and choice test

2. Increasing the number of items to be remembered

What were the results of the DNMS on general MTL lesions in monkeys? And how did this model HM?

Impaired performance of the DNMS

• 8-10 seconds→ no deficits

  • HM: similar to the short term memory of HM

• Delay dependent effect→ more deficits

However, the next question to answer…

What specific structures in the MTL are supporting recognition memory?

How was this question addressed

Different surgical lesions on different parts of the MTS:

1. Bilateral aspiration of hippocampus

2. bilateral aspiration of amygdala

3. combined bilateral aspiration lesions of amygdala and hippocampus

Allowed postoperative recovery

Procedure of how these lesioned monkeys were tested

1. retained on DNMS at the 10 second delay (note: trained before surgery as a control)

2. memory challenged by increaing delay to 30,60 and 120 seconds

3. challenged further by increasing number of objects to be remembered

   • 3,5,19

Results

1. Hippocampus alone→ negligible defects

2. Amygdala alone→ negligible defects

3. Combined→ severely impaired and severely deteriorated very rapidly across delays:

   • If retrained→ could do 10 second delay accurate

   • but 30 second delay→ 70% correct

   • and hardly any more for longer delays

Critique→ already down to 30 seconds in the normal results???

What did Mishkin conclude from this

Dual route hypothesis:

• if one is damaged, the hippocampus and amygadala can compensate for eachother

How did this explain the lack of deficits in early experiment that removed the hippocampus

• suggests that the surgical approach spared the amygdala

• so the amygdala could compensate for the lack of hippocampus?

So did Mishkin find a good model for HM? (How this model matched HM)

1. impaired on several different memory tasks but ability to acquire motor skills was intact

   • Evidence: Barrier motor skill taks, lifesaver motor-skill task

     • perform as control even after a month

2. Impairment in memory included modalities other than vision:

   • tactile recognition memory also impaired

Therefore: fitted HM’s global (polymodal) amnesia

Overall Mishkin’s model has all the hallmarks of a good animal model of amnesia

1. Short term memory intact

2. Long-term memory for new info disrupted

3. Skill learning was preserved

4. No obvious deficits in intellectual function

Problem with the model→ use of aspiration lesions

Removal via pumping sections out:

• Causes some damage to brain strucutures outside the amygdala or hippocampus:

  1. perihinal cortex

  2. parahippocampal cortex

  3. Entorhinal cortex

Why was this damaged deemed unimportant at first?

1. damage not consistent from subject to subject → so would even out across data

2. removal of hippocampus and amygdala were required to produce memory impairment

   • any damage to anything else could be contributing to the memory impairment

Evidence that the extra damage is causing memory deficits: 1 Mishkin

Damage to Rhinal cortex (Rhinal sulcus)→ Entorhinal and perirhinal cortical areas:

Result:

1. Amygdala + rhinal cortex damage→ severe amnesia

2. Hippocampus + rhinal cortex damage→ much less severe impairment

   • Suggests: amnesia produced with damage to amygdala alone if rhinal was also damaged

3. Amygdala intact + damage to rhinal + hippocampus→ memory spared

   • Suggests: critical neural substances for memory in MTS are

     • amygdala and rhinal cortex

     • (not the amygdala and hippocampus)

Evidence that the extra damage is causing memory deficits: 2 (conflicting) Squire

• damage amygdala + spared overlying cortex→ no memory deficits

Conclusion:

• hippocampus + adjacent cortical areas→ ‘medial temporal lobe memory’ system is critical to memory

Evidence that the extra damage is causing memory deficits: 3

Two later studies:

• Damage to perirhinal cortex alone (no amygalda or hippocampus damage)→ severe amnesia

Were is the rhinal cortex found?

In the ventral visual system

Next questions to answer

1. Is the rhinal cortex simply providing info to other MTL structures, or supporting memory in its own right?

2. Does the amygdala and hippocampus make unique contribution to memory?

3. maybe temporal cortical ablations impair memory because they are removing input to the amygdala and hippocampus??

With what help could this questions be answered

• Development of surgical methods → Excitotoxic lesions

• development of Magnetic resonance imaging (MRI)

Alvarez experiment with new technology (1)

• lesions limited to hippocampus→ significant DNMS deficit

  • Crituque:

    • note: still quite small compaired to temporal cortical removal

    • only present at long delays between 10 to 40 mins

Image:

• did not impair familiarity judgments?

In contrast: Murray and Mishkin (2)

Used MRI and neurotoxic lesions

• Amygdala→ no effect on DNMS performance

• Hippocampus→ not effect on DNMS performance

What are the perirhinal cortex and hippocamus contributing to DNMS performance: need to may a distinction between Familiarity and recollection

Familiarity:

• recognition/ ‘knowing’

  • e.g you recognise a person but do not know where they are from

Recollection

• recall/ ‘remembering’

  • e.g you recognise and recollect where they are from

Taking this into account: hippocampal damage results in

no impairment to familirarity judgments

Squire’s group found what

• regardless of the lesion hippocampal damage always produced deficits on DNMS at delays of 10 mins or longer

Conclusion:

• hippocampus might be needed for DNMS at longer delays?

Therefore what are the conclusions overall?

• whether hippocampus contributes to recognition memory is still controversial

• note: this is when modelling HM

But this does not match up with patient RB

• Patient RB→ developed amnesia after ischamic accident

  • Selective damage to subregion of hippocampus→ CA1 subfield

  • no damage to rhinal cortex

  • Results: impaired DNMS

this has been modeled in monkeys and rats

What doesn’t match up to previous model:

• how can lesions to one small region of hippocampus lead to deficits on DNMS

• BUT

• removing entire hippocampus→ no deficits

Investigating this: modelling RB and full hippocampal lesions in rats and performing DNMS

1. Learn DNMS

2. Ischemia induced

3. some have full hippocampal lesion some have just a region

Result:

Full→ DNMS intact

Region→ DNMS impaired

What did Baxter and Murray find in the relationship between hippocampal lesion size and DNMS impairment?

Hippocampal lesions:

• Small hippocampal lesions→ more impaired on DNMS

• compared to larger more complete hippocampal lesions→ less impairment on DNMS

  • negative correlation between hippocampal and DNMS

Rhinal cortex lesions:

• Increased Rhinal cortex damage→ increased DNMS impairment

  • Positive correlation between rhinal and DNMS

Hypothesis of these results

Ischemia leads to ‘covert damage’:

• neuropathy not due to loss of neurons→ so does not become apparent sing standard histological techniques

• Other histopathological techniques reveal wide-ranging changes after ischaemia

What do wide-ranging changes were shown to have happened when looking at different histopathological techniques

1. Damage to Cingulate cortex

2. hyperexcitablility of surviving nuerons

3. loss of expression of certain proteins normally seen in certain populations of hippocampal cells

How does this ‘covert damage’→ confirmation in rats

Experiment and observation:

• removal of hippocampus one hour after ischaemia prevents a deficit from occurring

Hypothesis of what is happening:

• Ischemica→ cells in the hypothalamus die

• abnormal firing or epileptiform activity

• this alters the function of distant brain regions without causing cell loss:

  • e.g rewiring of the rhinal cortex

    • so does not look damaged but actually is

Overall explanation of the earlier studies being misleading in terms of contribution of the amygdala and hippocampus and the relative importance of the adjacent cortical areas (2)

1. Methods used to ablate amygdala and hippocampus damaged some perirhinal cortex during surgery

2. (More important) Amygdala and hippocampal lesions also damaged white matter tracts in the temporal lobe

   • this disconnets the temporal cortical areas from important afferent and effeerents and disabling their functions

   • (even though the cortex itself was still structurally intact)

Overall conclusion

1. DNMS have been used to model animal recognition (declarative) memory deficits observed in human amnesic patients

2. Early (aspiration) lesions

   • showed that recognition memory depends upon the MTL (possibly hippocampus and/or amygdala)

3. More specific lesioning techniques

   • showed rhinal cortex was important for recognition of memory

   • (not the hippocampus and/or amygdala)

So what does the hippocampus do?

• see next lecture

Beyond the MTL memory system: damage outside of the temporal lobe can also produce what

• Impairments in recognition memory

Why is this not surprising

• given that patients with Korsakoff’s syndrome have memory impairments consequent to diencephalic damage

• rather than medial temporal lobe damage

Studies in monkey have shed light on the neuroanatomical basis of amnesia in these cases:

1. Large midline thalamic lesions in monkeys lead to large deficits in DNMS

   • These lesions damage the anterior and dorso-medial nuclei of the thalamus

   • → produces retrograde degeneration in the mammillary bdies

2. Bilateral lesions limited to either dorso medial nuclei or anterior nuclei produce

   • →Milder effects

3. Lesions to mammillary bodies alone

   • aslo produce mild deficits