"Throw Mama from the train a kiss, a kiss
And she throws one back from up high"
-Irving Gordon (Patti Page)

Purves et al., Chapter 31

Chapters 8 and 24 dealt with "learning" at the cellular level, sort of an extension of development.

General considerations:

Consider how important memory is in defining the human experience.
In many ways, memory seems to be like an input to the CNS, as significant as the only real input, namely sensory input.
Probably most believers' concept of an after-life relies on memories being intact.
In many ways memory formation is a continuation of development.
Forgetting (?) - intuition indicates how widespread forgetting is, but, when operant conditioning dominated American psychology, forgetting was denied - only extinction (sort of an "unlearning") existed.
Dementia - Alzheimer's syndrome is a reminder as to how fundamental memory is to the quality of human life.
The entire literature empahsizes short- and long-term memory.
Amnesia is informative: "retrograde" for period long ago (rare) vs. anteriograde, cannot learn new.
Recent memory loss, a patient might know how to play cards but not know how (s)he came to be playing that particular game.

Fig. 31.1, p. 696
Chapter emphasizes declarative memory (for facts, possibly involving language) and procedural (skill, practiced skills) memory.

Interesting stories:

Extraordinary memory of Luria's subject Sherashevsky.

Famous patient HM studied by Brenda Milner - lesion temporal lobe + hippocampus and amygdala at age 27 for epilepsy [grand mal seizures]- has anteriograde amnesia -after 50 yrs of study Milner still has to introduce herself - but HM can learn mirror drawing task (procedural memory).
Landmark Paper: WBScoville & B Milner, Loss of recent memory after bilateral hippocampus lesions, J Neurol Neurosurg Psychiat 20, 11, 1957, see also J NIH Res 8, 42-51, 1996

Another subject - NA, lesion [accidentally stabbed by roomate playing with fencing] of dorsomedial thalamus, mammillary bodies, right medial temporal lobe - amnesia like HM.

Another, RB, had ischemia with only loss of hippocampus, verified after his death.

Short-term memory-

presumably something electrical like Hebb circuits - easily disrupted, say, by electroconvulsive shock (used to treat depression).
Then there must be a consolidation for the sake of long-term memory which must involve permanent changes like changes in synapses. mRNA and protein MUST mediate change.
Retrieval is an important consideration.

Long term memory-

Biochemistry of memory got off to a terrible start


Classic (bad) papers

R. Thompson and J.V.McConnell (1955) Classical conditioning in planarian, Dugesia dorotocephala, J. Comp. Physiol. Psych. 48, 65-68.
Poor controls, not replicated
J.V.McConnell, (1962) Memory transfer through cannabalism in planarium, J. Neuropsychiat. 3 suppl 1 542-548 (eat RNA of worm that has learned, then worm knows it already)
very silly

Classic (spoof) paper

J. G. Nicholls, D. A. Baylor et al.. (i.e. the whole physiology department at Yale), Persistence transfer, Science 158, 1967:
...demonstrate the transfer of certain innate characteristics from one oscilloscope to another. Accordingly, a Tektronix Storage oscilloscope (RM 564)...was pounded with a Sears ball peen hammer (Cat. No. 28B4652) on a Fischer Lab bench (Cat. No. B158)...until all electronic components and the tube were reduced to sufficiently small pieces to pass through a filter made of 007-mesh nylon stocking (seamless). The storage oscilloscope fragments (SOF)...sprinkled over the chasis of a Tektronix 502 oscilloscope. The persistence of the afterglow was used as an index... In 18 of 33 experiments, there was an increase which was highly significant (,.001, t-test). While the average increase in persistence was not large - 3.2 msec - it nevertheless suggested that some change had been wrought in the recipient oscilloscope by the SOF. etc.


A book, (also a 1970 movie) Hauser's memory, describes events after a dead spy's RNA is transferred to gain his information.

Personal reflection.
One of the professors whose work I had to learn (to pass my Ph.D. exam) worked in this area. His graduate student was in my peer group. His research involved quickly dissecting the brain after teaching a rat in a T-maze and showing that RNA in the hippocampus changed. Before he was finished, his work was on control experiments showing that these changes might not be attributed to the maze learning experience.

In summary, RNA experiments were naively done with great optimism & poor controls


Landmark papers

B. W. Agranoff Memory and protein synthesis, June 1967 Scientific American, 115-122
long term memory must involve something like protein synthesis L. B. Flexner et al. Memory in mice analysed with antibiotics, Science, 155, 1967, 1377-1383
antibiotics like puromycin block protein synthesis
but return of memory with saline washout suggests interference with retrieval

How is memory stored in the brain?

Fig. 31.9, p. 706
Limbic system
How and where are memories stored?
Lashley - search for engram - found "equipotentiality" [in cortex] (vs. localization of function)
Pribram - it is like a hologram - everything is stored a little bit everywhere (lasers and holograms were popular science in the 1960s; half a hologram has all the information of the whole hologram, but degraded -- you have to "look around the corner" to see everything.).
The temporal lobe seems particularly important for establishment, but not storage.
Penfield - electrical stimulations

Working memory for spatial location

Fig. 31.10 p 707
Animal model of "working memory" - radial 8 arm maze put a food pellet on the end of each arm and rat uickly learns to visit each arm one time before any repeats - David Olton - rat has amazing spatial memory and hippocampal lesion disrupts that.
Personal reflection - he was an associate professor where I was an assistant professor; this demonstration, that became standard in many learning labs across the country, was the undergraduate project of Robert Samuelson, an undergraduate student, and was made by 2x4's thrown together in the wood shop. Although Scientific American was known to publish mostly articles invited from famous people, Dave broke the mold by submitting the paper (Spatial memory, June 1977, 82-98) that made their work known even in undergraduate courses across the country.

Alzheimer's disease

Box 31D - pp. 713-714
Alzheimer's disease - neurofibrillary tangles (tau) in cells and amyloid plaques (BA) outside cells -
5% are familial early onset -
beta amyloid precursor protein mutations on chromosome 21 (695-770 aa long. beta and gamma secretase cut to 42 aa fragment - bad-
presenillin 1 on chromosome 14
presenillin 2 on chromosome 1
also apolipoprotein E (E4 allele) varient (on chromosome 19) predisposes for this.
tau on chromosome 17
There is lots more information and it pours in fast these days.

More detail
several recent student presentations

Recent paper G Miller Computer game sharpens minds, Science 310, 1261, 2005
Can mental exercise help?
Garden view care center activity based dementia care

Exam questions from 2005 - 2012 relating to this outline

Hippocampal lesions interfered with performance on the radial 8 arm maze. Why was the memory this task tapped into called >working memory?<
if rat can scurry to all 8 arms without repeating one, it must remember a map short term
What does learning a mirror-drawing task say about Brenda Milners famous patient HM who had bilateral hippocampal lesions?
non-declarative task while declarative memory is lost
Rationalize why I was so dogmatic to say that mRNA must be involved in consolidation of long-term memory.
only a structural change, like in synapse efficiency, could endure and that would require protein synthesis
Mice were trained but before the memory could form, puromycin in the hippocampus interfered. What a disappointment when the mice exhibited memory when the puromycin was washed out! If it did not block consolidation, what could puromycin have blocked?
should have blocked consolidation by blocking protein synthesis, but memories formed so it must have interfered with retrieval

A pigeon learns well in a Skinner box and then is retired for many years in a home cage. Placed back in the Skinner box for the first time after many years, what is the performance like and why?

it is at the level years earlier suggesting that forgetting is not as important as extinction

"There is more RNA in the hippocampus of a rat that has gained mastery in a T-maze learning task than in a control." Say something wrong with this statement as a summary of one biochemical basis of memory.

is it mRNA being referred to? mRNA does not store memories, it funcrions according to the mechanisms of central dogma, control experiments suggested that the difference was not due to learned behabior

Patient HM, with bilateral ablation of his hippocampi, can learn a mirror drawing task. What dichotomy of types of memory does this fact address?

procedural vs declarative

Why is a rat's performance in the radial 8-arm maze considered an example of "working memory?"

each time, it must remember which of the arms it has already visited

Beta and gamma secretases cut (what?) into (what?) relevant to memory.

amyloid precursor protein into beta amyloid

What did Hebb propose that reverberatin circuits were used for?

with excitation only such a loop could hold short term memory

How is it known that Brenda Milner's tragic subject (HM, with the bilateral hippocampal lesion) does have procedural (non-declarative memory)?
he can "learn" a mirror drawing task
Storage oscilloscope fragments were sprinkled on a regular oscilloscope. The entire physiology department at Yale wrote this spoof to criticize what published "finding?"

that RNA from a flat worm that had "learned" (or cannibalism) could transfer the memory
Explain why the term "working memory" applies to the radial 8-arm maze task.
withour any defined pathway, the rat knows which of the arms (s)he has visited so as to get all 8 pellets without repeating an arm
Nobody had the slightest idea what went wrong in Alzheimer's disease for decades. Now they have identified the involvement of several non-functional enzymes. What breakthrough paved the way for this important understanding?

finding familial inheritance allowed identification of genes

With some neural damage, you might forget word meanings but still retain practiced motor skills. How does your text characterize this dichotomy?

declarative vs procedural

You've just gotten electroconvulsive shock. What are you likely to have forgotten? (Hint, the answer is not "The answer to this question.")

events during the hour before, not your earlier life

Perhaps it is true that McConnell found that Planaria that ate Planaria that had been "trained" were trained in less trials. What legitimate criticism was leveled at the claim that memory was transferred through RNA?

no controls for sensitization

Answer either (1) What did Lashley mean by "engram?" Or (2) Where did he find it to be?

the memory trace, distributed with equipotentiality throughout cortex

Why do they use the expression "working memory" for performance in the radial 8-arm maze?

each time, animal can accurately remember which of the arms visited until (s)he reaches all of them

List at least one of the products of the five most obvious genes underlying familial Alzheimer's disease?

amyloid precursor protein, presenillins 1 & 2, apolipoprotein E, tau

Even though it has been over 50 years since his famous textbook, Donald Hebb is still mentioned frequently in neuroscience. In what context?

reverberating circuits of excitation for short term memory

Why did researchers put puromycin, an antibiotic, into the brain?

blocks protein synthesis

What is the precursor for the material that makes extracellular plaques in Alzheimer's disease?
amyloid precursor protein

What was the mental defect in Brenda Milner's famous patient HM, with lesions of the hippocampus?

anterograde amnesia

Name the intracellular accumulation product in Alzheimer's disease.

neurofibrillary tangles of tau

Although "memory transfer through cannabalism" [of RNA] was debunked in planaria, mRNA must be involved in long-term memory. By what mechanism?

in mediating any long term changes in synaptic function by protein synthesis

What does Lashley's "search for the 'engram'" have to do with memory and localization of function?
memory is stored everywhere with equipotentiality

Brenda Milner's famous subject, HM (who had hippocampal lesions) ,could not remember what had just happened but could learn to draw in a mirror. What famous distinction between types of memory is addressed?

declarative vs procedural

By what mechanism would Alzheimer's disease interfere with axon transport?

the hyperphosphorylated protein, tau, regulates microtubules

Mutations in Presenilin 1, Presenilin 2, and the E4 allele Apolipoprotein are genetic risk factors. Mutations in what other protein is missing from the above list of risk factors for the accumulation of beta-amyloid plaques.

amyloid precursor protein

"Presenilins are key mediators of Notch signalling." How does that relate to Alzheimer's disease?

enzymatic cleavage of membrane proteins is not just a pathological mechanism, it causes release of intracellular domains of important signalling proteins

In what nervous system compartment are neurofibrillary tangles?

inside neuron (axon)

How do you show that a rat with a hippocampal lesion is impaired in learning to find an underwater platform?

as repeated trials go by, latency to find it goes down for control not for lesioned

How do you show that HM's nondeclarative memory is not as bad as his declarative memory?

Can perform on mirror drawing task

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