Memory

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

Interesting stories:

Extraordinary memory of Luria's subject Sherashevsky.

Fig. Box 31C
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

RNA

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.

Hollywood

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

Protein

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. 31.7
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. 31.8
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 - 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
Alzheimers
treatments

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 - 2007 relating to this outline

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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