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From arpa!Xerox.COM!merkle.pa Mon Jun 26 18:33:15 PDT 1989
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Date: Mon, 26 Jun 89 18:33:15 PDT
Subject: Re: CRYONICS mailing list #99 - Memory Mechanisms & Ischemic Damage
In-reply-to: "'s message of Mon, 26 Jun 89 19:32 EDT"
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There actually is quite a bit known about the human memory mechanism.
Following is a section from a paper I'm writing:


It is reasonable to ask whether the important structural elements
underlieing human memory and human personality are likely to be preserved
by cryonic suspension.  Clearly, if human memory is stored in a physical
form which is destroyed by freezing, then cryonic suspension won't work.
In this section we briefly review what is known about memory, and whether
known or probable mechanisms are likely to be preserved by freezing.

To see the Mona Lisa or Niagra Falls changes us, as does seeing a favorite
television show or reading a good book.  These changes are both figurative
and literal, and it is is the literal (or neuroscientific) changes that we
are interested in:  what are the physical alterations that underlie memory?
Briefly, the available evidence strongly supports the idea that memory is
stored by alterations in the synapses between nerve cells.  Gordon Shepherd
in "Neurobiology"[38, page 547] said:  "The concept that brain functions
are mediated by cell assemblies and neuronal circuits has become widely
accepted, as will be obvious to the reader of this book, and most
neurobiologists believe that plastic changes at synapses are the underlying
mechanisms of learning and memory."  Irving Kupfermann in "Principles of
Neural Science"[13, page 812] said: "Because of the enduring nature of
memory, it seems reasonable to postulate that in some way the changes must
be reflected in long-term alterations of the connections between neurons."
Lynch, in "Synapses, Circuits, and the Beginnings of Memory"[34, page 3]
said:  "The question of which components of the neuron are responsible for
storage is vital to attempts to develop generalized hypotheses about how
the brain encodes and makes use of memory.  Since individual neurons
receive and generate thousands of connections and hence participate in what
must be a vast array of potential circuits, most theorists have postulated
a central role for synaptic modifications in memory storage."  Alkon, in
"Memory Storage and Neural Systems,"[35] says:  "The formation of
associative memories appears to involve a sequence of molecular changes at
specific locations in systems of neurons."   Greenough and Bailey in "The
anatomy of a memory: convergence of results across a diversity of
tests"[39] say:  "More recently it has become clear that the arrangement of
synaptic connections in the mature nervous system can undergo striking
changes even during normal functioning.  As the diversity of species and
plastic processes subjected to morphological scrutiny has increased,
convergence upon a set of structurally detectable phenomena has begun to
emerge.  Although several aspects of synaptic structure appear to change
with experience, the most consistent potential substrate for memory storage
during behavioral modification is an alteration in the number and/or
pattern of synaptic connections."

It seems likely, therefore, that human memory is encoded by changes in
synaptic structure.  Sometimes this encoding involves the presence or
absence of a synapse, and other times it involves structural and functional
changes to an existing synapse.

What, exactly, might these changes be?  Very strong statements are possible
in simple "model systems".  Bailey and Chen, for example, actually
recovered learned memories from sea slugs (Aplysia californica) by direct
examination of the changed synapse with an electron microscope[36].  "Using
horseradish peroxidase (HRP) to label the presynaptic terminals
(varicosities) of sensory neurons and serial reconstruction to analyze
synaptic contacts, we compared the fine structure of identified sensory
neuron synapses in control and behaviorally modified animals.  Our results
indicate that learning can modulate long-term synaptic effectiveness by
altering the number, size, and vesical complement of synaptic active
zones."  Examination by transmission electron microscopy in vacuum of
sections 100 nanometers thick recovers little or no chemical information.
Lateral resolution is at best a few nanometers, and depth information
(within the 100 nanometer section) is entirely lost.  Specimen preparation
included removal and desheathing of the abdominal ganglion which was then
bathed in seawater for 30 minutes before impalement and intrasomatic
pressure injection of HRP.  Two hours later the ganglia were fixed,
histochemically processed, and embedded.  Following this treatment, Bailey
and Chen concluded that "...clear structural changes accompany behavioral
modification, and those changes can be detected at the level of identified
synapses that are critically involved in learning."

The following observations about this work seem in order.  First, several
different types of visible changes were present.  This provides redundant
evidence of synaptic alteration.  Inability to observe one type of change,
or obliteration of one specific type of change, would not be sufficient to
prevent recovery of the "state" of the synapse.  Second, examination by
electron microscopy is much cruder than proposed nanotechnological
techniques which literally propose to analyze every molecule in the
structure.  It can reasonably be presumed that further alterations in
synaptic chemistry will be detectable at the molecular level.  Third, it
seems unlikely that freezing would destroy all trace of the changes
actually observed.

Such satisfying evidence is at present confined to "model systems;" what
can we conclude about more complex systems, e.g., humans?  Certainly, it
seems safe to argue that synaptic alterations are also used in the human
memory system, that synaptic changes of different types are likely to take
place when the synapse "remembers" something, and that these changes
probably involve mechanisms similar to those used in lower organisms
(evolution is notoriously conservative).

Perhaps, however, some fundamentally new long term memory system has also
been evolved?  Even if this unlikely possibility were to prove true, any
such hypothetical system would be sharply constrained by the available
evidence.  It would have to persist over the lifetime of a human being, and
thus would have to be quite stable.  It would have to tolerate the natural
conditions encountered by humans and the experimental conditions to which
primates have been subjected without loss of memory (presuming that primate
memory is fundamentally very similar to human memory).  And finally, it
would almost certainly involve changes in tens of thousands of molecules to
store each bit of information.  Functional studies of the human memory
system suggest it has a capacity of only 10**9 bits (somewhat over 100
megabytes)[37] (though this excludes motor memory, e.g., the information
storage required when learning to ride a bicycle).  Such a low memory
capacity suggests that, independent of the specific mechanism, a great many
molecules are required to remember each bit.  It even suggests that many
synapses are used to store each bit (recall there are about 10**15 synapses
-- which implies some 10**6 synapses per bit of information stored in long
term memory).

Given that nanotechnology will allow the molecule-by-molecule analysis of
the structures that store memory, and given that such structures are large
on the molecular scale (involving tens of thousands of molecules each) then
it appears unlikely that such structures will survive the lifetime of the
individual only to be obliterated without trace by freezing.


13.  "Principles of Neural Science", second edition, by Eric R. Kandel and
James H. Schwartz.  Elsevier, 1985.

34.     "Synapses, Circuits, and the Beginnings of Memory," by Gary Lynch,
MIT press 1986.

35.     "Memory Storage and Neural Systems," by Daniel L. Alkon, Scientific
American, July 1989, pages 42-50.

36.     "Morphological basis of long-term habituation and sensitization in
Aplysia" by Craig H.  Bailey and Mary Chen, Science 220, April 1, 1983,
pages 91-93

37.      "How Much Do People Remember?  Some Estimates of the Quantity of
Learned Information in Long-term Memory," by Thomas K. Landauer, in
Cognitive Science 10, 477-493, 1986

38.     "Neurobiology," by Gordon M. Shepherd, Oxford 1983.

39.     "The anatomy of a memory: convergence of results across a diversity
of tests," by William T. Greenough and Craig H. Bailey, Trends in
Neuroscience, 1988, Vol. 11, No. 4, pages 142-147.

A postscript on nuclear changes and their relationship to memory.  It seems
likely that such changes are indeed taking place.  Indeed, given that the
nucleus of the cell plays a central role in the production of proteins, the
primary structural elements in neurons, then it would be remarkable if
significant long term structural changes could take place (e.g., the
addition, deletion, and structural alteration of synapses) without these
changes being reflected in the nucleus.  This appears to fit quite well
with the general idea that the changes significant for memory appear in
multiple places, and in multiple sub-systems.

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