X-Message-Number: 103 From arpa!Xerox.COM!merkle.pa Mon Jun 26 18:33:15 PDT 1989 Received: from Cabernet.ms by ArpaGateway.ms ; 26 JUN 89 18:33:25 PDT Date: Mon, 26 Jun 89 18:33:15 PDT From: Subject: Re: CRYONICS mailing list #99 - Memory Mechanisms & Ischemic Damage In-reply-to: "'s message of Mon, 26 Jun 89 19:32 EDT" To: Message-ID: <> There actually is quite a bit known about the human memory mechanism. Following is a section from a paper I'm writing: MEMORY 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. REFERENCES 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. Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=103