From the article by Georges Chapouthier. FROM THE SEARCH FOR A MOLECULAR CODE
OF MEMORY TO THE ROLE OF NEUROTRANSMITTERS: A HISTORICAL PERSPECTIVE

The third method, called memory transfers, was more likely to demonstrate specific effects. If trained brain extracts were in fact able to transfer memorized pieces of information from one animal to another, then a strong argument could thus be given for the existence of ’memory molecules’. This dramatic method does, however, come up against several methodological objections that will not be reviewed extensively.

A first attempt to use this method was made by McConnell and his research group on planarian worms, and will be presented below. Several reports can also be found in McConnell’s journal, entitled The Worm Runner’s Digest, kept from 1959 to 1979. The journal originally began as a laboratory documentary record, mixing serious scientific reports with lab jokes. In October 1964, the diary turned into a more lavish publication. In 1967, one half kept the name of The Worm Runner’s Digest and continued to publish humorous articles, while the other half took the more serious title of the Journal of Biological Psychology. The two halves combined to form a whole, and the journal could be turned upside down and read from both sides!

Planarian worms are capable of complete regeneration if cut into two or more pieces. They can also assimilate into their body ingested pieces of other animals of the same species, without major digestion; the phenomenon is similar to grafting, but is known as cannibalism. McConnell et al. claimed to have taught planaria several conditioning procedures. The research group argued that the conditioning remained after regeneration and using the cannibalism procedure could be transmitted from one animal to another one. The authors believed, however, that whereas regeneration could occur in water containing RNAse, the memory of this conditioning disappeared. Yet, RNA directly extracted from trained planarians seemed to be capable of ’transferring’ the acquired conditioning to naive animals. From all these data, McConnell’s group concluded that the memory of planarians was coded in RNA molecules and that these memory molecules could occasionally be transmitted from one worm to another.

As is often the case in work involving animal behavior, several biases were subsequently found in the studies and tended to undermine the provocative conclusions. The conditioning of planarians appears to be a more complex phenomenon than already thought. Such conditioning is often restricted to partial responses, far from the 100% responses of higher animals, and sometimes develops into a strange phase known as rejection of the reinforced goal. Yet the cannibalism itself was shown to modify certain behavioral responses in a way that Could appear to be conditioning - for example, hungry planarians, as could be the case for cannibalistic planarians, become more sensitive to light, which also happened to be one of the responses for conditioning chosen by McConnell et al..

These pioneer studies had induced similar results in vertebrates. In 1965, a number of research groups published data suggesting that it was possible to transfer memorized information by implanting brain extracts from donor rats into recipient rats. With the exception of Ungar, all the authors followed McConnell’s assumptions and used RNA extracts, but it was shown later that RNA could not be the agent responsible for the behavioral changes observed. Although the RNA extracts were certainly active, the effects on the planarians were probably caused by impurities in the extracts. This aspect was clearly demonstrated by the outstanding work conducted by Georges Ungar. Ungar showed that the agents responsible for the change were probably peptides, namely small proteins. In fact, the apparent memory transfer effects disappeared with either purified RNA or brain extracts treated with chymotrypsin, an enzyme able to digest proteins. Ungar then isolated from rat brain a cerebral peptide that he named scotophobin, which seemed to transfer learned fear of the dark when administered to recipient mice. When chemically synthesized, the same peptide was later shown to evoke the same behavioral actions as the natural brain peptide: mice treated with this peptide avoided dark areas. Ungar thus claimed to have isolated the first word in a chemical code for memory.

There is now a consensus on the interest of this original peptide, which is able to modify anxious behavior patterns in mice. The question arises, however, as to what the compound actually does. Is it, as suggested by Ungar, part of a chemical code for memory? Or is it simply a molecule able to modify emotions? This alternate hypothesis had already been proposed by Agranoff in 1970 at the meeting in Albuquerque, New Mexico, where Ungar presented his first data on scotophobin. Later work by Misslin et al. clearly demonstrated that scotophobin had a selective action on emotive mice, inducing marked avoidance of dark comers. The compound was therefore more likely to be an anxiolytic molecule rather than a chemical memory code word.

We can assume that, historically, the 1978 paper by Misslin et al. terminated, at least for the time being, the quest for a chemical code for memory. This conclusion does not mean that no molecule will ever be found to be involved in memory coding but rather suggests that if molecules do have a role to play in memory coding, then that role is likely to be more complex than that initially suggested by Hyden and Ungar. The idea of memory molecules acting without any direct link to the structural organization of the nerve pathways, or without structural interactions with networks such as the limbic system, seems unlikely. The structural organization of the nervous system and nerve pathways has led to modem approaches to the biochemistry of memory processes involving the action of brain neurotransmitters.

References to James McConnell