In Drosophila, each stage in memory formation depends on a different gene

Because much is known about its genetics, the fruit fly Drosophila brings distinct advantages to the study of mechanisms of learning and memory, even though its central nervous system (which has about 100,000 very small neurons) is more complex than that of the mollusk Aplysia. Research with Drosophila has corroborated findings obtained with Aplysia, and it has added new information about stages of memory formation and the genetics of these stages.

Research on mechanisms of memory in Drosophila began when geneticist William Quinn et al. (1974) developed a method to condition groups of Drosophila. They put about 40 flies in a glass tube and let them move upward toward one of two odors that normally are equally attractive. Reaching the upper part of one tube brought an electrical shock; the other odor was not associated with shock. The group could then be tested after various time intervals for approach to each of the odors. As the procedure was refined, about 90% of the flies avoided the odor associated with shock (Jellies, 1981). The geneticists then tested mutant strains of Drosophila. In 1976 they announced the isolation of the first mutant that failed to learn to discriminate the odors, and they named it dunce (Dudai et al., 1976).

Tests showed that dunce had a real problem with learning; its deficiency was not in olfaction, locomotion, or general activity. Three more learning mutants were isolated and fondly named cabbage, turnip, and rutabaga; another mutant, amnesiac, learned normally but forgot more rapidly than normal flies did (Quinn et al., 1979). Mutants found in other laboratories were also deficient in learning. Tests with other procedures showed that the failures of these mutants were not restricted to odor–shock training but occurred as well in other tests of associative learning, although the mutants appeared normal in nonlearning behaviors.

Further research showed that memory in Drosophila has four stages, which the investigators called short-term memory, middle-term memory, anesthesia-resistant memory (ARM), and long-term memory (Dubnau and Tully, 1998). Each stage can be canceled by deficiency in one or more genes specific to that stage. Thus, this genetic research provides independent support for the existence of separate stages of memory. Although ARM has not been reported in other animals, Dubnau and Tully (1998) argue that, given the many similarities between learning in Drosophila and other animals, ARM and LTM are likely present in vertebrates as well. In Drosophila, the formation of LTM leads to the extinction of ARM, suggesting that ARM is a provisional type of consolidated memory that gates or screens the information that is passed on to the more permanent LTM (Isabel et al., 2004).

We described earlier in this chapter the cascade of neurochemical events that occurs in LTP in the mammalian hippocampus. Recall that calcium ions activate protein kinases that bind to CREB (see textbook Figure 17.23). CREB, in turn, binds to promoter regions adjacent to various proteins and regulates gene transcription to alter the cell’s function. In Drosophila, genetic disruptions of the protein kinase A pathway impair memory (Tully, 1991), and repressing CREB before behavioral training prevents the formation of LTM without affecting the formation of other memory stages (J. C. Yin et al., 1994). Conversely, boosting expression of another protein kinase that activates CREB enhances memory in flies (Drier et al., 2002). Because genetic manipulation of CREB in both mammals and flies affects LTM formation, this protein may have a long evolutionary history of participating in memory formation.

References

Drier, E. A., Tello, M. K., Cowan, M., Wu, P., et al. (2002). Memory enhancement and formation by atypical PKM activity in Drosophila melanogaster. Nature Neuroscience, 5, 316–324.

Dubnau, J., and Tully, T. (1998). Gene discovery in Drosophila: New insights for learning and memory. Annual Review of Neuroscience, 21, 407–444.

Dudai, Y., Jan, Y.-N., Byers, D., Quinn, W. G., et al. (1976). Dunce, a mutant of Drosophila deficient in learning. Proceedings of the National Academy of Sciences, USA, 73, 1684–1688.

Isabel, G., Pascual, A., and Preat, T. (2004). Exclusive consolidated memory phases in Drosophila. Science, 304, 1024–1027.

Jellies, J. A. (1981). Associative olfactory conditioning in Drosophila melanogaster and memory retention through metamorphosis. Unpublished doctoral dissertation, Illinois State University, Normal, IL.

Quinn, W. G., Harris, W. A., and Benzer, S. (1974). Conditioned behavior in Drosophila melanogaster. Proceedings of the National Academy of Sciences, USA, 71, 708–712.

Quinn, W. G., Sziber, P. P., and Booker, R. (1979). The Drosophila memory mutant amnesiac. Nature, 277, 212–214.

Tully, T. (1991). Physiology of mutations affecting learning and memory in Drosophila—The missing link between gene product and behavior. Trends in Neurosciences, 14, 163–164.

Yin, J. C., Wallach, J. S., Del Vecchio, M., Wilder, E. L., et al. (1994). Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell, 79, 49–58.

Go