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Tim Tully Professor Cold Spring Harbor Laboratory Cold Spring Harbor, NY 11724

Neurogenetic Perspective of Memory

25 February Guest Lecture for Spring 2000 Graduate Seminar:   Evolution & Learning

ABSTRACT: To understand the biological basis of memory, a neurogenetic perspective asks, "What genes in the genome, when mutated, can produce learning/memory disabilities?" An adequate answer to this question will include the identification of (i) genes involved in molecular mechanisms of cellular plasticity, (ii) genes involved in the development of underlying neural architectures and (iii) genes involved in neurodevelopment and in the ongoing function of terminally differentiated neurons. Such a comprehensive genetic etiology of memory will lead initially to a valid biological categorization of cognitive dysfunction and finally to more effective behavioral and pharmacological therapies for memory loss. Obviously, hundreds of genes likely will be involved in a complex, "emergent" function such as memory formation. Few genes, however, currently have been identified. Hence, efforts now must be focused on new gene discovery. To this end, Drosophila has become a valuable model system with which to find conserved genes involved in behavioral plasticity. Detailed studies of Pavlovian olfactory conditioning in the fruit fly have revealed behavioral properties that are quite similar to those characterized for other tasks in other vertebrate and invertebrate species. Such "functional homology" suggests common molecular mechanisms. The challenge now is to achieve a vertical integration of gene function with behavior manifestation via cellular and systems analyses. Molecular identification of Drosophila genes involved with olfactory learning supports this notion. Disruptions of several enzymatic components of the cAMP second messenger system all produce olfactory learning/memory deficits. In particular, transgenic manipulations of the cAMP-responsive transcription factor, CREB, have revealed a molecular switch for the induction of protein synthesis-dependent long-term memory (LTM). Down-regulating this switch blocks LTM, while up-regulating this switch permits the formation of LTM with less training. This "photographic" memory in fruit flies is the first case of an experimentally induced supranormal memory in history. CREB and cAMP signaling also are involved in several forms of behavioral and synaptic plasticity in rodents and mollusks. More generally, these observations demonstrate that regulation of gene expression underlies the formation of new long-term memories most likely via the growth of new synapses. This cascade of molecular and cellular events will be elucidated further with continued study of gene function in various animal model systems, thereby accomplishing a horizontal integration of biological basis of memory formation.   RELATED READING: Pinto S., Quintana D.G., Smith P., Mihalek R.M., Hou Z.-H., Boynton S., Jones C.J., Hendricks M., Velinzon K., Wohlschlegel J.A., Autsin R.J., Lane W.S., Dutta A., and T. Tully. 1999. Iatheo encodes a subunit of the Origin Recognition Complex and disrupts neuronal proliferation and adult olfactory memory when mutant. Neuron 23: 45-54. Rohrbough J., Pinto S., Mihalek, R.M., Tully, T. & K. Broadie. 1999. latheo, a Drosophila gene involved in learning, regulates functional synaptic plasticity. Neuron 23: 55-70. Dubnau, J. & T.Tully. 1998. Gene discovery in Drosophila: New insights for learning and memory. Annual Review Neuroscience 21: 407-444.   ONLINE RESOURCES: Dr. Tully's CSHL Page

OTHER SPRING 2000 SPEAKERS:   Colin Allen   .  Alan Kamil   .  Michael Fanselow   .  Leda Cosmides

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