email tully@cshl.edu, phone (516) 367-8455, fax (516) 367-8496

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 will likely 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. 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. 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 produced a “photographic” memory in fruit flies.

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.

Asztalos, Z., Arora, N., and Tully, T. 2007. Olfactory jump reflex habituation in Drosophila and effects of classical conditioning mutations. J. Neurogenet. 21: 1–18.

Xia, S., Miyashita, T., Fu, T.-F., Lin, W.-Y., Wu, C.-L., Pyzocha, L., Lin, I.-R., Saitoe, M., Tully, T., and Chiang, A.-S. 2005. NMDA receptors mediate olfactory learning and memory in Drosophila. Curr. Biol. 15: 603–615.

Tully, T., Bourtchouladze, R., Scott, R., and Tallman, J. 2003. Targeting the CREB pathway for memory enhancers. Nat. Rev. Drug Discov. 2: 267–277.

Bourtchouladze, R., Lidge, R., Catapano, R., Stanley, J., Gossweiler, S., Romashko, D., Scott, R., and Tully, T. 2003. A mouse model of Rubinstein Taybi Syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. Proc. Natl. Acad. Sci. USA. 100: 10518–10522.

Dubnau, J., Chiang, A.-S., Grady, L., Barditch, J., Gossweiler, S., McNeil, J., Smith, P., Buldoc, F., Scott, R., Certa, U., Broger, C., and Tully, T. 2003. The staufen/pumilio pathway is involved in Drosophila long-term memory. Curr. Biol. 13: 286–296.