Recorded: 01 Aug 2003
So, Jerry Yin who I collaborated with this on, he was a postdoc in my lab in the early 1990’s, cloned the fly CREB gene, the rat CREB gene had been cloned so it was a relatively straightforward thing to clone the fly gene. It only took four years. And as he characterized the CREB gene in flies, he realized that there were two different splice forms that gave rise to different protein isoforms, and one of which acted as an activator of gene expression, the other was a repressor of gene expression. So one essentially would act as an on switch for memory formation and the other would act as an off switch. In our fly system we have the genetic tools and techniques to genetically engineer flies, make transgenic flies that would express one form of CREB or the other, but not both. We could make these trans-genes inducible by using a heat shock promoter and put that trans-gene in an otherwise normal fly, grow them up normally without the trans-gene being expressed, and then in our experiments three hours before training them as adults, we would expose them to heat which would induce massive over expression of the trans-gene. We could train them and ask what happens when massive amounts of the trans-gene are expressed during memory formation.
We first did those experiments with CREB repressor. What we found was that our hypothesis was correct. When you over express CREB repressor and do the additional spaced training that we do to induce long term memory, long term memory was not induced in the CREB repressor transgenic flies, but they showed normal learning and early memory. Okay, so CREB was involved in long term memory formation and it was involved specifically at that step where the short term effects of cyclic AMP signaling are converted into the long term effects of CREB dependent gene transcription and translation and protein synthesis, okay.
Then we did the opposite experiment where we over expressing CREB activator, and there we saw something rather amazing. When we gave flies their usual repetitive, spaced training in the presence of CREB activator, nothing happened. They had normal memory. It didn’t make more memory and having all of that CREB activator around didn’t interfere with normal memory formation. What we saw instead was that now the protein synthesis dependent long term memory in these transgenic CREB activator flies would form after only one training session instead of the usual ten repetitive sessions that a normal fly requires to commit things to long term memory. That was very specific. That means that it was enhancing memory in a very specific way, which was to allow long-term memory to form, to be induced with less practice.
Tim Tully is a molecular geneticist, interested in finding the genetic and biological basis of memory in order to better identify pharmacological and behavioral treatments for memory loss. In 1981, he received his Ph.D. from the University of Illinois. Tully joined the Cold Spring Harbor Laboratory staff in 1991 to work on discovering genes involved with memory. He became the St. Giles Foundation Professor of Neuroscience and led the Drosophila learning and memory program. In 1998 he founded Helicon Therapeutics, Inc., a development-stage biotechnology firm that works on new therapies for memory loss and other cognition disorders. In June, 2007, Tully left Cold Spring Harbor Laboratory to become Helicon's Acting Chief Scientific Officer, and assume a key role in the Michigan-based Dart Foundation as it expands its interest in funding neuroscience research.
His work on the transcriptional factor CREB gave way to the first experimental demonstration of enhanced memory formation in genetically engineered animals. Tully works to identify genes involved with long-term memory formation. Tully has determined that by the regulation of gene expression, new, long-term memories can be formed due to the growth of new synapses.