Recorded: 01 Aug 2003
Well, this is the functional equivalent of photographic memory. We’ve all known people who can memorize a verse of Shakespeare in one evening and they got it. And they can remember it perfectly well every day thereafter. Whereas schmucks like me have to practice every night for two weeks in order to commit it to memory if at all. That’s exactly what was happening with the flies. A normal fly needed ten training sessions with a rest in-between them in order to form a long term memory of this ODOR SHOCK association, but the CREB transgenic flies could form that long term memory from only one training session. It was amazing! This was the first genetic manipulation in any animal, the first in history that created a supra-normal memory. And again as my buddy Jeff Hall said at that time with some hubris, that result brought the psychology of memory to its biological knees.
And what he meant, of course, is that because it was a gene and because it was molecular biology and molecular biological techniques that were being manipulated into the lab to have this enhancing effect on memory, it suddenly became clear to everyone that memory was just another biological process that could be manipulated with all the approaches and tools that we have been doing for cancer genes and everything else in the modern age of molecular biology. That was a watershed event. It told everybody that this can be tackled and we will learn specific things about specific types of cognitive dysfunction in animal models and eventually humans.
Research Highlights: Finding Genes Involved with Long Term Memory (5)
It has been reproduced in various other species in particular rodents and mammals. Other labs, like Eric Kandel’s, for instance, have been studying the cell biology of CREB in neurons at that level. And they’ve shown that the underlying cell biology of a neuron when it’s learning something new and forming a long-term memory is also controlled by CREB in a way that makes sense.
CREB is involved in a growth process that makes the connections between neurons stronger. That’s been shown to be enhanced when CREB is enhanced genetically in the aplysia model. So it really does look like CREB is acting as a control switch for when memory is induced and the effect of forming long-term memory is to grow a stronger connection between neurons.
So all of that has been shown. CREB has been studied now in various regions of the brain, including the cortex. It appears to be generally involved in this form of cellular plasticity that underlies memory formation. So the original observations from flies appear to be generally true, and evolutionarily conserved up into mammals, which is important for one of the other things that we have done.
Now in the meantime, if CREB is a transcription factor that means that it’s regulating the expression of other genes, other downstream genes, which presumably are the effectors that produce the growth at the connection between neurons which underlies the appearance of long term memory. My lab since 1994 [and] 1995 has been involved in two types of approaches to try to identify more of these downstream genes that are involved in forming a long-term memory. It’s taken a lot of people many years to make some progress in, but to date we have found sixty new genes by making memory mutants, screening behaviorally and then cloning the genes, and we’ve been using DNA microarrays to see changes in gene expression levels that result during memory formation in a normal fly. And there’s overlap between those two approaches which means that we found legitimate new downstream players involved in this process of growth and memory formation.
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.