That white-and-black-striped little bird in the pet-store cage is a zebrafinch (Poephila guttata). Whenever it hears another zebra finch singingits species-specific bird song, P. guttata responds by joining in. But thesignature tune of any other songster leaves it silent.How does the zebra finch remember the exclusive melody it learnedfrom its parents as a fledgling?Avian neurophysiologists have found that the bird laid down a uniquememory trace in its brain, expressed by a bird song-remembering gene,zif 268. That physical record of recall has been the driving grail ofneurophysiologists for decades. They named the mirage-like cerebralfootprint of memory the "engram" defined as "a physical alterationthought to occur in living neural tissue in response to stimuli."Molecular neurobiologists are bringing the engram quest a little closerto realization. Assuming that genes are indeed the source of the trace,they are analyzing the genomic effect of artificial, measurable stimulion regions of the brain involved in processing memory.One such engram-hunter is molecular geneticist Ted Abel of the Centerfor Neurology and Behavior at Columbia University's College ofPhysicians & Surgeons. Abel is co-author of a paper in the issue ofScience out today titled: "Requirement of a Critical Period ofTranscription for Induction of a Late Phase of LTP."LTP stands for "long-term potentiation," Abel told BioWorld Today."That's a memory process by which neurons change at their synapsesas a result of their experience."LTP's early phase, which lasts about an hour, he explained, isindependent of gene expression. The later, longer-lasting phasefollows, if the stimulus is stronger than the one-hour experience."The basic question we wanted to ask is `How does LTP becomestable?' The memory that lasts for days or weeks in an animal," headded, "is not likely to be maintained merely by the phosphorylationstate of an existing protein, which is transient. It's more likely to bestabilized by a change in the protein that a nerve cell makes."The senior author of the paper is neurophysiologist Eric Kandel, one ofColumbia University's distinguished professors at large. Since the1960s, he has pioneered memory studies in Aplysia, a sizableinvertebrate model of the nervous system.Kandel and Abel are exploring the role of gene transcription in thehippocampal region of the mammalian brain. A sort of relay station, itrecords memorable events temporarily, after receiving their preliminarysignal from the cortex.Stabilizing LTP, Abel suggested, can be compared to pressing the"save" button on one's computer keyboard. "The hippocampus is anintermediate phase where things are saved," he said. "You've hit thesave button; you're still in the file," he added, "But you haven't reallyput it on your hard disk, so there's no backup. The cortex is in a sensethe backup. You can always go to it; it's long-term solid."In rats, the hippocampi, one in each brain hemisphere, lie just above acerebral cavity, the lateral ventricle. "That's what makes thehippocampus attractive," Abel said. "You can inject various reagentsinto the ventricle which eventually bathes the hippocampus."He created memories in the hippocampal tissue by subjecting slices ofit to "tetanization," a series of high-voltage shocks that the tissue isn'tlikely to forget any time soon.Simultaneously with the electro-stimuli, he bathed the tissues in knowninhibitors of gene transcription, such as actinomycin. These dulyblocked the late phase of LTP."What all this implies," Abel explained, "is that there are genes that areinduced by the stimulation, and those genes then act to give a stablechange in synaptic transmission. And that's what we were aiming toshow in this paper."Conversely, he went on, "You can mimic this late phase of LTP, andenhance nerve synapses, by applying the `second messenger,' cyclicadenosine monophosphate [cAMP]. What all this is arguing," heconcluded, "is that cAMP acts to produce this long-lasting change insynaptic transmission, by modifying gene transcription. Now we needto identify which genes."Abel's next big push is to generate transgenic mice with shortmemories. They would be mutated as to a variety of transcriptionfactors presumably involved in the LTP late phase."All of this," he observed, "implies that the human genome responds tochanges in its environment. It happens, for example, every time we getan injection of body-building steroids. Building muscle anddevelopment are typical gene responses to environment."And for treating human neurological conditions," he went on, "If youcould find the right `steroid,' so to speak, to affect the hippocampusand enhance memory, then you could do that permanently."Turning from pure to applied research, Abel foresees that, "If we canidentify the transcription factors that are involved, and how theyfunction in inducing these genes, then they're real potential targets fordrugs that would have long-lasting effects, to increase memory andperformance."A lot of what's going on in our society," he continued, "with aging,and loss of memory _ if we can find a way to address these conditionspharmacologically, then it's really going to be a great improvement inquality of life. And there is a huge market _ every person over the ageof 70, and more than a few over the age of 55 who have variations ofAlzheimer's disease." n

-- David N. Leff Science Editor

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