By David N. Leff
"Use it or lose it" is a dictum that fits neatly into the retention or lapsing of memories.
Until fairly recently, neuroscientists took for gospel that brain cells, once formed at the outset of life, dwindled in old age, and were absolutely irreplaceable in between. (See BioWorld Today, Nov. 18, 1998, p. 1.)
Since the advent of neural stem cells as a source of replacement, this dogma largely has been superseded by the insight that in fact new neurons do proliferate in the brain, in at least two cerebral regions - the olfactory bulb and the hippocampus - the latter which conducts the orchestra of memory. So the question naturally arose: Does this plethora of new neurons, multiplying daily in the thousands, result in enhanced memory?
Today's issue of Nature, dated March 15, 2001, reports an affirmative answer, albeit limited to rats and to one specific type of memory. Its title: "Neurogenesis in the adult is involved in the formation of trace memories."
This seminal finding emerges from a joint research project between two behavioral neuroscientists, Elizabeth Gould, at Princeton University, and Tracey Shors, at Rutgers University. The two are co-senior authors of the paper.
"It appears," Shors told BioWorld Today, "that the new neurons become involved in memory about a week to two weeks after they are generated, and they are involved in memories normally handled by the hippocampus.
"What we wanted to know," she recounted, "is the function of these new neurons that are generated in the adult brain. It looks as if they have a role in the acquisition of certain types of new memories, and that's what we determined.
"One of the reasons we were interested in these cells to begin with," Shors continued, "is that a lot of them tend to be concentrated in the hippocampus - the part of the brain we know is involved in the acquisition of certain types of memories. Thousands of them are generated every day. What's unusual and interesting about these brain neurons is that most of them die within several weeks."
Any Rhyme Or Reason For Untimely Cell Demise?
"So we asked: Why would the brain continue to make new neurons if they're just going to die? A couple of years ago we reported that if we trained adult rats on certain learning tests, we could rescue these cells from death. Their survival was enhanced by the learning experience.
"This suggested that the cells were somehow sensitive to learning, but it didn't really tell us if they were involved in the learning process. So this Nature study takes an opposite approach: What happens if we took out the cells? Will the animals still learn? So we reduced the number of neurons by about 80 percent, using a chemical toxin that kills proliferating cells, and found that their learning was impaired in tasks requiring the hippocampus. However, they could learn other tasks that required other brain regions, such as the cerebellum.
"The task we found most effective by the reduction of cells," Shors explained, "is called trace conditioning. This is an extension of Pavlovian conditioning, where in this task the animal gets a stimulation of its eyelid, which makes it blink its eye. It's applied through an electrode implanted in the eyelid. That's called the unconditioned response.
"If we precede the stimulation with an audible tone," Shors went on, "the rat learns that the sound predicts the stimulation. So when the tone is played, the animal blinks. It hears this tone and thinks, 'That means I'm probably going to get a stimulation to my eye,' and so it blinks. In a normal conditioning task, the tone comes on and it's immediately followed by the stimulation, so it's tone/stimulation/tone/stimulation. Now in this trace-conditioning task the tone and the stimulation are separated in time - only half a second. But its task is more difficult, because now the animal has to maintain a memory trace of the tone, so it can later make the association with the stimulation.
"It's been shown in the past," Shors recalled, "that if you take out the hippocampus, the animal can't learn that task. What we've shown is that it's these specific cells in the hippocampus that are involved in this learning. These results indicate that newly generated neurons in the adult are not only affected by the formation of a hippocampal-dependent memory, but also participate in it.
"Trace-conditioning eye-blink studies are done in humans all the time to look at their ability to learn," she observed. "It's making associations between stimuli that don't occur together in time."
The co-authors conducted three in vivo experiments. "In the first one," Shors recounted, "we just wanted to see if reducing the number of cells would affect learning. And it did. It affected one type of learning, the hippocampal, but not others, such as stimuli that are not separated in time but co-occur.
"In the second experiment, we just wanted to determine whether or not other functions of the hippocampus were affected by these cell-reducing toxins. And in the third experiment we wanted to know if we let the cells recover, does learning recover? And it does."
Brain Repair, Neurodegenerative Treatment?
Shors made an added point: "The fact that the brain has this self-renewing capacity is fairly encouraging for the prospect of brain repair. And one could imagine treatment strategies that enhance proliferation of cells, and might be somehow beneficial."
Apropos brain repair, an editorial by Harvard University clinical neuroscientist Jeffrey Macklis pointed out, "If the development of immature neurons and precursor cells could be controlled, those cells might replace neurons that are dead or dying, as a result of neurodegenerative disease, stroke or spinal-cord injury, for example. But," he cautioned, "the obstacles to achieving such precise control over neuronal fate are immense."
In their ongoing research, the co-authors have "another interesting story to tell. It has to do," Shors concluded, "with sex differences. Females make more cells than males, and also learn certain memory tasks more than males. We're trying to determine the reason why." n