Botox Sheds Light on Alzheimer's

ByLee Dye

Dec. 11, 2003 -- Could a cosmetic drug that has taken the country by storm help scientists figure out how to treat such disparate illnesses as Alzheimer's and strokes? Maybe, if you bring songbirds into the equation. Seriously.

Researchers at Wesleyan University are using botulinum toxin A, marketed under the name of Botox, to study how songbirds are able to pull off a unique miracle in the animal kingdom and regrow the brain cells that die as they age.

They are working under the hypothesis that the key to regeneration of neurons lies in singing, at least for the zebra finch, a small bird of Australian origin that spends its life trying to master the perfect song.

"We're basically asking the question, is it singing a correct song that matters in terms of regulating this process (of neuro-regeneration)?" says John Kirn, associate professor of biology and chair of the neuroscience and behavior department at Wesleyan.

Botoxed Birds

Kirn has been at this for awhile now, especially since he and fellow researchers found that a songbird that has lost its hearing tends to sing less and less, and slacks off on adding new neurons to its brain. That finding raised an intriguing question. Is the process of responding to an auditory signal, namely the sound of its own song, the key to the finch's ability to regrow neurons?

The researchers figured that if they could just deaden the finch's hearing for awhile, they could measure the impact of that auditory feedback and perhaps find an answer to that crucial question. And that's where Botox comes in.

Botox removes wrinkles, at least temporarily, by relaxing certain muscles, and that has made the drug one of the hottest items in the field of cosmetics. Other researches across the country soon found several other uses for the muscle relaxant, including everything from treating migraine headaches to curbing an overactive bladder.

While it can be deadly if taken in high doses, a small amount can be effective in relaxing muscles, and that's just what the researchers at Wesleyan were looking for.

Under the sponsorship of the National Institutes of Health, Carolyn Pytte, a postdoctoral fellow in Kirn's department, and graduate student Yi-Lo, are injecting Botox into the voice box of zebra finches. The result is temporary, but for about a month the bird can continue to sing, but really badly. Unfortunately for the bird — but luckily for the researchers — the finch can still hear its song, lousy though it may be.

And that's just the result the researchers were looking for.

"Singing is really a complicated act," Kirns says. When a bird sings to attract a mate, it has some idea what it's song is supposed to sound like. That "auditory feedback," as Kirns puts it, tells the bird whether it's singing the right tune, and that gives it a chance to correct anything that's wrong.

"Just like humans, every time a bird sings it's got some expectation of what that sound is going to be like, and so there's evidence that birds' brains are making comparisons between expected and received auditory feedback," Kirns says.

"But when the expected and received signals don't match, that creates what we would call an error signal, and then the bird presumably uses this error signal to make corrections to subsequent vocalizations."

That correction could involve regeneration of neurons, but the only way to find out would be to mess up the bird's song and see what happens. That's the role of Botox.

Learning to Sing Again

The injection introduces an error signal by making the bird sing a tune it really doesn't want to hear. The bird then struggles mightily to correct its song, and that — according to the theory — could stimulate all sorts of brain activity, including the regeneration of neurons. It's still too early to tell if that is happening but previous research suggests that it should.

Some of the birds in Kirn's lab have been deafened, and the time in their lives when the deafening occurred turns out to be crucial.

"If you deafen an adult bird, it's song will gradually degrade," he says, but if the bird is quite old, the degradation is much less than if the bird is younger. The older the bird is, the better its song, so the bird needs very little "auditory feedback" to maintain the right tune.

And that turns out to be very important because older birds produce fewer new neurons, and the decrease in production corresponds quite nicely with the decline in the bird's reliance on that auditory feedback.

The bird doesn't need to hear itself singing to maintain its song, so it doesn't need to keep fiddling with its "mental machinery," as Kirn puts it, and thus it grows fewer and fewer new neurons. In addition, fewer neurons die, so the bird has achieved a perfect balance, no longer needing to make adjustments in its level of neurons.

That would suggest — and at this point suggest is the right word — that the long effort to sing correctly is at the heart of the zebra finch's ability to grow new neurons."

Nobody in Kirn's lab is suggesting that Botox will cure Alzheimer's. But if it allows the researchers to pinpoint the precise way that the birds maintain their mental machinery as they age, that better understanding might lead to human applications further down the road. Strokes, Alzheimer's and paralysis result from, or cause, a reduction in neurons and a devastating loss of mental faculties."

So the hope here is that this kind of research will eventually help humans do what the tiny zebra finch does so easily. Just the thought of it is enough to make you want to sing.

Lee Dye’s column appears weekly on A former science writer for the Los Angeles Times, he now lives in Juneau, Alaska.

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