A journey of a thousand miles begins with the first step, as the Chinese philosopher Lao-Tse is reported to have said 2,600 years ago. People have been saying it ever since. But you never hear much about the second step.
Think about it: That second step is taken by your other leg and requires the coordinated contracting of a completely different set of muscle groups, each of them on the opposite side of your body from the ones you used on the first step. There has to be some kind of switch in your brain that unconsciously transitions your exertions from one set of muscle groups to the other set. (Caution: Do not think about this while you're walking. You'll trip.)
It's not just walking that involves such "serially ordered" actions: You'd certainly want to precede that long journey by putting your pants on, a performance best executed one leg at a time. In fact, pretty much everything we do is actually a sequence of seamlessly switched component actions, carried out under the command of brain circuitry about which we know next to nothing.
And that's fine, until some aspect of said circuitry isn't working right, as occurs in various movement disorders. That's when we want to look under the hood, so to speak, at the brain's immensely complicated mesh of interwoven nerve-cell circuits, in the hopes of ferreting out and fixing the wiring that's relevant to the disorder.
The brain doesn't make this easy. Unlike the snaking bundles of insulated wires in the gizmos we humans devise, the brain's circuits never come color-coded. Only in recent years have advanced laboratory techniques allowing precise explorations of individual brain circuits become available.
In a study just published in NEURON, intrepid Stanford neuro-spelunker Rob Malenka, MD, PhD - who's teased apart brain circuitry involved in motivation, depression, friendship, addiction and more - and his Stanford colleagues applied these state-of-the-art techniques to mice.
Mice's brain wiring diagrams are remarkably similar to ours as long as we're not talking about high-level skills required for reading, doing arithmetic, telling lies and so forth. But, being four-legged creatures, mice aren't ideal subjects for studying the order in which they put on their pants.
So Malenka and his team tried a more mouse-adapted approach. Using chocolate pellets as an incentive, the team trained the mice to first poke their noses into one of two recessed ports in a wall, and then to press one of two levers. Only by performing the two tasks in order, and making the correct choices in each case, did a mouse earn a pellet paycheck. Via a combination of highly selective brain-circuit manipulations and electrophysiological and behavioral tests, Malenka's group was able to pinpoint a specific set of neural connections (running from the motor cortex to the midbrain) that was essential to the mice's proper execution of these serially ordered tasks.
The findings will help guide research into the brain malfunctions that underlie conditions such as Parkinson's disease or Huntington's disease. But of course, this is just one step in a long journey.
Previously: Obscure brain chemical indicted in chronic-pain-induced "Why bother?" syndrome, "Love hormone" may mediate wider range of relationships than previously thought, Revealed: the brain's molecular mechanism behind why we get the blues and Better than the real thing: how drugs hot wire our brain's reward circuitry
Photo by Elliott Brown