RAT #1 IS DELIBERATE. He swims strongly, in a straight line, nose held high, obviously looking for something. Then, 11 seconds into his first trial of the day, he finds it: a pedestal an inch and a half below the surface of the water. He climbs onto it, shakes himself vigorously, and rests, his AT4 system kicking in, the extracellular matrices in his brain’s hippocampus presumably reforming and strengthening, preparing him for his next trial.
“He’s good,” says Starla Hunter, admiration in her voice. She writes some notes on a clipboard, then lifts the rat from the water, wraps him in a towel—and gently places him in the water again, but in a different section of the six-foot-diameter tank.
As he swims, looking for the pedestal, a computer monitor next to Hunter traces the rat’s movements. Whereas the lines on the computer monitor were straight and simple on his first immersion, this time the screen traces additional loops and curlicues.
Hunter is a graduate student working under WSU neurobiologists Jay Wright and Joe Harding. Wright and Harding have been working together for the last decade on a system composed of “angiotensin IV” and the “angiotensin receptor subtype IV,” a mouthful of biochemical interaction, condensed to “AT4,” that has various, and intriguing, roles in the body. Angiotensin is a messenger peptide that binds at a receptor site on a cell that recognizes such a substance and enables it to activate the cell. The brain angiotensin system in general plays a variety of nervous system functions: helping to regulate blood pressure, body fluid homeostasis, the cycling of reproductive hormones, sexual behavior, and pituitary hormones. Wright and Harding discovered the AT4 receptor subtype in 1990 and for some time concentrated on the system’s role in cardiovascular health.
But when they discovered that AT4 receptors also existed in the hippocampus, neocortex, and cerebellum of the brain, they set out on an altogether new path.
Among other roles, the hippocampus helps us develop spatial memory. It helps us find our way. How it does this, as is the case with most functions of the brain, is still generally mysterious. However, Wright and Harding are piecing together a hypothesis of how spatial memories form, key to which is a process called “neural plasticity,” the changeability of the neural system, particularly in response to experience.
Meanwhile, back at the water tank, Rat #2 is a floater. He seems to have no interest in neural plasticity, nor any inclination to perform for science. He floats quietly, nose to the side of the tank. Finally, he pushes himself away and swims aimlessly, finding the pedestal, it is clear, only by chance.
Hunter lets him rest and orient himself for 30 seconds, picks him up and wraps him in a towel, then places him in the water again. This time he strikes right out, back and forth across the tank, creating an intricately random squiggle on the computer monitor.
Definitely a “nonproductive strategy,” says Hunter.
What Hunter is examining is not the rat version of slacker aimlessness, however, but rather how the rats learn to orient themselves in the water tank and find the refuge of the pedestal. The water in the tank is kept at about 77 degrees F., not cool enough to be uncomfortable, but also not warm enough to reduce the rats’ motivation. Though they swim well, rats do not like water, and these rats had never been in water prior to their first trial a couple of days earlier. Thus, they are amply motivated, in spite of the anomalistic rat #2, to locate the hidden pedestal. Even though few of them will find the hidden pedestal on day one, by day five they have learned to use visual clues in the small room—black circles on the west wall, white squares on the north, red triangles on the east—to swim directly to the pedestal, there to shake themselves in disdain at scientists and their curious endeavors.
But their behavior in the tank and the corresponding reconfiguration going on in their little rat hippocampuses are revealing much about how the brain remembers.
Wright, Harding, and Hunter believe that the AT4 system is instrumental in helping the rat’s hippocampus remember where the pedestal is by stimulating it to degrade and reform the extracellular matrix, or ECM.
The ECM is a protein framework that holds neurons and glial cells together in the brain and spinal cord, preserving memories formed by a network of neuronal synapses.
Imagine that you are visiting a new city. You have no map, so you must venture from your hotel the first day, with no guidance, in search of coffee, like a rat swimming desperately in search of respite. You find your coffee shop, finally, but your desperation has made you careless, and you can barely retrace the route back to your hotel. However, your hippocampus is starting to change.
A network of synapses among neurons in your hippocampus is starting to form. This network is the chemical and physiological substance of your eventual memory.
IF YOU VISIT the coffee shop only once, then return to the same city after a couple of years, chances are you won’t be able to dredge up any permanent spatial memory of the shop’s location. However, if you visited the coffee shop regularly, a memory of its location probably ensconced itself firmly within your brain. Here is how Wright and Harding think it did so.
First, the matrix had to dissolve, so that the synapses between the various neurons involved could form the new memory. As your memory solidified, as the neurochemical record of buildings, street corners, and other landmarks congealed, a new network of neuronal synapses formed. The matrix then solidified, establishing a permanent memory of where to find coffee in this particular city. And where had that memory resided all this time? Harding and Wright do not think it stayed in the hippocampus, but probably retired to the neocortex. They’re working on this.
But wait, you say, what degrades the matrix so that the new spatial memory can form? That’s where the AT4 system seems to come in. Wright and Harding initially showed, in cell culture, that the AT4 system affects enzymes called matrix metalloproteinases, or MMPs, which in turn break down the matrix proteins. Hunter’s experiment, with others, is attempting to establish a biochemical and behavioral link. What they have found is that the expression of the MMPs mirrors the curve of the rats’ performance. On day three of the experiments, the rats are starting to figure out pretty well where the pedestal is located. Correspondingly, the amount of MMPs is increasing. By day four or five, they’ve got it down—and the expression of MMPs is extremely high.
So what does this mean?
More than simply a stimulus for degeneration, the AT4 system seems to be a cognitive enhancer. It seems to improve rats’ ability to form new memories. Harding and Wright have demonstrated this by manipulating the system with drugs.
First of all, they can approximate Alzheimer’s disease symptoms in rats by injecting a certain protein into their hippocampus. Prior to their work, such a procedure would have meant that the animal was doomed to a life without long-term memory.
However, Wright and Harding have been able to restore the ability of these animals to form new memories by treating them with drugs that stimulate the AT4 receptor sites. In other words, they were able to reverse Alzheimer’s-like symptoms.
They believe the improvement occurs because activating the AT4 site excites the neurons of the hippocampus and neocortex. This in turn promotes ECM breakdown and the subsequent reconfiguration of synapses—enabling new memories.
SO HAS THE CURE for Alzheimer’s been discovered in a laboratory at WSU?
Their success is with laboratory rats. Also, says Harding, they are not creating actual Alzheimer’s pathology in the rats, but merely similar symptoms.
Take heart, however, in the fact that like the rat’s, the human brain also has AT4 receptors in the hippocampus, neocortex, and cerebellum. Furthermore, these observations are supported by recent evidence that Alzheimer’s patients suffer a diminishing ability to reconfigure the ECM and thus form new synapses.
Interestingly, the drugs work only when the animals’ cognitive ability has been somehow compromised. If their memories are impaired, the drugs can reverse the effects. However, if the animals are normal, the drugs cannot improve their memory and can even be detrimental.
“My thinking,” says Harding, “is that the synaptic structure [in healthy animals] is optimized. If you start mucking around with it, it just confuses it.”
Regardless of whether Wright and Harding’s work will actually apply to Alzheimer’s symptoms in humans, they have made a significant contribution to our understanding of the brain. For one thing, prior to their work, angiotensin IV was generally dismissed as being of minor significance. In addition to its seeming to be a cognitive enhancer, the AT4 system led them into the larger realm of neural plasticity, a profoundly dramatic understanding that has overturned much of our previous belief about the brain.
“Until recently,” says Wright, “the idea was that only developing organisms could possess plasticity. Once you’re an adult, especially an older adult, you’re kind of fixed in terms of how those synapses are wired.”
Well, little did we know! Here’s where Wright and Harding’s work takes on its true significance. The very fact that they can reverse cognitive disability encourages the revolution of understanding that is neural plasticity.
“The human brain is “not quite the black box it was,” says Harding, cautiously. “We know . . . some physical and biochemical changes that are happening. But it’s still not put together by any stretch of the imagination.”
IF IT TURNS OUT that their ideas are validated, however, Harding says their contribution will have been the idea that ECM is a critical component in the neuronal restructuring that leads to new memories. Which brings us back to Alzheimer’s. But there’s a catch.
“Data show that people who are cognitively active have far smaller probability of Alzheimer’s,” says Harding. “One explanation is that cognitive activity equates neuronal plasticity. Mechanisms involved in plasticity are very active in these people. If there is a problem, they can work around it.”
Mind, in other words, is no different from body. You use it or you lose it.
And think about it. If the rat model does apply, someday when you return to your old haunt, your memory a little compromised by the intervening years, and find yourself in need of coffee, maybe you can just pop a pill that will stimulate your AT4 receptors, guiding you straight to your addiction.
Actually, says Harding, he and Wright did an analogous experiment a few years ago. That’s exactly the effect the rats enjoyed, and Harding and Wright published a paper from the results.
“But we forgot it,” they say, nearly in unison, laughing.