Harry Sinnamon's lab, like most neurobiology labs, is filled with sophisticated equipment. Electrodes record the tiny electrical pulses of neurons in a rat's brain. They feed the information into a computer which tabulates and graphs data as it is received. Treadmills, video cameras and computer modeling software are all present. The tools and methods used in Sinnamon's research are as complex as any you would find on Wesleyan's campus. However, the questions that Sinnamon ultimately hopes to answer are relatively simple. What motivates organisms to move? How does desire translate into locomotion? These are the big questions that Harry Sinnamon has been trying to answer in his over 20 years of neurobiological research. It is the nature of science that hundreds, or perhaps thousands, of smaller questions need to be answered before the responses to these larger questions begin to appear. Sinnamon is focused, however, and never loses sight of his overarching questions even as he records the microscopic ticks of individual neurons.

Sinnamon's path to brain research was roundabout. He was a psychology student during his undergraduate days. He had visions of entering advertising, since he thought that would be a way to apply the psychological knowledge that he had acquired. Sinnamon was a self-described "typical college student", though. He changed course midstream and turned his interest toward neurological study. His interest in behavior and its mechanisms led him from the more clinical world of psychology to the physiological questions of biology. As Sinnamon says, "I'm essentially a biologist now, who came in through the back door, through behavior."

Sinnamon's current research centers on the initiation of stepping in anesthetized rats. The term "stepping" simply means the act of taking steps during locomotion. A rat that is walking around its cage is stepping. Sinnamon studies stepping in the anesthetized rat because it is a model. A model has the essential features of the process of interest but it is simplified and more manageable than the actual process. In the case of Sinnamon's research, the process that he is ultimately interested in is locomotion. Locomotion, however, carries broader connotations than stepping. Stepping simply means the act of taking steps with the legs. The act of locomotion involves the rat's whole body from head to tail. Stepping, on the other hand, is a phenomenon of the legs alone and is the part of locomotion that Sinnamon focuses on. When he investigates the way a rat walks, what he is really looking at are the processes that start the stepping episode, not all the other postural changes associated with locomotion.

It may seem counterintuitive that anesthetized rats can step, but they can, just not on their own. Sinnamon stimulates his research subjects to step and then studies the stepping he elicits. In most experiments, a rat is placed in a stereotaxic apparatus. A stereotaxic apparatus allows the precise placement of probes into the brain of the test subject. The rat's head and torso are held immobile by small arms and his legs are left dangling so that they can push a wheel as he steps. The apparatus ensures that the recording and stimulation electrodes in the brain aren't jostled by the animal's movements. Tickling a rat's brain in order to make him walk may not seem like much of a feat, but eliciting locomotion is hardly that simple. Besides the difficulty of identifying areas of the brain that may be responsible for stepping and the precise placement of electrodes, there is the problem, as Sinnamon says, that "even if you're [stimulating] a good site [in the brain], he may not walk because you have to warm them up a little bit." This phenomenon of "warming up" is called priming. Priming a rat for locomotion consists of giving the locomotor area of its brain more than one stimulation. In spite of the fact that both stimulations are equal in intensity, the effect is greater after the second stimulation. The first burst will cause the rat to step a little bit, the second will cause him to step a lot. It is said that the first burst "primed" the rat and allowed the greater response to the second stimulation.

"Everybody should run with [their ideas] the way that they think it should be done and see what kind of story they can tell."

But why priming? Why not just record from the neurons in the rat's brain while he is awake and actually stepping on his own? Priming is important to Sinnamon's research because it allows him to directly control the level of excitability of the rat's locomotor system. Being able to control the excitation of the rat's locomotor system allows Sinnamon to search for correlations between locomotor activity and neural activity. From the point of view of Sinnamon's research, a rat's locomotion has two parts: the neural activity that triggers the muscles and the actual physical activity of those muscles. Sinnamon can control one half of the equation, and he uses it to search for patterns and correlations in the other half.

This sort of precise stimulation allows Sinnamon and his staff to draw more meaningful conclusions from their tests. Sinnamon's research looks for correlations between cause and effect. The more exactly the causes can be controlled and manipulated, the more convincing the range of effects will be. Sinnamon says that priming is valuable because it allows him to elicit a range of highs and lows in a short period of time. In a test that studies priming for locomotion, Sinnamon can elicit a range of levels of locomotor excitation in only twenty seconds. Sinnamon compared this to a researcher who was interested in studying sleep/waking states. "If you want to understand the neurons involved in sleep, you have to let the animal go to sleep, wake up, sleep, wake up. That could take an hour and you have to be recording the correct things over that time. If you have to maintain your measurement for a long time it's harder. So I think priming is a gift."

Sinnamon's most recent and "favorite" research project is an extension of his investigation into priming. The question in his latest research effort is "How do you know if a neuron is responsible for locomotion?" Sinnamon stimulated various points in the brain in order to discern whether or not those areas had direct effect on the animal's locomotion. He stimulated the hypothalamus, an area of the brain that controls basic movements such as stepping. He stimulated the brain at a constant level over several seconds. At first, the rat showed no locomotor response to the stimulation of its brain. However, after three or four seconds, most rats began to step. Presumably, the three to four seconds of inactivity were due to the fact that the rat's locomotor system was being primed for movement and didn't begin to elicit movement until they had been properly "warmed up".

As he stimulated the hypothalamus, he simultaneously recorded the electrical activity of neurons in the brain stem. The brain stem is the portion of the brain that actually sends impulses down the spine that cause an animal's legs to move when he starts to walk. In most cases, Sinnamon found that the animal started to step within three to five seconds of the beginning of the stimulation in the hypothalamus. What he found is that some of the motor neurons, that is, the ones in the brain stem responsible for causing stepping, displayed the same gradual increase in activity that was present in the stimulation. The fact that the stimulation was gradual allowed Sinnamon to discover correlations that wouldn't have been possible with bursts of stimulation. Sinnamon looks for concomitant variation between the stimulated area and the neuron responsible for locomotion. When two things vary concomitantly, they parallel one another; when the cause changes, the effect changes in the same way. That means that if the stimulation doubles, all other things being equal, the rat should step ten times instead of five. A gradual stimulation allows for more points of comparison between cause and effect. Sinnamon found that many of the neurons in the brain stem vary concomitantly with those in the hypothalamus. This is the sort of simple correlation that allows Sinnamon to hypothesize that the neurons whose output rises and falls with the stimulation are the ones that are responsible for locomotion.

The notion of concomitant variation seems so simple and logical that it would be hard to argue with. However, discovering a simple interdependence doesn't mean that you've found the reason why something is happening. As the old scientific adage says, correlation does not equal causation. Sinnamon acknowledges that his work on this problem isn't finished. "What you really need to do, and this has to be done, is directly manipulate the system. If this is a stepping neuron, I should be able to activate it and directly facilitate stepping." In other words, Sinnamon needs to reverse his experiment in order to discover whether or not the neurons he has found are responsible for the stepping motion or if they just happen to be active during stepping.

"Patients who have not moved in ten years, will get up and run for a few steps if someone yells "Fire!" in their ward"

Besides researching locomotion in rats, Sinnamon has plans for an investigation with more concrete application for humans. A study on locomotion in a Parkinson's model is in the works for Sinnamon's lab. Parkinson's is a degenerative brain disorder that causes difficulty in all sorts of physical activities. Patients' hands shake, their posture becomes slumped and, in the latest stages of the disease, voluntary movement stops altogether in a condition called akinesia. Parkinson's is linked to a shortage of dopamine, which is a brain chemical that allows for the brain to coordinate and control movements. In a Parkinson's patient, the area

of the brain that creates and distributes dopamine is unable to deliver its payload to the brain, causing movement to gradually dry up until the patient can't move on their own. The voluntary locomotion systems are damaged, but the patient maintains other systems of locomotion. The so-called "motivational" systems are still intact. That is, the basic systems that cause humans to walk towards things they like, such as food or sex, and away from things they don't, like predators, still function. It is a bizarre truth that Parkinson's patients, who may not have moved from their wheelchairs in ten years, will get up and run for a few steps if someone yells "Fire!" in their ward. The system that causes such behavior is the defensive locomotor system. The system that would cause a patient to walk toward a cheeseburger if they were hungry is called the appetitive locomotor system. Sinnamon hopes that the appetitive system might be intact in addition to the defensive system. It is difficult to stimulate the appetitive system the same way the defensive system can be; yelling "Pizza!" is unlikely to send anyone, let alone an akinetic Parkinson's patient, sprinting to the dinner table.

Sinnamon will try to mimic the Parkinson's state in the rat by administering drugs that would cause the rat's dopamine containing cells to degenerate. He will then try to stimulate the rat's hypothalamus, an area of the brain that houses many of the motivational systems, in hopes that he can elicit locomotion. Sinnamon says he will concentrate on the appetitive portion of the brain to avoid causing the test subjects any discomfort. "I assume that when you stimulate the escape locomotion system, it feels bad. That's a big inference on my part. Granted, I'll never know how it feels, but I'd rather not stimulate in a place where I wouldn't want to be stimulated. I'd much rather stimulate in a place where I would like to be stimulated."

Such empathy for the rats that he uses in his testing seemed unusual for a scientist. I asked Sinnamon about his opinion on the recent slew of protests against animal testing in Wesleyan labs. Sinnamon replied, "Well, it happens every year to a greater or lesser extent. I think those are fundamental issues that need to be dealt with. I think that everyone who works with animals, unless they're either callous or stupid, has to deal with them and has to work it out. Everybody should be ready to justify what they do."

Harry Sinnamon struck me as having a wonderful sense of why science is worthwhile. It seems that it would be easy to get buried in the minutia of his scientific labors. However, Sinnamon has held on to the notion that science, for as private and complicated an enterprise it may be, can answer simple questions and can help people. His attitude toward certain debates in the scientific world can be broadened to science as a whole: "I often find myself in positions where molecular-type biologists and neuroscientists would say that the questions I'm asking are too global and other psychologists would say that they're so mechanistic that you've taken all of the mystery and life out of the issue. I think the way you solve the problem is by not going into the debate. What you do is you see what you can do with it. Everybody should run with [their ideas] the way that they think it should be done and see what kind of story they can tell after ten years. If they can tell a story that is scientifically satisfying and aesthetically satisfying then it's worked."