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'Model T' Research Yields a Novel Dopamine Pathway

By Anette Breindl
Science Editor

In neural projections, what goes up must not necessarily come down. But researchers at the University of Montreal have identified one instance in which it does – and they believe their findings could have implications for Parkinson's disease.

"Neurons that are known to project up to the basal ganglia also project down," senior author Rejean Dubuc told BioWorld Today. "And those projections are also lost in Parkinson's disease."

In fact, Dubuc said that many of the motor symptoms of Parkinson's disease patients can be better explained by the loss of those downward projections than by the loss of the projections to higher brain areas that are currently considered to be the main source of trouble in Parkinson's.

Not that Dubuc and his team are really, technically speaking, looking at the basal ganglia at all. Their animal model of choice is a lamprey – a type of eel – and its equivalent structure is called the posterior tuberculum.

In the animal model tradeoff between simplicity and similarity to humans, the lamprey is clearly further on the side of simplicity. But Dubuc pointed out the advantages of such simplicity.

He likened the lamprey to a Model T: "It has all the same features as a modern car, but not the extras you get in a new Rolls Royce."

And because they do, it is possible to do experiments on the details of neural connections using the whole brain of a lamprey. While such connections can be studied in mammals by using brain slices, those slices necessarily look at only two dimensions of the three-dimensional network.

In contrast, "we can put the entire brain in vitro, and it survives very well," Dubuc said. "That's the power of the lamprey."

The work of Dubuc and his colleagues focused on the control of locomotion, and they decided to look for, and at, possible descending projections of the basal ganglia in lampreys after such a projection had been identified in monkeys. Lampreys, he said, have "far fewer neurons, but the same basic connections" as mammals, and so the team used a combination of electrophysiology and dye injections to confirm the existence of the pathway in the eels.

Electrically stimulating the equivalent of the basal ganglia in the eels led to dopamine release in the brainstem, and the scientists next looked at the effects of blocking and enhancing dopamine release, respectively, on movement in the lamprey. Blocking dopamine activity in the brainstem reduced the animals' ability to move their tails – the lamprey equivalent of walking.

The team published its results in the Aug. 5, 2013, advance online edition of the Proceedings of the National Academy of Sciences.

Using the approach of basically turning the whole lamprey brain into a test tube system, Dubuc and his team next want to look at the way the dopaminergic projection interacts with a parallel projection that uses another neurotransmitter, glutamate, in cellular detail.

The brainstem is largely responsible for involuntary motor functions, while the motor symptoms of Parkinson's disease are more often thought of as affecting more complex aspects of movement. But Dubuc said that to what degree complex functions need higher brain regions depends on the details.

"If you walk on a treadmill, you probably don't use your cortex much. But if you walk on a street in Montreal, you do," driven by both the need to think about the destination, and be aware of everything from puddles to people that need to be taken into account on the way to that destination.

Returning to the Model T analogy, Dubuc said that "our ignition and steering wheel is in the brainstem, and the navigation system is in the cortex."

The basal ganglia are part of the forebrain and so, the equivalent of the navigation system. "They will select particular behaviors," Dubuc said, integrating visual input and goals to make the decision to move. But the details of that motion will be left to the brainstem. "They will not control step by step locomotion."