Parallel Brainstem Circuit Discovery Suggests New Path in Parkinson’s Research

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Parallel Brainstem Circuit Discovery Suggests New Path in Parkinson's Research
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News Release

 

[Writer] This is research news from U-I-C – the University of Illinois at Chicago. Today, Simon Alford, professor of biological sciences, describes work he and colleagues in Montreal did that lead to the discovery of a parallel brainstem circuit in vertebrates – a finding which may be applicable to research on Parkinson’s disease.

Here’s Professor Alford:

[Alford] This is an issue that relates to how an animal or a human starts to walk, or swim or fly – depending on the type of creature you’re talking about. It’s an area we don’t know a lot about. We know that all vertebrates – everything from a fish on up to a human – activates locomotion by switching on a region of the brain called the mesencephalic locomotor region, and perhaps by another region called the diencephalic locomotor region. These then project information down through the brainstem, to make synapses on to neurons in the brainstem – we call those neurons reticulospinal neurons — they further project to the spinal cord. The spinal cord generates what we might call the “precise motor synergy,” the complicated movements and little tweaks of muscles that cause you to walk in the right way, or a fish to swim in the right way, or a goose to fly in the right way.

The commonalities of this system really relate back to that brainstem system, and we were very interested in how you activate and sustain locomotion.

But the work was an accident. A colleague of mine from Montreal came to visit and wanted to test the effect of a large class of drugs that act on a group of receptors that are called muscarine receptors. These are a type of receptors that respond to a neurotransmitter called acetylcholine, which is released in a large number of areas in the brain. Rejean Dubuc, my colleague from Montreal, was interested in how musacrinoreceptors depress sensory inflow. Imagine you start to walk. You don’t want a branch brushing your face to distract you too much, especially if you’re walking for a particular reason, like to go to something or run away from something. But in fact, what we discovered when we tested this class of substances on the brainstem is that it’s incredibly excitatory and causes animals to go into a series of bursts of locomotion. And this unusual finding caused us to throw away the study we were going to do when Rejean visited, and we started studying this second piece of work that (former graduate student) Roy Smetana joined me and Rejean to work on – which is, how does muscarine cause you to locomote?

We work on a very primitive fish called the lamprey. The reason for this is mostly because we can take out the entire central nervous system and work on it and put electrodes into the cells that we think are relevant and interesting to the question we work on. In fact, you can evoke a form of activity in this fish we call fictive locomotion – (that is) locomotion that would be locomotion if the central nervous system was connected to muscles. But we’ve experimentally separated the animal from its muscles, so when the animal tries to swim it generates the pattern of activity in the spinal cord that corresponds to locomotion – but of course there’s no locomotion because the animal is effectively paralyzed.

Working on this preparation then, we were able to look at the individual neurons and their contributions to this activity from the brain all the way down to the spinal cord. It’s a piece of work that’s been pioneered from a group in Sweden led by a well-known professor, Sten Grillner, and we used the animal preparation, this lamprey, to study this to start looking at this problem of muscarine and how it activate locomotion. And we discovered a nucleus that exists in the brainstem of vertebrates that nobody was aware existed before.

And it does quite interesting things.

When you want to start walking, you don’t want to start walking either tripping over your own feet or walking in circles. So there has to be a very equivalent output of locomotor or neural power to both sides of your body, which translates in the spinal cord to both sides of the spinal cord at the same time. So imagine two signals going down one side of the spinal cord and the other side; if one of those signals is stronger than the other, you’ll walk in circles. Or if you’re a lamprey, you’ll swim in circles.

What we found was this output from these neurons we discovered – that we call muscarinoceptive neurons (or) neurons that respond to muscarine – one of the things we found was there was a quite remarkable symmetry between the two sides of the brainstem that these neurons project. It’s actually a symmetry that’s so precise that it must result from learning during the animal’s lifetime. It couldn’t just grow that way. It’s too precise to give that kind of symmetry, so there must be some feedback telling the neurons on either side to adjust.

That was one feature of the study that was important to us. The other is that these neurons in response to a short stimulus, a very short period of time of acetylcholine release, which is the neurotransmitter, caused a very extended period of locomotion. So it was like you decided to locomote, you made that decision, but you don’t have to keep on thinking about it. And we’ve all been through this experience. You might be driving and thinking about something else, then you suddenly realize you’ve driven 10 miles and you can’t remember a single tree or sign or anything you saw on the way. You keep doing something repetitively without higher centers thinking about it. They get sub- served thinking about something else like what’s for dinner tonight or other things like that. With locomotion it’s the same thing. You can start to walk or run, but you don’t have to keep on saying left-right, left-right, left-right. So these neurons switch on, turn on, and keep generating an output to the locomotor system. And it goes on for quite some time. And when I’m talking about quite some time, I’m talking about maybe up to 1 or 2 minutes. That may not seem a lot, but if you think about getting up and walking, you can go a long way in two minutes. So this is quite an interesting phenomenon.

The other interest of this particular phenomenon relates back to some of the oldest treatments for Parkinson’s disease. Before the days of L-dopa and our knowledge of what Parkinson’s disease really is, which is a loss of neurons that release a neurotransmitter called dopamine, before that was known, the earlier treatments for Parkinson’s disease was treatment of tissue with antagonist muscarine receptors. And it’s thought now –
although we may need to change this idea – that part of the inability to initiate movements that’s associated with Parkinson’s disease is a mismatch, an imbalance between output into muscarinoceptive systems, or muscarine systems, release of acetylcholine, and a balance between that a dopaminergic systems.

Unfortunately, because we know so little about this so far that this is a very simplistic idea. One would like to hope that you could have a much more sophisticated idea of how these neurons are interacting. But we hope that this finding will aid in that a little bit, to make these ideas a little more sophisticated.

[Writer] Simon Alford is professor of biological sciences.

For more information about this research, go towww.news.uic.edu … click on “news releases.” … and look for the release dated May 19, 2010.

This has been research news from U-I-C – the University of Illinois at Chicago.

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