A Fault In The Supercomputer

Your brain is the most advanced supercomputer in the world. But in Huntington’s disease (HD), a core processor of this computer starts to malfunction. Using advanced imaging techniques, a research group at UCLA has taken a close look to identify and visualize the specific circuits going haywire in the parts of the brain most impacted by HD – and how the disease causes them to look different. They found that the specific circuits of a central brain region (the striatum) that are affected in HD, called medium spiny neurons, are less connected and less spiny than they should be.

The most complex computer in the world

The most complex computer in the world is not made of microchips – it’s sitting right inside your head. Although the fastest supercomputers rival the human brain for raw computational power, nothing can match the extraordinary flexibility and efficiency of your brain. 

Just to give you a rough idea, the most powerful supercomputer right now, named “El Capitan” in California, crams cutting-edge equipment across the area of two tennis courts and takes up the energy of a small town. The brain is only about the size of a grapefruit and runs on the energy of a dim lightbulb, yet miraculously achieves the same computing capacity. Not to mention that El Capitan can’t dance, sing, catch a ball, or countless other amazing things your brain can do!

Clearly it’s worth understanding how this incredible computer in your head works, and also how it malfunctions in HD. So what part of this computer is affected in HD, and how can we understand what’s going wrong? A cutting-edge research group at UCLA has applied some inventive approaches to answer these questions.  

A central computing malfunction in HD

The brain is not quite like a computer made of microchips, but there are some similarities. For one thing, the brain processes information through inputs and outputs. This processing happens using specialized cells called neurons, which operate a bit like circuits in a microchip. And like a computer, the brain is organized into different parts that process different things. 

The brain has an incredible 86 billion neurons and just as many supporting cells, which together is about as many cells as there are stars in the Milky Way Galaxy. The scale of what your brain can do with all these brain cells is truly astounding. El Capitan comes nowhere close. 

One of the most important parts of our amazing computer is a central region of the brain called the striatum, which is further divided into the caudate and putamen.

You can think of the striatum as Grand Central Station for many brain processes – a place where many circuits connect to. The striatum is one of the most affected parts of the brain in HD, which is why symptoms of HD can be so diverse, including uncontrolled movements, mood problems, and difficulty thinking. So to understand HD, you have to understand the striatum.

A special kind of circuit is affected in HD

Some parts of the brain have dozens and dozens of different kinds of neurons, but fortunately the neurons found in the striatum are not as diverse as in other parts of the brain. This makes the striatum a bit easier to understand. 

You can think of the striatum like a processing cluster in your computer, with many circuits that are similar to each other. These circuits in the striatum are called medium spiny neurons, and they represent most of the neurons found there. “Medium spiny neuron” might seem like a made-up name but that’s really what scientists call them, because of how they look! They are medium sized and very spiny. You may have also seen them called MSNs for short.

Why are medium spiny neurons so spiny? That’s because each medium spiny neuron receives signals from many other neurons in the brain, and each of these inputs happens through a little spine that sticks out from the medium spiny neuron. Medium spiny neurons have many inputs, so that’s why they have many spines. It’s Grand Central Station for the brain, remember? 

Medium spiny neurons are clearly very important, but we don’t know exactly how they are individually connected to the rest of the brain, just that they have many inputs. It’s medium spiny neurons that are particularly vulnerable in HD, which scientists think causes the striatum to malfunction and cause the symptoms of HD.

Mapping out the circuits in three dimensions

Surprisingly, very little research has been done on what medium spiny neurons look like, apart from them being spiny. Do they all look the same? How do they look when they are damaged in HD? A renowned research group at UCLA led by Dr. X. William Yang decided to map out what medium spiny neurons look like in the brain, and what happens to them in HD.

To do this, the group labeled medium spiny neurons so they glow under a microscope, and also labeled each spine – called dendritic spines, or simply dendrites. They could not do this labeling in human brains, so instead they did this in mouse brains that also have a striatum. After labeling the medium spiny neurons and their spines (dendrites), they sliced the striatum into slabs and took detailed images of each slab to see what the medium spiny neurons looked like. 

This is sort of like slicing a dense Jell-O mold with small fruits scattered inside, so you can more easily see the fruit. This allowed the researchers to see what the medium spiny neurons looked like in three dimensions within each slice. Remarkably, this is the first time anyone has looked at medium spiny neurons in this way! So what did they see?

Not all circuits look the same

The striatum is actually divided into further processing clusters, even though they all have medium spiny neurons that are affected in HD. So the researchers decided to assess what medium spiny neurons look like across these different clusters. 

They measured all kinds of variables about the medium spiny neurons, like how many spines they have, how long they are, and how frequently spines branch into smaller spines. This is a bit like looking at the circuits in a specific part of a computer, and studying how long each of the circuits are and where they go. 

Interestingly, medium spiny neurons look a bit different in different parts of the striatum. In some parts of the striatum the spines are longer than others, in other parts they are shorter. In some parts of the striatum the spines are more numerous, and in some parts they are more branched. Clearly there’s a lot more going on with how these medium spiny neurons are wired in the striatum than we previously knew.

In HD, fewer circuit connections than there should be

Medium spiny neurons of the striatum are especially vulnerable in HD, and start to malfunction and disappear very early in the disease. So what did the scientists observe about the shape and appearance of these different medium spiny neuron circuits in HD? 

To study this, they did the same labeling, brain slicing, and microscope imaging, but this time in a mouse that models HD with an expanded CAG repeat. Intriguingly, medium spiny neurons in the HD mice were less complex, and had fewer branches.

This suggests that in HD, there may be fewer circuit connections than there should be between medium spiny neurons and the rest of the brain. In other words, the malfunction of the striatum in HD may be related to lower connectivity with the rest of the brain, like a processing core losing connections to the rest of the computer.

Understanding how neurons that are affected in HD lose their connections with the rest of the brain is critically important for understanding how to repair them, or stop them from malfunctioning in the first place. With more studies like these, we can develop better ways to track and treat the causes of HD in the future.

Summary

• Your brain is the most complex computer in the world
• HD causes a specific part of this computer, the striatum, to malfunction
• Specific circuits in the striatum, called medium spiny neurons, seem to be lost in HD
• The research suggests that medium spiny neurons have slightly different appearance and connections across different parts of the striatum
• Medium spiny neurons appear to be less complex in HD and have fewer connections