Huntington’s Disease (HD) can cause a range of movement, mood and cognitive symptoms. Some people have more of some symptoms than others, and we still don’t know exactly why. We know that damage to a part of the brain called the Anterior Cingulate Cortex (or ACC for short) is associated with the mood symptoms of HD. The cingulate cortex is part of the cortex, which is the layer that wraps around the outside of the brain and looks like a walnut. The cingulate cortex is near the middle of the cortex, close to where the two halves of the cortex meet. It has roles in regulating mood and some aspects of thinking. The Middle Cingulate Cortex (MCC) is right next to the ACC. Because it also plays a role in mood, it is possible that damage to this part of the brain is also responsible for creating some of the mood symptoms of HD. There is also a theory that too much inflammation is causing or exacerbating a lot of the symptoms of HD. No one had looked at the role of inflammation in the MCC in HD before, so Dr Thulani Palpagama, a scientist who works at the Centre for Brain Research, and Miss Aimee Mills, a PhD student at the centre, decided to conduct an investigation, with help from others in their team.
MRI scan of a human brain with the Cingulate Cortex shown in red. The Cingulate Cortex can be subdivided into Anterior (front), Middle, and Posterior (back) regions.
To find out whether the MCC might contribute to mood problems in HD, brains from 20 people who died of HD were examined, alongside brains from 8 people who died without HD. Each of the HD patients was placed into one of three categories, depending on which symptoms they mostly suffered from. The categories were: movement problems, mood problems, and mixed (for those who had both). The brains of people who died without HD were placed in a fourth category called ‘neither’.
Thin slices of brain were cut from the MCC of each brain. The brain slices were then stained so the research team could look at three things in detail. One was clumps of mutant Huntingtin protein. Clumps of this protein in the brain are the main problem unique to HD. The researchers wanted to see if people with different symptoms had different amounts of it in their MCC. They then looked at two cell types involved in inflammation in the brain. One cell type is called microglia. These are small cells that are part of the immune system. When they detect an injury or infection, they multiply and change shape so they can wiggle through the brain to the site of the issue. The other cells are called astrocytes because they are shaped a bit like a star. Astrocytes support neurons (the brain cells that send messages) and keep them healthy. However, astrocytes can also change their function to help respond to brain injuries.
Image Created with BioRender.com
When the research team looked at the amount of Huntingtin protein in the MCC, they saw none in the brains of people who died without HD, and lots in the brains of those with HD. This was to be expected. When they compared the three symptom groups (movement, mood and mixed) they saw no difference between them. However, there were differences in both microglia and astrocytes in the MCC of people in the mood or mixed groups compared to the movement group.
The number of microglia in the MCC was the same between all groups including those without HD, which shows that the microglia weren’t multiplying in the HD brains. Instead, in those with HD, a lot more microglia had changed their shape to become more mobile. Many of the microglia were also found next to clumps of Huntingtin protein, which shows they were responding to it. However, in the HD brains, and especially in people with mostly mood symptoms, very few microglia had adopted the amoeboid shape needed to engulf the protein. This might mean that even though the microglia are responding to toxins, they are not doing a very good job of clearing it out of the brain.
The astrocytes in the MCC of people with mood symptoms also looked different. They had less receptors for glutamate, which is a chemical that neurons use to talk to each other. Although the brain needs glutamate, at high levels it is toxic. One of the important jobs of astrocytes is to remove excess glutamate to keep neurons safe. If there are less glutamate receptors, it may mean that these astrocytes are unhealthy and cannot do their job properly.
The differences in microglia and astrocytes show that these two cell types are not functioning as they should in the MCC of people with HD, particularly in those who experience mood symptoms. Although the researchers couldn’t determine why with this study, it is likely that inflammation plays a role. These types of changes are usually linked to inflammation. Inflammation is important for healing injuries, but it can cause problems if it continues for too long. It is still unclear if these particular changes in cells create inflammation, are a response to it, or both. However, similar changes to microglia or astrocytes have been seen in other disorders, such Alzheimer’s disease and bipolar disorder. Future research is needed to examine these connections.
This study is the first to look at inflammation in the MCC in HD. It is an important step in determining why people with the same disease can have such different symptoms. It is also important for understanding the role of inflammation in HD. By looking at which processes are affected, scientists can work out which parts of the brain to target with new medicines. This information adds to the research necessary for finding a cure.
About the Author
Natasha is a postdoctoral scientist who works with sheep models of Alzheimer’s Disease (AD), with the hope of finding a method of prevention. Her PhD project was to create a sheep model of Alzheimer's Disease using CRISPR-Cas9 gene editing technology. Her job now is to assess the model to prove that it will be a useful tool in AD research. This work was funded by a combination of the Freemason’s of New Zealand, the University of Auckland and Brain Research New Zealand. Before starting her PhD, she completed a Bachelor of Science at Massey University, majoring in genetics and zoology. She then went on to complete a Master’s Degree with First Class Honors in Evolutionary Biology, studying the natural hybridization of different species of tree weta, a native New Zealand insect, and how that affected the gene pool of each species. She has wide ranging interests across the biological sciences, and is passionate about learning, research, and education.
