Immune cells cause OCD?

Toward to end of the class, we’ve been focusing a lot on brain disorders like Alzheimer’s disease or Huntington’s disease. Part of the discussion about them, other than the potential metabolic contributing factors, is the significant mark of inflammation in the brain. Therefore, I’d like to talk more about the cross talk between immunology and neuroscience this time.

The research paper I am introducing to you today is about the role of a kind of immune cell, called microglia, in obsessive compulsive disorder (OCD). OCD is an anxiety disorder characterized by uncontrollable thoughts and repetitive, ritualized behaviors. Patients with OCD feel compelled to complete a certain behavior. Among one of the behaviors, there is one called trichotillomania, which is characterized by excessive hair-pulling, so the patients end up with a bald head. Interestingly, mice can also exhibit this type of behavior so that they can be a good model to be studied. These mice have a perfectly normal grooming syntax (the order and the way how they groom), but their grooming frequency is abnormally high. This will cause a bald patch, usually on their chests. These mice may also grooming other mice in the same cage.

Previous studies have shown that the mutation of a gene called Hoxb8 will cause the above excessive grooming behavior as well as defected nociception (pain sensation). Scientists in this group thus begins with examining which cells in the brain was of Hoxb8 lineage. They used a mouse model called Hoxb8-IRES-Cre/ROSA26-YFP. What’s special about these mice is that, in these mice all the cells that once expressed Hoxb8 genes will also express YFP (yellow fluorescent protein). Therefore, all the cells related to Hoxb8 gene was labelled with YFP, no matter if they’re expressing Hoxb8 currently or not. What scientists found is that cells in the brain labelled with YFP are microglia cells. However, not all microglia are YFP positive. Microglia are immune cells in the brain that eat the garbage. These “cleaner cells” are thought be have two origins, one from hematopoietic stem cells, the other from neurons. The fact that only around 40% of microglia are YFP positive also support this fact, suggesting that the YFP negative microglia are from neuron origin because Hoxb8 is expressed in hematopoietic cells.

Since expression of Hoxb8 is found in hematopoietic cells, scientists tried to perform bone marrow transplantation on these Hoxb8 mutant mice that exhibit excessive grooming behavior. The results turn out to be good. Mutant mice transplanted with normal bone marrow are rescued from the abnormal grooming behavior.

However, questions still remained for the defected nociception in Hoxb8 mutant mice. Does this defect also contribute to the excessive grooming behavior? In order to address this question, scientists first examined the cause of this nociception defect. By doing anatomy, they found that interneurons at the dorsal horn of the spinal cord decreased significantly in Hoxb8 mutant mice compared to normal mice. Interneurons at the dorsal horn are known to be responsible for the route of sensation from peripheral to the brain, a decrease in number makes sense to be the cause of defected nociception.

Scientists then did a conditional deletion of Hoxb8 gene only in microglia and a conditional deletion of Hoxb8 gene only in spinal cord interneurons. They found that microglia with a non-functional Hoxb8 gene will cause excessive grooming behavior but will not cause nociceptive defect, whereas spinal cord interneurons with a non-functional Hoxb8 gene will cause nociceptive defect but will not cause excessive grooming behavior.

At this moment, they made the conclusion that Hoxb8 mutation in microglia is responsible for excessive grooming behavior in OCD mice.

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