Over the last decade, scientists have been discovering that microglia, a type of immune cell that resides in the brain, do more than respond to illness and infection.
Now, new research in mice has linked the dysfunction of microglia of a particular genetic lineage to anxiety and obsessive-compulsive disorder (OCD).
The recent Cell Reports study also shows that female sex hormones can worsen the anxiety symptoms that arise when this subset of microglia do not function correctly.
The discovery sheds light on the brain biology of anxiety and conditions that relate to it, such as OCD, whose root causes have remained unclear.
“More women than men experience debilitating anxiety at some point in their lives,” says lead study author Dimitri Traenkner, Ph.D., a research assistant professor in biological sciences at the University of Utah in Salt Lake City.
“In this study,” Traenkner adds, “[we] were able to link anxiety to a dysfunction in a type of microglia and to female sex hormones.”
Since their discovery in the 1920s, scientists have come to appreciate the important roles that microglia play in the brain following injury, infection, and illness.
They have shown that these innate immune cells play a part in conditions ranging from Alzheimer’s disease and multiple sclerosis to brain cancer.
More recently, however, a wealth of research has revealed that microglia have a large repertoire of functions.
Studies have shown, for instance, that microglia contribute to many aspects of brain development, including the generation of the myelin sheath that protects nerve fibers and the stimulation and pruning of connections between brain cells.
In addition, scientists are starting to appreciate that the influence of microglia extends into behavior.
In their study paper, Traenkner and colleagues cite studies that have suggested that under conditions of prolonged stress, abnormal microglia activity may cause depression or anxiety.
They also explain that not all microglia are the same. For example, in their own research, they “recently demonstrated that there are at least two different lineages of microglia” and that it is possible to program them to do different things.
In that earlier work, the team identified a specific subset of microglia whose precursors express the protein Hoxb8 during embryonic development.
Hoxb8 is a transcription factor, which is a protein that can alter cell behavior by switching genes on and off.
It appears that about one-third of all microglia in the adult mouse brain descend from Hoxb8 precursors.
Other researchers have also shown that mice that have no Hoxb8 tend to overgroom, a behavior similar to the human disorder trichotillomania, a type of OCD that causes individuals to pull out their hair. However, they did not establish which cells are involved.
What Traenkner and colleagues did in the new study was to identify the cells responsible for this behavior as microglia that have descended from precursors with a Hoxb8 lineage.
Their experiments showed that inactivating Hoxb8-lineage microglia in mice caused overgrooming and that active Hoxb8-lineage microglia can stop the compulsive behavior.
“Researchers have long suspected,” notes Traenkner, “that microglia have a role in anxiety and neuropsychological disorders in humans because this cell type can release substances that may harm neurons.”
So, the fact that microglia can protect against anxiety surprised them, he adds.
In their experiments, the researchers also saw how female sex hormones can worsen the OCD and anxiety that arises from dysfunctional Hoxb8-lineage microglia. The symptoms were consistently more severe in the female mice than in the male mice.
In addition, female mice displayed anxiety that was not present in the males. The team saw evidence of this in a new test that they developed and validated, in which the animals’ pupils dilated markedly under stress conditions.
To confirm that female sex hormones were driving the symptoms of OCD and anxiety, the researchers varied the animals’ levels of two female sex hormones: estrogen and progesterone.
When the team manipulated these hormone levels in the female mice to resemble those typically present in males, the OCD and anxiety symptoms in the female mice were like those of males.
Conversely, when the hormones in males were at the levels typically present in females, the OCD and anxiety symptoms in the male mice were like those of females.
Traenkner suggests that these findings make a strong case for the existence of a mechanism that links biological sex and genetic family history in the risk of developing anxiety-related disorders.
The team does not claim to have found a cure for anxiety but suggests that the findings point to a new direction in which to look for new drugs to treat the condition.
The symptoms of anxiety can be so severe that they disrupt people’s relationships and their ability to work, study, and carry out their daily activities.
“[This study] opens up a new avenue for thinking about anxiety. Since we have this model, we have a way to test new drugs to help these mice, and hopefully, at some point, this will help people.”
Dimitri Traenkner, Ph.D.