Inside Neuroscience: Glial Cells and the Neuro-immune Axis
Neurons are the main actors of the nervous system, but they cannot function alone. They need help from a large supporting cast of glial cells, which make up about half of the cells of the brain.
Glial cells perform a variety of tasks from supporting neurotransmission and synaptic pruning to tidying up after neuronal death. These cells also perform the key function of mediating inflammatory responses in the brain. They have also been implicated in a host of neuronal diseases from autism to Alzheimer’s disease.
Shane Liddelow
“There's this very tight regulation of the neuro-immune glial contribution to neuronal health. This is important for not only for neural development, but also neuropsychiatric and neurodegenerative diseases,” said Shane Liddelow, associate professor at the NYU Grossman School of Medicine.
Liddelow hosted a press conference at Neuroscience 2024 highlighting the field, titled “The Mighty Immune System: How Inflammation Shapes the Brain.”
Researchers at the session studied the links between prenatal exposure to cocaine and aberrant brain function; inflammation during pregnancy and neurodevelopmental disorders in offspring; and specialized immune-dampening cells and anxiety. They also investigated how glial cells called astrocytes mediate the fear response, research that is relevant for post-traumatic stress disorder (PTSD) and related conditions.
Scientists are just beginning to understand the close linkages between inflammation, glial cells, and disease. Research in the area promises to reveal new drug targets and potential novel treatments beyond the current therapeutic emphasis on neurons, said Liddelow.
“Neurons are sort of like the teenagers of the brain. They make a lot of noise, but they can't make their own food and they can’t clean up after themselves. That's for the neuro-immune glial component,” said Liddelow.
Quelling Cocaine
The brain is sensitive to a variety of environmental insults in utero, including drugs such as cocaine, which affects fetal brain growth and is associated with neurological deficits.
Keith Murphy
To study the effects of cocaine during this sensitive period of development, Keith Murphy turned to brain organoids, three-dimensional models of human brains derived from stem cells grown in a petri dish.
Murphy exposed the organoids to cocaine and showed a rise in the number of inflammatory astrocytes. These additional astrocytes strengthen signaling to other cell types and quell the production of new neurons. “This would fundamentally change the brain structure as it emerges in development,” said Murphy, a professor of neuropharmacology at University College Dublin in Ireland.
Murphy plans to test potential treatments for reversing the effects of cocaine on brain organoids. “In theory, drugs discovered that way might also be useful for treating addiction in the adult brain,” said Murphy.
Autism in Utero
Researchers have long been intrigued by studies suggesting a link between viral infections in pregnant women and neurodevelopmental disorders such as autism in offspring.
Irene Sanchez
“Healthy pregnant women maintain a balance between the nervous system and the immune system,” said Irene Sanchez Martin, a postdoctoral fellow at Cold Spring Harbor Labs in New York. Inflammation during infection can throw off this balance.
Researchers typically study this process in mice by experimentally inducing inflammation during pregnancy and then studying the behavior of the offspring. These offspring often display increased autism-like behavior such as repetitive actions and anxiety.
Martin looked earlier, at the immediate effects of inflammation on the embryos. Inflammation resulted in major shifts in gene expression in the placenta and amniotic fluid within 24 hours, including in immune mediators. Curiously, about half of the male embryos also showed visible impairments in development, but none of the female embryos.
Further studies could help answer the longstanding question of why males are more often diagnosed with autism spectrum disorders.
Suppressor Cells
The brain has its own specialized resident immune cells called microglia and astrocytes. But immune cells circulating throughout the body may also play a role in the brain, including regulatory T cells (Tregs).
Tregs help quell the immune system and keep it in check. They mediate neuroimmune interactions between microglia and astrocytes. Reduced levels of Tregs are associated with mood-spectrum conditions such as anxiety and depression.
Freya Shepherd
Such findings “have led us to believe that we might be able to tackle these problems from an immunological point of view,” said Freya Shepherd, who recently finished her PhD at Cardiff University, Wales.
Shepherd studied the effect of experimentally depleting Tregs in mice using an inducible system. In this system, diptheria toxin is applied to mice engineered to express the toxin receptor in Tregs, killing the cells. Treg-depleted female mice showed an increase in anxiety in a maze-based test while the male mice showed a less pronounced increase.
The findings align with the increased susceptibility of women to some mood-spectrum conditions. Shepherd next plans to test the mice using other measures of anxiety and depression.
Memories of Fear
The interaction of glial cells with neurons is a growing area of research.
Olena Bukalo headshot
Olena Bukalo examines such interactions using a calcium indicator to track the activity of astrocytes, which she monitors using optical fibers. She employs these techniques to study memories related to fear.
She also employs an older technique — training mice to associate a tone with a shock. After training, mice will freeze in response to the tone, which is a fear response. The mice then undergo extinction training where they learn that the tone is no longer associated with the shock and their freezing behavior ebbs.
“These two memories, fear and extinction memory, co-exist in the brain,” said Bukalo, a staff scientist at the National Institute on Alcoholism and Alcohol Abuse.
Bukalo found that calcium activity in astrocytes in the basolateral amygdala tracked with fear. Calcium was high when fear was high and decreased with extinction training.
She then experimentally depleted calcium in the astrocytes and found that neurons involved in fear encoding were less engaged, including neurons in the amygdala that project to the prefrontal cortex. The mice also showed less fear.
High fear states can dominate in the brain or fail to be extinguished, which can lead to conditions such as anxiety or PTSD. Targeting astrocytes might offer a future solution, said Bukalo.
Speaking to development of research in the glial cell field, “Maybe in 20 years we will be at a glial science meeting where we will discuss the brain processes from the glial perspective,” said Bukalo.
