Astrocytes in mouse amygdala encode emotional state

Astrocytes—but not neurons—in the amygdala encode anxiety-like states in mice, according to a paper published today in Neuron. The findings suggest that the cells—which are altered in people with some neuropsychiatric conditions, including autism—contribute to mental health difficulties documented in such groups.

“In a very sophisticated way, the [study] shows that astrocytes are these core computational cells for highly complicated behaviors,” says Michael Wheeler, assistant professor of neurology at Harvard University, who did not contribute to the new work. “Astrocytes are understanding and signaling computations in these circuits.” 

Violent movies and other stressful stimuli activate the amygdala, human imaging studies have shown. And in mice, neurons in the basolateral amygdala are active when the animals are placed in exposed environments, which they find aversive, previous research has found. But that neuronal activity appears to mark shifts between defensive and exploratory behaviors rather than tracking anxiety-related ones, according to a later study. 

The new findings suggest that astrocytes not only help neurons to regulate anxiety—as previous studies have shown—but “instruct local neurons from the top down,” says study investigator Ciaran Murphy-Royal, associate professor of neuroscience at the University of Montreal. The cells’ activity appears to function as a “safety signal,” that relays danger to other brain regions, he says.

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urphy-Royal and his colleagues used calcium imaging to measure astrocytic activity in the mouse basolateral amygdala. Calcium release tracked with freezing, hesitancy and other behaviors reminiscent of anxiety as mice investigated various environments, the team found. In the elevated plus maze, for example, astrocyte activity rose when the rodents explored an open arm of the maze and surged whenever mice peeked over the edge of the suspended setup.

And mice that readily explored exposed environments showed overall lower astrocyte activity than did mice that spent more time in concealed areas, the study found.

By contrast, neuronal activity tracks poorly with an anxiety-like state, calcium imaging of those cells revealed. And when the team trained a machine-learning model on either the astrocyte or neuronal calcium data, the astrocyte decoder could predict with 82 percent accuracy whether a mouse was in the open or closed arm of the plus maze. 

“It’s fascinating,” says Marc Freeman, director of the Vollum Institute at Oregon Health & Science University, who was not involved in the study. Based on astrocytic activity alone, you can tell whether a mouse is in its comfort zone, he says. “I bet people who are afraid of public speaking, their astrocytes have got calcium through the roof.”

The decoder trained on neuronal data, however, performed little better than would be expected to occur by chance, the study found. Those findings suggest that astrocytes are “not just echoing local neurons,” Murphy-Royal says.

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timulating astrocytes in the basolateral amygdala promotes freezing and hesitancy in mice, suggesting that astrocytic signaling causes the behavioral changes. That effect appears to be mediated by noradrenaline binding to alpha-1 adrenoreceptors, Murphy-Royal’s team found. Astrocytes in slices taken from the rodents’ amygdala respond to noradrenaline, and mice lacking alpha-1 adrenoreceptors showed blunted astrocyte activity and appeared to be less apprehensive than typical mice.

“[The] paper is yet another example that classical neuromodulatory systems are being leveraged by astrocyte networks to regulate neural activity in completely distinct ways from how neurons do,” says Kira Poskanzer, associate professor of biochemistry and biophysics at the University of California, San Francisco, who was not involved in the study. The findings emphasize the need to study those systems holistically, she adds.

That astrocytes are being independently modulated by noradrenaline—not just following local neural circuit activity—is exciting, says Nicola Allen, professor of molecular neurobiology at the Salk Institute for Biological Studies, who was not involved in the work. But a “key next step” is to understand how that signal is translated from astrocytes to neurons to change behavior, she says. 

The team is planning to investigate those downstream pathways, Murphy-Royal says. The researchers also aim to probe whether anxiolytic drugs work by dampening astrocytic activity, he says. Initial clues suggest they might—ketamine curbs helplessness in zebrafish by altering the activity of astrocytes, another group has shown. Similar medications may also act on the glial cells to lessen anxiety, Murphy-Royal says.