One way social isolation changes the mouse brain

Social isolation is an intensely stressful environment for mice. When animals are stressed, they generally become much more reactive to a variety of negative stimulants, and these reactions or behaviors persist longer than in non-stressed animals.

In a paper published May 17 in the journal Cell, scientists present what they believe is one of the mechanisms by which chronic social isolation in mice causes the brain to change in a profound way. The researchers found that social isolation for two weeks in mice resulted in the upregulation of the signaling molecule neuropeptide, tachykinin 2(Tac2)/neurokinin B (NkB). The researchers believe that Tac2/NkB is the brain chemical that is responsible for causing the animals to display much more persistent responses to threatening stimuli compared to group-housed mice.

"We discovered that Tac2/NkB is upregulated broadly throughout the mouse brain in multiple brain regions that are involved in different types of emotional coping behaviors and aggression," says senior author David J. Anderson, of the California Institute of Technology, whose laboratory studies the neural circuitry related to emotional behaviors.

Anderson's team, led by postdoctoral fellow Moriel Zelikowsky, noted that the diverse behavioral effects of the Tac2/NkB peptide do not appear to be exerted in a top-down manner by a single master control region in the brain. Instead, the peptide is overproduced in multiple locations of the brain, each of which causes one of the different behavioral changes that persist in social isolation. "We think Tac2/NkB is a chemical modulator that coordinates a whole inter-brain state that is caused by social isolation; one that operates in a distributed manner in the brain," he says.

The researchers also discovered that they could block the behavioral effects of social isolation on the mice using osanetant, a drug that blocks the NkB receptor. Systemic osanetant injection blocked the aggressive or reactive behaviors when the mice were challenged with fearful or threatening stimuli.

This research follows from earlier studies that Anderson conducted with tachykinin 2 in fruit flies. In a 2014 Cell paper (10.1016/j.cell.2013.11.045), they found that the peptide controls the effects of social isolation to increase aggression in Drosophila. "The fact there is some conservation of function from fruit flies to mice makes me think this peptide might have some role in some forms of stress and their effects on the brains of humans," says Anderson.

In this study, the researchers developed and applied a new way to artificially over- produce and release Tac2/NkB from the brains of mice in group-housing conditions. "When we did that, we can mimic many of the effects of social isolation," says Anderson.

He noted that while socially isolated mice are so aggressive that they normally cannot be returned to group housing, after treatment with osanetant, the mice no longer attacked their cage mates. "To me, it brings up the question whether this drug could mitigate the well-known deleterious effects of solitary confinement, such as increased violent behavior in incarcerated individuals," he says.

Osanetant was developed as a potential therapy for schizophrenia and bipolar disorder. While it was safe and well-tolerated in human studies, it failed to show any efficacy for these disorders. "Our study raises the possibility that this drug might be repurposed to treat other psychiatric disorders that are related to effects of social isolation in humans–not just in solitary confinement but perhaps in bereavement stress or other types of stress," says Anderson.

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This work was supported by grants from the National Institute of Mental Health, Gordon Moore Foundation, Ellison Medical Research Foundation and Simons Foundation, a NARSAD Young Investigator Award, the L'OREAL for Women in Science award (Moriel Zelikowsky), and a NIMH K99 Pathway to Independence award.

Cell, Zelikowsky, M, et al, "The neuropeptide Tac2 controls a distributed brain state induced by chronic social isolation stress" http://www.cell.com/cell/fulltext/S0092-8674(18)30361-1

Cell (@Cell), the flagship journal of Cell Press, is a bimonthly journal that publishes findings of unusual significance in any area of experimental biology, including but not limited to cell biology, molecular biology, neuroscience, immunology, virology and microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. Visit: http://www.cell.com/cell. To receive Cell Press media alerts, contact [email protected]

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http://dx.doi.org/10.1016/j.cell.2018.03.037

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