Chronic social isolation is often associated with depression and post-traumatic stress disorder in humans. Caltech scientists conducted a study on this topic- chronic social isolation and found that it causes the build-up of a particular chemical in the brain and that blocking this chemical eliminates the negative effects of isolation.
Scientists found that the social isolation leads to a broad array of behavioral changes in mice. These include increased aggressiveness towards unfamiliar mice, persistent fear, and hypersensitivity to threatening stimuli. For example, when encountering a threatening stimulus, mice that have been socially isolated remain frozen in place long after the threat has passed, whereas normal mice stop freezing soon after the threat is removed. These effects are seen when mice are subjected to two weeks of social isolation, but not to short-term social isolation—24 hours—suggesting that the observed changes in aggression and fear responses require chronic isolation.
In a past investigation of the Drosophila fly, the Anderson research center had found that a specific neurochemical called tachykinin assumes a part in promoting aggression in socially isolated flies. Tachykinin is a neuropeptide released from certain neurons when they are activated.
In order to find out how tachykinin improves social isolation-induced aggression, scientists turned to laboratory mice. In mice, the tachykinin gene Tac2 encodes a neuropeptide called neurokinin B (NkB). Tac2/NkB is produced by neurons in specific regions of the mouse brain such as the amygdala and hypothalamus, which are involved in emotional and social behavior.
Scientists discovered that the chronic isolation causes an increment in Tac2 gene expression and the production of NkB throughout the brain. But injecting of a drug that chemically blocks NkB-specific receptors enabled the stressed mice to behave normally, eliminating the negative effects of social isolation.
The researchers also inhibited the function of Tac2 and its receptors in multiple specific brain regions. They found that suppressing the Tac2 gene in the amygdala eliminated the increased fear behaviors, but not aggression, while conversely suppressing the gene in the hypothalamus eliminated increased aggression but not persistent fear. The results imply that Tac2 must increase in different brain regions to produce the various effects of social isolation.
The work, led by postdoctoral scholar Moriel Zelikowsky, was done in the laboratory of David J. Anderson, Seymour Benzer Professor of Biology, Tianqiao and Chrissy Chen Leadership Chair, Howard Hughes Medical Institute Investigator, and director of the Tianqiao and Chrissy Chen Institute for Neuroscience. A paper describing the research appears in the May 17 issue of the journal Cell.
The laboratory of David J. Anderson said, “The approach used here allowed us both to compare the effects of different manipulations of Tac2 signaling in the same brain region, as well as to compare the effects of the same manipulation across different brain regions. The rich dataset generated by these experiments revealed how this neuropeptide acts globally across the brain to coordinate diverse behavioral responses to social isolation stress.”
Zelikowsky said, “Humans have an analogous Tac2 signaling system, implying possible clinical translations of this work. When looking at the treatment of mental health disorders, we traditionally focus on targeting broad neurotransmitter systems like serotonin and dopamine that circulate widely throughout the brain. Manipulating these systems broadly can lead to unwanted side effects. So, being able to precisely and locally modify a neuropeptide-like Tac2 is a promising approach to mental health treatments.”
Though the work was done in mice, it has potential implications for understanding how chronic stress affects humans. Scientists suggest that the work has potential applications for treating mental health disorders in humans.