Hughes, D. N.; Klein, M. H.; Walder-Christensen, K. K.; Thomas, G. E.; Grossman, Y.; Waters, D.; Matthews, A. E.; Carson, W. E.; Filali, Y.; Tsyglakova, M.; Fink, A.; Gallagher, N. M.; Perez-Balaguer, M.; McClung, C. A.; Zarate, J. M.; Hultman, R. C.; Mague, S. D.; Carlson, D.; Dzirasa, K.

In rodents, anxiety is charactered by heightened vigilance during low-threat and uncertain situations. Though activity in the frontal cortex and limbic system are fundamental to supporting this internal state, the underlying network architecture that integrates activity across brain regions to encode anxiety across animals and paradigms remains unclear. Here, we utilize parallel electrical recordings in freely behaving mice, translational paradigms known to induce anxiety, and machine learning to discover a multi-region network that encodes the anxious brain-state. The network is composed of circuits widely implicated in anxiety behavior, it generalizes across many behavioral contexts that induce anxiety, and it fails to encode multiple behavioral contexts that do not. Strikingly, the activity of this network is also principally altered in two mouse models of depression. Thus, we establish a network-level process whereby the brain encodes anxiety in health and disease.