Neural Markers of Vulnerability to Anxiety Outcomes after Traumatic Brain Injury

Anxiety outcomes after traumatic brain injury (TBI) are complex, and the underlying neural mechanisms are poorly understood. Here, we developed a multi-dimensional behavioral profiling approach to investigate anxiety-like outcomes in mice that takes into account individual variability. Departing from the tradition of comparing outcomes in TBI versus sham groups, we identified a subgroup within the TBI group that is vulnerable to anxiety dysfunction, and present increased exploration of the anxiogenic zone compared to sham controls or resilient injured animals, by applying dimensionality reduction, clustering, and post hoc validation to behavioral data obtained from multiple assays for anxiety at several post-injury time points. These vulnerable animals expressed distinct molecular profiles in the corticolimbic network, with downregulation in gamma-aminobutyric acid and glutamate and upregulation in neuropeptide Y markers. Indeed, among vulnerable animals, not resilient or sham controls, severity of anxiety-related outcomes correlated strongly with expression of molecular markers. Our results establish a foundational approach, with predictive power, for reliably identifying maladaptive anxiety outcomes after TBI and uncovering neural signatures of vulnerability to anxiety.