Anxiety, and the depressive disorders with which anxiety is frequently comorbid, constitute an enormous illness burden in the US and elsewhere. Approvals of new drug treatments for these disorders have slowed in recent years, largely because preclinical studies have not predicted efficacy well in clinical trials. Detailed analyses of response to threat in laboratory rodents suggest a particular defensive behavior, risk assessment (RA) as a transdiagnostic behavioral biomarker for both anxiety and depression; a view strongly supported by recent studies of rumination and anxiety/depression, eye-gaze patterns of anxious individuals, and facial expressions associated with anxiety. Subcortical brain systems activated by predator (cat) or conspecific attacker threat have been systematically outlined in the laboratory of Dr. Newton Canteras, in Sao Paulo. Analyses of human anxiety disorders as typically reflecting attention to evolutionarily 'prepared' threat cues in conjunction with stressful events consonant with danger, suggest that such a model may increase translational value. Preliminary studies involving behavioral analyses of rats confronting snake species with which they have only a very distant evolutionary history confirm that these encounters produce much higher levels of RA and fewer flight or freezing defenses than those with cats/conspecific attackers: Subcortical activity patterns are similar but not identical to those seen to either of these. Using a non-coevolved snake stimulus this project will investigate the subcortical and cortical systems involved in RA. A variety of molecular techniques including c-fos expression, and both chemical and optogenetic inactivation of relevant structures, will be used to track the systems involved. Time-based comparisons of RA and theta oscillation patterns in conjunction with rapid on-set - off-set of regional inactivation should result in enhanced understanding of the relationship between these measures, and their association with anxiety. The program should produce details of the brain systems underlying both sets of measures, suggesting significantly improved methods for modulating these potential biomarkers of anxiety.
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