Anxiety Disorders — Animal Models & Behavioral Testing

For anxiolytic drug screening, start with diazepam validation on the elevated plus maze — this establishes assay sensitivity. For sustained GAD-like anxiety, chronic corticosterone produces reliable anxiety phenotypes over 4–7 weeks. For PTSD, single prolonged stress (SPS) uniquely recapitulates impaired fear extinction and enhanced negative feedback of the HPA axis. Predator odor engages innate fear circuits without conditioning, ideal for studying unconditioned anxiety.

Both measure approach-avoidance conflict between exposed (anxiogenic) and enclosed (safe) arms. The elevated plus maze has a center square where all four arms intersect — time spent in this zone is ambiguous (neither open nor closed). The zero maze replaces the intersection with a continuous annular track with alternating open and closed quadrants, eliminating the center zone problem. The zero maze provides cleaner data but is less widely published than the EPM.

SPS combines three sequential stressors (2 hours restraint, 20 minutes forced swim, ether until unconsciousness) followed by 7 days of isolation. This produces the neuroendocrine signature of PTSD: enhanced negative feedback of the HPA axis, with low baseline cortisol and exaggerated dexamethasone suppression. Behaviorally, SPS animals show enhanced fear acquisition, impaired fear extinction, exaggerated startle, and anxiety-like behavior — matching the DSM-5 PTSD symptom clusters.

Yes. Chronic corticosterone produces both anxiety-like behavior (reduced open arm time on EPM, increased thigmotaxis) and depressive phenotypes (anhedonia on sucrose preference, increased immobility on FST). Similarly, CUMS produces anxiety alongside anhedonia. This comorbidity mirrors clinical populations where ~60% of patients with MDD also meet criteria for an anxiety disorder. Using models that produce both phenotypes is more clinically relevant than studying either in isolation.

The core anxiety battery includes the elevated plus maze (open/closed arm conflict), light-dark box (illumination avoidance), open field (center zone exploration and thigmotaxis), and zero maze (annular open/closed conflict). For PTSD specifically, add fear conditioning with extinction trials and acoustic startle with prepulse inhibition. All assays are based on the approach-avoidance conflict principle — anxiety is quantified by avoidance of exposed, bright, or novel environments.

Predator odor (cat fur, fox urine TMT, or synthetic 2MT) triggers innate defensive behaviors without any prior conditioning or learning. This engages hardwired amygdala, BNST, and hypothalamic circuits that evolved for predator defense. The advantage over conditioned fear models is ecological validity — you are studying anxiety-relevant circuits without the confound of associative learning history. Predator odor can also sensitize subsequent conditioned fear, making it useful for studying vulnerability to PTSD-like fear learning.