DISTINCT BRAIN ACTIVATION PATTERNS UNDERLYING HEIGHTENED ANXIETY-PROCESSING IN AUTISM-RELATED AND TRAIT ANXIETY MODELS

Anxiety disorders constitute a major clinical burden across neurodevelopmental and affective conditions, yet therapeutic responses remain highly variable. Anxiety is particularly prevalent in individuals with autism spectrum disorder (ASD) and is often more treatment-resistant than normotypic pathological anxiety suggesting distinct underlying neural mechanisms. However, the extent to which anxiety-related circuits dissociate between ASD-associated and trait anxiety remains unclear. To address this, we examined anxiety-like behaviour and neuronal activation patterns in ASH1L haploinsufficient (ASH1L+/−) mice, a genetic model of a high-confidence ASD risk factor, and in mice with high anxiety-related behaviour (HAB), alongside their respective controls. Animals were exposed to the blocked open arm (OA) of the elevated plus maze, and neuronal activation was assessed using c-Fos immunohistochemistry. Both male ASH1L+/− and HAB mice explored the distal OA less than their controls indicating heightened anxiety-related behaviour. HAB mice showed OA–induced hyperactivation of classical stress- and anxiety-related limbic, hypothalamic, and brainstem regions. In contrast, while ASH1L+/− mice displayed a tendency toward increased neuronal activation in frontal and somatosensory cortices, c-Fos expression was unaltered or reduced in classical regions critical for anxiety regulation and cognitive appraisal, including amygdala subnuclei and prefrontal, motor, and insular cortices following OA exposure. Notably, c-Fos induction was reduced in the cingulate cortex of both models relative to controls. Together, these findings demonstrate that similar anxiety-like behaviours can arise from distinct neural mechanisms, highlighting the need for circuit-informed stratification of anxiety phenotypes to guide personalized neuropsychopharmacological treatment strategies.
Supported by the Austrian Science Fund FWF FG 18-B.