Loss of circTulp4 increases behavioral inhibition in conflict contexts

Circular RNAs (circRNAs) are non-coding RNAs that have attracted increasing attention due to their diversity and high abundance across tissues, yet their biological functions remain largely unclear, partly because generating precise loss-of-function models is technically challenging. Our lab previously identified numerous circRNAs in human and mouse brain, observing that many are more abundant than their linear counterparts in neural tissue. We focused on circTulp4, a highly expressed circRNA enriched in brain and synaptic fractions, and used CRISPR/Cas9 to generate the first circRNA-deficient (CD) mouse model for a brain circRNA, disrupting circTulp4 biogenesis while preserving linear mRNA and protein expression. Tulp4CD mice show impaired excitatory neurotransmission despite normal neuronal morphology, and altered coping with stress-related challenges. Tulp4CD mice show a categorical, all-or-none failure to initiate approach under motivational-threat conflict (passive avoidance, novelty-suppressed feeding), while fear learning, active avoidance, and unconditioned anxiety-like behavior remain intact, ruling out enhanced aversive memory, impaired active responding, or trait anxiety. This points to a discrete endophenotype of dysregulated approach-avoidance resolution, reminiscent of situational phobia. New data implicates infralimbic PFC-to-amygdala circuits; we are combining RNA pull-down and optogenetic approaches to identify the molecular and circuit mechanisms involved.