LONG-LASTING ANXIETY FOLLOWING STRONG FEAR CONDITIONING DEPENDS ON REACTIVATION OF AUDITORY MEMORY TRACES IN THE HIGHER-ORDER AUDITORY CORTEX

Traumatic experiences can lead to persistent anxiety and social withdrawal long after the trauma, yet the neural mechanisms linking fear memories to generalized maladaptive states remain poorly understood. While trauma-related anxiety is commonly attributed to diffuse stress effects and fear generalization, it remains unknown whether sensory-specific fear memories actively sustain anxiety after trauma. Here, we show that strong auditory fear conditioning in rats induces enduring anxiety- like behavior and social deficits. Using activity-dependent neuronal tagging, we identify a population of neurons in the higher-order auditory cortex (Te2) that encodes auditory fear memory and is reactivated in anxiogenic environments even in the absence of the conditioned stimulus. This reactivation occurs only after strong, but not mild, conditioning, and selectively during anxiety- related states, but not during exploration of non-anxiogenic environments. Strikingly, selective pharmacogenetic disruption of these memory-encoding neuronal ensembles long after conditioning normalizes anxiety-like behavior and restores social interaction, while leaving contextual fear
memory intact. This effect is modality-specific and independent of auditory perception, as deafened animals continue to display elevated anxiety.
Together, our findings establish a causal link between a discrete cortical fear memory ensemble and persistent anxiety-like and social behavioral alterations, providing a mechanistic framework for understanding how intrusive sensory memories drive long-term maladaptive emotional states.