CS - plasticity and behavioral-state integration in the posterior insula during auditory fear learning

During fear learning, animals learn to associate sensory cues (conditioned stimulus, CS) with aversive outcomes, and neurons in several brain areas become entrained to the CS. The posterior insular cortex (pInsCx) contains representations of internal states and sensory cues, amongst them auditory stimuli. Nevertheless, the possibility of plastic encoding of auditory responses in the pInsCx during fear learning, and its underlying synaptic mechanisms have not been addressed. Using single-unit recordings in the pInsCx of male mice during fear learning, we find that ∼ 10% of putative principal neurons acquire a response to an auditory CS during fear learning (“CS learners”). CS learners are enriched in the insula auditory field (IAF) of the dorsal pInsCx, and strongly overlap with a larger neuronal subpopulation which increases its activity during movement initiation. Using optogenetic circuit mapping, we find that the IAF receives glutamatergic synapses from the non-lemniscal auditory thalamus and the auditory cortex (A1); fear learning induces a postsynaptic form of LTP at the cortical, but not at the thalamic input synapse. Combined single-unit recordings and optogenetic axon silencing showed that the acquired CS-response during fear recall depends on transmission at the A1 → pInsCx synapse. Our study shows that the pInsCx generates a plastic representation of an auditory CS during fear learning, driven by LTP of an associative cortical input. Future work should further investigate how the integration of CS- and movement information in the insula contributes to the expression of auditory-cued fear memories.