A brain-state-informed framework for simultaneous extinction of fear and functional magnetic resonance imaging...

Adequately responding towards a threat is a crucial mechanism for survival. Adapting this response when a threat-associated stimulus or situation has become safe requires extinction learning and formation of an extinction memory. Functional magnetic resonance imaging (fMRI) affords to longitudinally monitor network activity, yet, in the rodent, still suffers from significant variability of results and practical restrictions, mainly related to the different approaches of subject immobilization. Physical restraint of awake animals permits only short scanning times, while anesthesia can induce uncontrolled brain states with limited stimulus responsiveness and processing. Here, we implement a paradigm where light medetomidine sedation permits long scanning times in a stable brain state with functional characteristics comparable to the human resting state. We observe responsiveness of the brain to visual stimulation and large-scale resting-state network activity with small-world connectivity features. After visual fear conditioning outside the MRI scanner, rats exposed to the unreinforced visual conditioned stimulus in this stable persistent activity state inside the scanner (extinction) exhibit a significantly lower conditioned fear response when re-exposed to the conditioned stimulus days after scanning (test). We present a brain state-informed paradigm easily adaptable for future studies involving invasive neural manipulations to causally investigate extinction and its memory consolidation.