Circular RNAs (circRNAs) consist of closed loops of single-stranded RNA that are highly stable and abundant within the brain, particularly within synapses (Rybak-Wolf et al., 2015, You et al., 2015). As a result of their unique structure, circRNAs are resistant to exonuclease-mediated RNA degradation and are long-lived, exhibiting a median half-life at least 2.5 times greater than their linear counterparts (Enuka et al., 2016, Jeck et al., 2013). They are also highly conserved and abundant within the brain of many organisms, exhibit dynamic regulation across different cell types, developmental stage, and level of neural activity, and implicated in neurodegenerative and neuropsychiatric disorders (Jeck et al., 2013, Knupp and Miura, 2018, Lukiw, 2013, Rybak-Wolf et al., 2015, Wang et al., 2018, You et al., 2015, Zimmerman et al., 2020). Given these features, circRNAs are widely speculated to act as “memory molecules”; however, few studies have directly linked circRNA function with memory.

One particularly robust memory protocol with relevance to human health is Pavlovian fear conditioning and fear extinction, which is behaviourally analogous to exposure therapy in humans and has well-established neuronal circuitry. In particular, the medial prefrontal cortex (mPFC) is a region that is critical for fear extinction memory and contains the prelimbic cortex and infralimbic cortex, which mediate fear expression and fear extinction memory consolidation and retrieval, respectively (Sierra-Mercado et al., 2011, Stern et al., 2014, Thompson et al., 2010). Here we investigated the functional role of circRNAs in fear extinction memory, finding that the expression of circRNAs in the mPFC of fear extinction-trained mice occurs in a compartmentalised manner, and that the activity of cerebellar degeneration-related protein 1 antisense RNA (Cdr1as) within the neural processes of the infralimbic cortex is directly involved in fear extinction.