Bidirectional emotional regulation through prefrontal innervation of the locus coeruleus

Abstract Traumatic experiences produce powerful emotional memories which can subsequently be enhanced or reduced through cognitive control mechanisms. Noradrenaline from the brainstem locus coeruleus (LC) is activated during aversive emotion-inducing experiences and upregulated in individuals suffering from anxiety and trauma related disorders. The medial prefrontal cortex (mPFC) participates in cognitive and emotional control processes such as production of learned defensive responses and suppression of aversive memories through extinction. However, it is unclear whether or how distinct mPFC regions influence the LC to regulate learned emotional responding. Using viral based anatomical tracing techniques, we found that the LC receives topographically organized projections from the prelimbic (PL) and infralimbic (IL) subregions of mPFC. Furthermore, optogenetic approaches revealed that PL and IL inputs to LC are required to inhibit or facilitate, respectively, the extinction of aversive memories. Moreover, LC-projecting neurons in PL and IL exhibited distinct activity patterns during extinction learning, with IL-to-LC neurons displaying sustained, sensory cue-evoked activation, while activity in PL-to-LC inputs is elevated during periods of externally and internally generated aversive emotional responding. Together, these results demonstrate that mPFC subregions bidirectionally regulate extinction of emotional memories through differential modulation of the LC-noradrenaline system.