Bidirectional emotional regulation through prefrontal innervation of the locus coeruleus

Traumatic experiences produce powerful emotional memories which can subsequently be adaptively or pathologically modified through cognitive-evaluative mechanisms such as fear extinction learning. Noradrenaline from the brainstem locus coeruleus (LC) is activated during aversive emotion-inducing experiences, participates in extinction learning and is upregulated in individuals suffering from anxiety and trauma related disorders. The LC-noradrenaline system receives input from the medial prefrontal cortex (mPFC), a brain region important for cognitive and emotional control. However, it is unclear whether mPFC projections to LC regulate extinction and, if so, how distinct mPFC regions influence the LC to modulate emotional memories. 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 in rats. Optogenetic inhibition approaches revealed that PL and IL inputs to LC inhibit or facilitate, respectively, the extinction of aversive memories. Moreover, LC-projecting neurons in PL and IL exhibit 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 opposingly regulate emotional memory extinction through their projections to the LC-noradrenaline system. These findings have important implications for understanding trauma related disorders which arise in part due to disrupted cognitive-emotional evaluations and impaired extinction.