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Bidirectional emotional regulation through prefrontal innervation of the locus coeruleus

Molecular Psychiatry volume 30, pages 3568–3578 (2025)Cite this article

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Abstract

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.

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Fig. 1: Anatomical connectivity from prefrontal subregions to LC-noradrenergic neurons.
Fig. 2: Prelimbic and infralimbic inputs to LC oppositely control formation of extinction memories.
Fig. 3: Distinct calcium dynamics in prelimbic and infralimbic inputs to LC during fear extinction learning.
Fig. 4: Freezing-locked calcium increases in PL-to-LC but not IL-to-LC pathway neurons.

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Data availability

All data used in this paper will be shared through the RIKEN repository (https://neurodata.riken.jp/). Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Code availability

All code used in this paper will be shared through the RIKEN repository (https://neurodata.riken.jp/). Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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Acknowledgements

We thank Yuri Sugiyama, Reiko Yoshida, and Nisha Jose for technical assistance and Kun-Lin Hsieh for assistance and code related to the breathing recording and analysis. We thank Dr. Andrew Murray for gifting the Neuro2A cell lines used for packaging CVS-strain rabies virus. This work was supported by funding from the RIKEN Center for Brain Science and KAKENHI (19H05234) to JPJ, JST-FOREST (JPMJFR2243), AMED-PRIME, and KAKENHI (21H05176, 22H02942, 19H03541) to AU, and RIKEN Junior Research Associate Program to MW.

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Authors and Affiliations

  1. RIKEN Center for Brain Science, Wako, Saitama, Japan

    Mayumi Watanabe & Joshua P. Johansen

  2. Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan

    Mayumi Watanabe & Joshua P. Johansen

  3. Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan

    Akira Uematsu

  4. International Research Center for Neurointelligence, The University of Tokyo, Tokyo, Japan

    Akira Uematsu

  5. Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan

    Akira Uematsu

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  1. Mayumi Watanabe
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MW, AU and JPJ conceived the project and designed experiments. MW carried out the experiments. MW and JPJ wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Joshua P. Johansen.

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Watanabe, M., Uematsu, A. & Johansen, J.P. Bidirectional emotional regulation through prefrontal innervation of the locus coeruleus. Mol Psychiatry 30, 3568–3578 (2025). https://doi.org/10.1038/s41380-025-02944-y

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