Endocannabinoid modulation of a reciprocal fronto-coerulear connection in contextual discrimination
The prefrontal cortex (PFC) and locus coeruleus (LC) form a bidirectional circuit essential for cognitive control and arousal. LC-derived norepinephrine (NE) influences PFC network dynamics, yet the mechanisms by which descending PFC inputs regulate LC activity and gate its neuromodulatory feedback remain unclear. Here, we describe an anatomical and functional PFC-LC loop subject to endocannabinoid (eCB) negative feedback. Optogenetic activation of PFC terminals in the LC enhances NE release and recruits NE-sensitive neuronal activity in the PFC. Under behaviorally relevant patterns of activation, LC-derived eCBs are mobilized, thereby weakening PFC-to-LC synaptic transmission. This limits subsequent NE release in the PFC and constrains the recruitment of NE-sensitive PFC neuronal assemblies. Modulation of this PFC-LC interaction shapes outcome discrimination in place conditioning tasks. By elucidating how eCB signaling modulates the PFC-LC loop, our findings reveal how these lipid molecules fine-tune NE signaling in the PFC, which is involved in cognitive and arousal-related processes.
Authors
- Fabio Boi (ORCID: https://orcid.org/0000-0002-4541-8326)
- Dan P. Covey (ORCID: https://orcid.org/0000-0001-9596-108X)
- J. Ribeiro
- Sara Migliarini (ORCID: https://orcid.org/0000-0003-2741-269X)
- Raffaella Tonini (ORCID: https://orcid.org/0000-0003-1652-4709)
- Massimo Pasqualetti (ORCID: https://orcid.org/0000-0002-0844-8139)
- Ieva Misevičiūtė (ORCID: https://orcid.org/0000-0002-4497-8209)
- Gian Nicola Angotzi
- Luca Nava (ORCID: https://orcid.org/0000-0002-4650-5958)
- Andrea Locarno (ORCID: https://orcid.org/0000-0003-0640-1510)
- Noemi Barsotti (ORCID: https://orcid.org/0000-0002-6399-436X)
- Joseph F. Cheer (ORCID: https://orcid.org/0000-0001-5086-7559)
- Yann Pelloux (ORCID: https://orcid.org/0000-0001-8262-9969)
- Luca Berdondini
- Alessandro Caltabiano
- Ruyi Cai
- François E. Georges
- Matteo Vincenzi
- Yulong Li
Institutions
- University of Pisa (IT)
- University of Maryland, Baltimore (US)
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Italian Institute of Technology (IT)
- Chinese Institute for Brain Research (CN)
- Center for Neuroscience and Cognitive Systems (IT)
- Center for Life Sciences (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-03-23
- DOI
- https://doi.org/10.1016/j.celrep.2026.117141
- Primary Topic
- Cannabis and Cannabinoid Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00