Juan-Carlos Cerpa, Alessandro Piccin et al. in eLife

Updating goal-directed actions requires noradrenergic signaling in the ventrolateral orbitofrontal cortex

In a constantly changing environment, organisms must track the current relationship between actions (A) and their specific outcomes (O), and use this information to guide decision-making. Such goal-directed behaviour relies on circuits involving cortical and subcortical structures.

Notably, a functional heterogeneity exists within the medial prefrontal, insular, and orbitofrontal cortices (OFC) in rodents. The role of the latter in goal-directed behaviour has been debated, but recent data indicate that the ventral and lateral subregions of the OFC (vlOFC) are needed to integrate changes in A-O relationships.

Neuromodulatory agents are also crucial components of prefrontal functioning and behavioural flexibility has been suggested to rely upon the noradrenergic (NA) modulation of the prefrontal cortex. Therefore, we assessed whether NA innervation of the vlOFC plays a role in updating A-O relationships in rats.

After learning initial A-O associations, the animals were required to flexibly encode and use new associations during an instrumental reversal task. First, we depleted NA fibres using anti-DβH saporin and observed a profound deficit in the ability to use the reversed A-O associations to guide choice. This deficit was not present when we depleted dopaminergic innervation using a combination of 6-OHDA and desipramine.

Then, we investigated the temporal and anatomical specificity of our effect using viral vector-mediated expression of inhibitory DREADDs. We found that silencing NA projections from the locus coeruleus (LC) to the vlOFC, but not to the medial prefrontal cortex, impaired the rats’ ability to acquire and express the reversed instrumental contingencies.

Collectively, our data suggest that NA projections to the vlOFC are likely required for both encoding and recalling the identity of an expected instrumental outcome, specifically when that identity has changed.

Figure adapted from Cerpa, Piccin et al. 2023. (A) Extent of viral expression across subjects injected with CAV PRS hM4Di in the vlOFC, representative whole-brain photomicrograph showing injection site (mCherry, visible staining), and example of high colocalization of immunofluorescent staining for HA (tag of inhibitory DREADDs) and mCherry in the LC of the same representative rat. (B) Reversal training in rats injected with CAV PRS hM4Di in the vlOFC (Veh n=12; DCZ n=13). (C) Reversal instrumental test following satiety-induced devaluation in rats injected with CAV PRS hM4Di in the vlOFC. Animals with bilateral LC:vlOFC NA projections silenced during the reversal training (+/-), or the outcome devaluation test (-/+), or during both phases (+/+), failed to display a preference for the new non-devalued action.


Juan Carlos Cerpa*, Alessandro Piccin*, Margot Dehove, Marina Lavigne, Eric J. Kremer, Mathieu Wolff, Shauna L. Parkes+, Etienne Coutureau+. (2023)
Inhibition of noradrenergic signalling in rodent orbitofrontal cortex impairs the updating of goal-directed actions.

* Authors contributed equally to the work
+ corresponding authors

The authors

Juan-Carlos Cerpa

(University of Oxford)
PhD student in the team until December 2019

Alessandro Piccin

(INCIA, Bordeaux)

Mathieu Wolff

Directeur de recherche
(INCIA, Bordeaux)

Shauna L. Parkes

(INCIA, Bordeaux)

Etienne Coutureau

Directeur de recherche
(INCIA, Bordeaux)

Team “Decision and Adaptation” (Team leader: Mathieu Wolff), INCIA
Univ. Bordeaux, CNRS, INCIA, UMR 5287, F-33000 Bordeaux, France

Publication: 10/05/23
Mise à jour: 17/05/23