The nucleus accumbens (NAc) responds to both natural and non-natural rewards as well as aversive stimuli; however, it remains unclear how motivationally relevant rewarding and aversive experiences are represented within NAc neuronal ensembles. Here we used Fos-CreERT2-based activity-dependent tagging to label NAc neuronal ensembles activated by a potent non-natural reward, cocaine, or by foot shock. We found that the cocaine ensemble consists predominantly of dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs), whereas the foot shock ensemble contains both D1- and D2-MSNs.
One-photon calcium imaging in freely moving mice revealed that acute cocaine primarily excites D1-MSNs while inhibiting most D2-MSNs, whereas foot shock induced excitatory responses in both types of MSNs. Optogenetic reactivation of the cocaine-ensemble elicited a strong behavioral preference, whereas reactivation of the shock-ensemble produced only modest behavioral effect. Together, these findings indicate that rewarding and aversive experiences recruit partially overlapping NAc ensembles with distinct cellular composition, activity dynamics, and behavioral outcomes.
While both stimuli engage shared neuronal populations, only reactivation of cocaine-responsive ensembles change behavioral preference and reinforcement, highlighting functional differences in how motivationally relevant experiences are represented within the NAc. This work was funded by the Portuguese Foundation for Science and Technology (FCT) under the scope of the project 2022.01467.PTDC (DOI: 10.54499/2022.01467.PTDC), a FEBS (Federation of European Biochemical Societies) Excellence Award and “Maria de Sousa” Award attributed to Carina Soares-Cunha by Bial Foundation and Ordem dos Médicos. This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 101003187) and by the “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/HR20/52400020.
CS-C received financial support from FEDER, COMPETE 2030 and national funds from FCT through the project 2023.17631.ICDT (COMPETE2030-FEDER-00708300; DOI: 10.54499/2023.17631.ICDT) and FCT project 2024.14660.PEX (DOI: 10.54499/2024.14660.PEX). CS-C and BC have Scientific Employment Stimulus contracts from FCT (2023.08896.CEECIND/CP2841/CT0023 (DOI: 10.54499/2023.08896.CEECIND/CP2841/CT0023); CEECIND/03898/2020 (DOI: 10.54499/2020.03898.CEECIND/CP1600/CT0015)). RC has an FCT PhD grant (DOI: 10.54499/2021.06818.BD).
Host laboratory is funded by National funds, through FCT - projects UIDB/50026/2020 (DOI 10.54499/UIDB/50026/2020), UIDP/50026/2020 (DOI 10.54499/UIDP/50026/2020) and LA/P/0050/2020 (DOI 10.54499/LA/P/0050/2020). Supplementary information is available at TP’s website. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal Raquel Correia, Ana Verónica Domingues, Leandro AA Aguiar, Margarida Cunha-Macedo, Daniela Vilasboas-Campos, Natacha Vieitas-Gaspar, Rafael M.
Jungmann, Eduardo Teixeira, Bárbara Coimbra, Ana João Rodrigues & Carina Soares-Cunha ICVS/3B’s-PT Government Associate Laboratory, Braga/Guimarães, Portugal The authors declare no competing interests. All animal experiments complied with ARRIVE guidelines and European Union (EU) Directive 2010/63/EU and were approved by the ICVS Ethics Committee (ORBEA) and the Portuguese regulatory authority – Direção-Geral de Alimentação e Veterinária (DGAV; reference 008332). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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