4.5 Conclusions
Our findings demonstrate that a brief EE exposure dynamically modulates the glutamatergic synapses in mPFC-NAc-Hipp circuitry, which play an important role in reward and reward-related processes. Particularly, brief EE exposure was able to alter postsynaptic NMDA/AMPA receptor configurations, through changes in subunit composition of such receptors, as well as changes in the expression of their main scaffolding proteins.
An added value of our study derives from the fact that each investigated region showed its specific modulation profile of the glutamate synapse. Consistently with our previous behavioral findings (Pintori et al. , 2022a), this metaplastic fingerprint induced by EE supports the hypothesis that brief EE exposure potentiates sucrose-seeking behaviors affecting subsequent learning processes, such as renewal or Cx-memory reactivation and reconsolidation. In line with this speculation, the reduction of cortical excitability induced by EE experience, along with a concomitant increase of Ca2+ permeability in the NAc and the Hipp, may alter salience attribution and behavioral response to reward-associated stimuli, thus enhancing sucrose-seeking behaviors when re-exposed to sucrose-paired context (Fig. 4).
In conclusion, our data confirm the modulatory activity of brief EE manipulation on glutamatergic synapses, which could pave the way to develop innovative configurations of EE - with greater translational value feasibility - to improve existing therapeutic approaches against addiction and addiction-related CNS disorders.
Author contributions Cristiano Chiamulera: Conceptualization; methodology; project administration; resources; writing. Nicholas Pintori: Conceptualization; methodology; investigation; data curation; formal analysis; visualization; writing. Fabio Fumagalli: Conceptualization, methodology; writing. Alessandro Piva: investigation; data curation; visualization. Francesca Mottarlini: Investigation; data curation; formal analysis; visualization. Coralie Maggi: Investigation; data curation; visualization. Lucia Caffino: Investigation; data curation; formal analysis; visualization.
Funding and disclosure Research was supported by Fondazione Cariverona (Italy) for the project ”The role of neurogenesis and enriched environment in maladaptive memories” and by grants from MIUR Progetto Eccellenza 2023-2027. Nicholas Pintori was the recipient of a fellowship from Fondazione Cariverona for the same project. Francesca Mottarlini is the recipient of a fellowship from the Zardi-Gori Foundation.
Data Availability The data sets generated during and/or analyzed during the current study are not publicly available due to the confidentiality restrictions of the funding body but are available from the corresponding author on reasonable request.
Ethics Approval This study was approved by the ethical committee (OPBA) of the University of Verona and by the Ministry of Health (authorization n. 780/2019-PR) in compliance with the European Union regulations and Directive 2010/63/EU.
Conflict of Interest The authors declare no competing interests.