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.