1 Introduction
Environmental enrichment (EE) has been shown to produce beneficial and
therapeutic effects in several preclinical models of central nervous
system disorders. Due to a combination of social, cognitive, and
sensorimotor stimulations, EE leads to a variety of positive effects,
ranging from cellular and molecular (e.g., neurogenesis, changes in the
expression of genes and receptors subunits, neurotransmitters and BDNF
levels) to cognitive and behavioral changes (e.g., enhanced learning and
memory performance, altered emotional state), in both health and disease
models (Falkenberg et al. , 1992; Kempermann et al. , 1997;
Moser et al. , 1997; Chapillon et al. , 1999; Young et
al. , 1999; Rampon et al. , 2000a; Rampon et al. , 2000b;
van Praag et al. , 2000; Roy et al. , 2001; Tang et
al. , 2001; Lee et al. , 2003; Benaroya-Milshtein et al. ,
2004; Leggio et al. , 2005).
EE-induced neuroplasticity is also involved in the protective and
curative effects of addiction disorders, with experimental evidence
suggesting stress-related mechanisms as possible targets of the
anti-addictive effect of EE (Solinas et al. , 2010; Croftonet al. , 2015). However, given the configurational complexity of
environmental stimulation, the underlying mechanisms still need further
investigation.
EE exposure duration and components (i.e., social, sensorimotor,
cognitive) seems a critical parameter for its effects. Indeed, although
chronic and acute exposure to a complex EE (with social, cognitive, and
sensory-motor components) reduces drug/sucrose-taking and -seeking
behaviors (Grimm et al. , 2008; Solinas et al. , 2008; Grimmet al. , 2013; Grimm et al. , 2016; Margetts-Smith et
al. , 2021), we however recently demonstrated that a brief EE exposure
in rats (22 hours, without motor and social components) potentiates
conditioned context (Cx)-induced sucrose-seeking (a phenomenon calledrenewal ) and Cx-memory reconsolidation after reactivation
(Pintori et al. , 2022a).
Thus, the wide variety and complexity of EE features (e.g., length of
exposure, location, type of stimulation, and many others) limited the
translation into clinical practice so far. Therefore, understanding the
mechanisms underlying acute brief EE manipulation could be useful to
develop new and innovative configurations of EE - with translational
value and feasibility - to improve existing therapeutic approaches
against addiction and addiction-related CNS disorders.
Based on data about EE-induced enhancement of memory and learning
abilities [13,26, 87], we suggested that this brief EE exposure may
act as a proactive interference agent , influencing subsequent
memory processes (i.e., renewal, Cx-memory reactivation/reconsolidation)
(Pintori et al. , 2022a). From a neurobiological point of view,
this proactive action might potentially act as a metaplastic
effect (defined as “the plasticity of synaptic plasticity” (Abraham
& Bear, 1996)), as recently suggested by electrophysiological evidence
(Eckert & Abraham, 2013; Schmidt et al. , 2013; Chiamuleraet al. , 2020). Importantly, the ability of EE to affect long-term
potentiation (LTP) and long-term depression (LTD) seems related to
alterations of glutamatergic signaling particularly at the level of NMDA
and AMPA receptors (Duffy et al. , 2001; Foster & Dumas, 2001; Liet al. , 2006; Thomas et al. , 2008; Eckert et al. ,
2010).
In the present paper, we aim to investigate whether brief EE exposure
influences the homeostasis of the glutamate synapse that could be
correlated to the behavioral effects previously reported (Pintoriet al. , 2022a). To this end, adult male Sprague-Dawley rats were
exposed to EE for 22h, and two hours after the end of EE exposure we
analyzed the expression of glutamate determinants such as: vesicular
glutamate transporter (vGluT1), which participates in the regulation of
presynaptic glutamate release and glial glutamate transporter (GLT-1),
which is responsible for glutamate reuptake, together with the
expression of the main subunits of NMDA (GluN1, GluN2A, GluN2B) and AMPA
(GluA1 and GluA2) receptors and their related scaffolding protein SAP102
(synapse-associated protein 102), SAP97 (synapse-associated protein 97)
and GRIP (glutamate receptor interacting protein). Further, we set out
to explore the potential structural effects of brief EE exposure by
measuring the expression levels of the integral protein of the glutamate
synapse post-synaptic density protein 95 (PSD95) and the cytoskeletal
protein activity-regulated cytoskeleton-associated protein (Arc/Arg3.1).
These analyses were performed in the medial prefrontal cortex (mPFC),
nucleus accumbens (NAc), and hippocampus (Hipp), both in the whole
homogenate, which provides information essentially about translational
changes, as well as in the post-synaptic density (PSD), which, instead,
informs primarily about the synaptic localization and composition of
critical determinants of the glutamatergic synapse.