Understanding cellular and molecular modifications occurring in reward-related behaviors is nowadays an intense field of scientific investigation. The reward system is a complex circuit composed of several interconnected brain structures responsible for incentive salience, associative learning, reinforcement and positive emotions (i.e. pleasure). One of the most critical regions of this system is represented by the nucleus accumbens (NAc), a hub region that receives and sends information. Several cellular and molecular modifications have been observed at the level of the medium spiny neurons (MSNs) of the NAc, but we are still far from having a clear picture of their detailed mechanisms.
In a recent PLOS ONE article, Mittal and colleagues (University of California Los Angeles, UCLA) decided to investigate the role of a family of proteins, the β-arrestins, in reward-related behaviors.
β-arrestins: how do they work?
β-arrestins are versatile adapter proteins that form complexes with most G-protein-coupled receptors (GPCRs) following ligand binding and consequent activation of the receptors. It is well known that they play a critical role in the interrelated processes of GPCR desensitization and sequestration, which in turn lead to the termination of G protein activation and signaling cascades. This causes specific dampening of cellular responses to specific stimuli such as hormones, neurotransmitters, or sensory signals. While β-arrestin 2 (β-arr2) has been implicated in several aspects of reward-related learning and behaviors, very little is known about the behavioral function of β-arrestin 1 (β-arr1). Both isoforms regulate remodeling of the actin cytoskeleton to influence chemotaxis and trafficking of specific G-protein coupled receptors and they are ubiquitously expressed in the central nervous system.
β-arrestins and the brain reward system
In their article, Mittal and colleagues hypothesized that β-arr1, “may influence basal glutamatergic signaling and cocaine-induced adaptations of this [the glutamatergic] excitatory system within the NAc”. This would alter specific aspects of reward processing. Thus, using β-arr1 knock-out (KO) mice as well as behavioral and electrophysiological assays to examine this hypothesis the authors have defined specific roles of β-arr1 and glutamate receptors NMDA-Rs in reward processing.
Interestingly, mice lacking β-arr1 showed a delay in the initial phases of both the acquisition and extinction of cocaine self-administration, a behavioral test that allows researchers to study changes in distinct aspects of drug-taking behavior that model behaviors observed in drug addicts. This first set of behavioral results indicate that β-arr1 is involved in regulating the acquisition and extinction of instrumental cocaine self-administration. To determine whether these impairments induced by β-arr1 deletion could be generalized to other rewarding stimuli, the authors conducted a series of experiments using a battery of food-motivated behaviors. Surprisingly, β-arr1 KO mice also showed an impairment in developing Pavlovian conditioned (goal-directed) behavior and in the amount of efforts needed to obtain palatable food. Altogether these results suggest that β-arr1 may play a central role in driving reward-related behaviors.
Next, in order to fully explore the molecular mechanisms underlying the behavioral performances observed in β-arr1 KO mice, Mittal et al. performed electrophysiological recordings at the level of the excitatory glutamatergic synapses of the NAc. It must be mentioned that glutamatergic transmission within the nucleus accumbens is a central component of reward-related adaptations. The synaptic strength was then measured as the AMPA/NMDA (A/N) ratio. “We found that deleting β-arr1 increased the A/N ratio and reduced GluN2B-NMDARs in NAc shell MSNs”, say Nitish Mittal, the leading author of the paper.
Since β-arr1 plays an important role in regulating actin turnover to modulate exocytosis and endocytosis it may be possible that actin dynamics regulate the trafficking of the GluN2B subunit of the NMDA receptors. In fact, pharmacological blockade of actin remodeling was able to alter synaptic strength in wildtype littermates but not in β-arr1 KO mice, thus suggesting a molecular link between β-arr1 and NMDA receptors. “Based on our findings”, say Wendy Walwyn, the senior author of the study, “it is possible that deleting β-arr1, or inactivating cofilin [actin dynamics], disrupts actin turnover and microtubule disassembly to reduce the transport of GluN2B-containing NMDARs to the cell membrane, or stability once in place”. Given the fact that β-arr1 genetic ablation disrupts GluN2B-NMDA receptor functions, the authors investigated whether chronic inhibition of GluN2B-NMDA receptors in the NAc would produce similar behavioral impairments as observed in β-arr1 KO mice.
At the behavioral level, pharmacological inactivation of GluN2B subunits significantly inhibited instrumental lever pressing behavior in WT littermates, thus suggesting a potential link between NMDA and β-arr1. However, the same pharmacological strategy was not performed in β-arr1 KO mice, thus making the final assumption not definitively proved.
“Although further studies are needed to fully define the underlying cellular mechanisms and causal relationships, this study is the first to examine the role of this arrestin isoform in reward-motivated behaviors”, conclude the authors.
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Any views expressed are those of the author, and do not necessarily reflect those of PLOS.
Giuseppe Gangarossa received his PhD in Biomedical Sciences, specialty Neuroscience, from the University of Bologna. He has been a visiting fellow at the Karolinska Institutet (Sotckholm, Sweden), the French Inserm (Montpellier, France) and the Collège de France (Paris, France). Giuseppe is currently Assistant Professor of Physiology at the University Paris Diderot. His main research topic is dopamine-related brain disorders. You can follow him on twitter @PeppeGanga