Abstract
The mu opioid receptor (MOR) plays a critical role in modulating social behavior in humans and animals. Accordingly, MOR null mice display severe alterations in their social repertoire as well as multiple other behavioral deficits, recapitulating core and secondary symptoms of autism spectrum disorder (ASD). Such behavioral profile suggests that MOR dysfunction, and beyond this, altered reward processes may contribute to ASD etiopathology. Interestingly, the only treatments that proved efficacy in relieving core symptoms of ASD, early behavioral intervention programs, rely principally on positive reinforcement to ameliorate behavior. The neurobiological underpinnings of their beneficial effects, however, remain poorly understood. Here we back-translated applied behavior analysis (ABA)-based behavioral interventions to mice lacking the MOR (Oprm1−/−), as a model of autism with blunted reward processing. By associating a positive reinforcement, palatable food reward, to daily encounter with a wild-type congener, we were able to rescue durably social interaction and preference in Oprm1−/− mice. Along with behavioral improvements, the expression of marker genes of neuronal activity and plasticity as well as genes of the oxytocin/vasopressin system were remarkably normalized in the reward/social circuitry. Our study provides further evidence for a critical involvement of reward processes in driving social behavior and opens new perspectives regarding therapeutic intervention in ASD.
Highlights
Within the opioid system, the mu opioid receptor (MOR) plays a key role in mediating the rewarding properties of natural and artificial stimuli such as food or drugs of abuse[1,2]
We assessed social behavior using the direct social interaction test in mice belonging to the four experimental groups (NoT, OI-R, stranger every day without receiving a reward (SI-NR), SI-R) before behavioral intervention
We focused on immediate early genes and markers of plasticity (C-fos, activity-regulated cytoskeletalassociated protein (Arc)/Arg3.1, Bdnf), genes of the oxytocin/vasopressin system (Oxt, Avp, Oxtr, Avpr1a, Avpr1b) because of their key role in social behavior and evidences of altered function in Oprm1−/− mice[9,11], autism gene candidates (Nlgn[1], Foxp[1], Crh) whose expression was dysregulated in this model[9] and Grm[4], encoding mGluR4 receptors whose activation relieves autistic symptoms[9]
Summary
The mu opioid receptor (MOR) plays a key role in mediating the rewarding properties of natural and artificial stimuli such as food or drugs of abuse[1,2]. Consistent with this, genetic knockout of MOR (Oprm1−/−) in mice produces severe alterations of their social repertoire, from early life to adult age[9,10,11,12], further demonstrating that MOR is essential for establishing appropriate social behavior. Pujol et al Translational Psychiatry (2018)8:197 unique face validity for this model[16] These animals show several neurobiological landmarks of the disease, such as altered striatal function, decreased activation of the reward circuit in response to social stimuli or reduced oxytocin in the nucleus accumbens[9,11,17,18,19,20,21] that, together with the identification of ASD patients bearing mutations in the OPRM1 gene[7], demonstrate construct validity for this model. A growing body of literature points to reward deficits in patients with ASD7,18, in agreement with the social motivation theory of autism proposing that disrupted social interest in these patients would result primarily from early deficits in their motivation for attending, enjoying and prolonging social interactions[22,23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
