Balance between direct and indirect pathways of the nucleus accumbens controls social behavior in mice

Abstract

Background: Deficient social interactions are a hallmark of major neuropsychiatric disorders, and cumulating evidence point to altered social reward and motivation as key underlying mechanisms in these pathologies. In the present study, we aimed at assessing the role of the two striatal projecting neuronal (SPN) populations bearing either D1R or D2R dopamine receptors (D1R- and D2R-SPNs), in modulating social behavior and other behaviors often altered in neuropsychiatric disorders. Methods: We selectively ablated D1R- and D2R-SPNs using an inducible diphtheria toxin receptor (DTR)-mediated cell targeting strategy and assessed social behavior as well as repetitive/perseverative behavior, motor function and anxiety levels. We tested the effects of optogenetic stimulation of D2R-SPNs in the Nucleus Accumbens (NAc) and pharmacological compounds repressing D2R-SPN. Results: Targeted deletion of D1R-SPNs in the NAc blunted social behavior in mice, facilitated skill motor learning and increased anxiety levels. These behaviors were normalized by pharmacological inhibition of D2R-SPN, which also repressed transcription in the efferent nucleus, the ventral pallidum (VP). In contrast, ablation of D1R-SPNs in the dorsal striatum had no impact on social behavior, impaired motor skill learning, and decreased anxiety levels. Deletion of D2R-SPNs in the NAc also produced motor stereotypies but facilitated social behavior and impaired skill motor learning. We mimicked excessive D2R-SPN activity by optically stimulating D2R-SPNs in the NAc and evidenced a severe deficit in social interaction that was prevented by D2R-SPN pharmacological inhibition. Conclusions: Repressing D2R-SPN activity may represent a promising therapeutic strategy to relieve social deficit in neuropsychiatric disorders.

Nucleus accumbens D1- and D2-expressing neurons control the balance between feeding and activity-mediated energy expenditure

“…Even though speculative, overall, our findings suggest that chronic dysfunction in the balance of activities of D1- and D2-neuron of the NAc could participate to the etiology of EDs by altering, positively or negatively, the willingness to engage in, and/or the rewarding value of, physical activity. These findings expand the importance of the balance of activities between striatal D1- and D2-neurons to control behavior 52,53 .…”

The cortico-striatal circuitry in autism-spectrum disorders: a balancing act

“…Targeted loss of the endocannabinoid receptor-mediated signaling pathway in the dorsal striatum, but not the nucleus accumbens, impairs social behavior, an effect reproduced by a targeted loss of the signaling pathway in dMSNs but not iMSNs ( Shonesy et al, 2018 ). Loss of dMSNs in the accumbens nucleus, but not the dorsal striatum, also blunts social behavior ( Le Merrer et al, 2024 ). Interestingly, the detrimental effect of loss of dMSNs on social behavior in mice can be reversed by the pharmacological inactivation of iMSNs ( Le Merrer et al, 2024 ), suggesting a complementary role of the two pathways.…”

“…Loss of dMSNs in the accumbens nucleus, but not the dorsal striatum, also blunts social behavior ( Le Merrer et al, 2024 ). Interestingly, the detrimental effect of loss of dMSNs on social behavior in mice can be reversed by the pharmacological inactivation of iMSNs ( Le Merrer et al, 2024 ), suggesting a complementary role of the two pathways. This conclusion is also supported by evidence that optogenetic activation of iMSNs in the nucleus accumbens of stress-naïve mice induces social avoidance following a subthreshold exposure to a social defeat stressor while chronic social defeat stress is paralleled by a decreased activity of dMSNs that parallels social avoidance ( Francis et al, 2015 ).…”

“…This effect is paralleled by a decreased synaptic inhibition of dMSNs ( Rothwell et al, 2014 ). Similarly, impairment of the endocannabinoid pathway in nucleus accumbens dMSNs results in excessive repetitive grooming ( Shonesy et al, 2018 ) and inactivation of dMSNs in the nucleus accumbens, but iMSNs in the dorsal striatum, induces stereotypies ( Le Merrer et al, 2024 ). A contribution of the nucleus accumbens to repetitive behaviors appears consistent with recent evidence that both the nucleus accumbens and the dorsal striatum are implicated in the generation of sequential movements ( Fraser et al, 2023 ).…”