Impact of the circadian nuclear receptor REV-ERBα in dorsal raphe 5-HT neurons on social interaction behavior, especially social preference

Abstract

Social interaction among conspecifics is essential for maintaining adaptive, cooperative, and social behaviors, along with survival among mammals. The 5-hydroxytryptamine (5-HT) neuronal system is an important neurotransmitter system for regulating social behaviors; however, the circadian role of 5-HT in social interaction behaviors is unclear. To investigate whether the circadian nuclear receptor REV-ERB & alpha;, a transcriptional repressor of the rate-limiting enzyme tryptophan hydroxylase 2 (Tph2) gene in 5-HT biosynthesis, may affect social interaction behaviors, we generated a conditional knockout (cKO) mouse by targeting Rev-Erb & alpha; in dorsal raphe (DR) 5-HT neurons (5-HTDR-specific REV-ERB & alpha; cKO) using the CRISPR/Cas9 gene editing system and assayed social behaviors, including social preference and social recognition, with a three-chamber social interaction test at two circadian time (CT) points, i.e., at dawn (CT00) and dusk (CT12). The genetic ablation of Rev-Erb & alpha; in DR 5-HTergic neurons caused impaired social interaction behaviors, particularly social preference but not social recognition, with no difference between the two CT points. This deficit of social preference induced by Rev-Erb & alpha; in 5-HTDR-specific mice is functionally associated with real-time elevated neuron activity and 5-HT levels at dusk, as determined by fiber-photometry imaging sensors. Moreover, optogenetic inhibition of DR to nucleus accumbens (NAc) 5-HTergic circuit restored the impairment of social preference in 5-HTDR-specific REV-ERB & alpha; cKO mice. These results suggest the significance of the circadian regulation of 5-HT levels by REV-ERB & alpha; in regulating social interaction behaviors. Animal behavior: Nighttime decrease in serotonin important for social interactionDaily fluctuation of serotonin levels during the day, controlled by a nuclear receptor called REV-ERB & alpha;, is important in social behavior and may offer insights into conditions such as autism spectrum disorder (ASD). The neurotransmitter serotonin influences behavior and mood, but how its circadian fluctuations affect social behavior is not fully understood. Kyungjin Kim at the Daegu Gyeongbuk Institute of Science & Technology in Daegu, South Korea, and co-workers used mice lacking REV-ERB & alpha; to investigate links between brain chemistry and social behaviors. These mice, in contrast to controls, showed no preference for a novel mouse over an empty cage. Real-time measurement linked this behavior to higher nighttime levels of serotonin in the brains of the receptor-deficient mice. These results contribute to understanding the biology underlying social behavior and may help identify interventions for conditions such as ASD.