Lateral habenula 5-HT4 receptor signaling restores social novelty preference after acute isolation.

Social homeostasis-the maintenance of stable social contact-is disrupted by acute social stressors such as isolation. While the lateral habenula (LHb) is known for encoding negative emotional salience, it also modulates social behavior. However, how the LHb contributes to restoring social balance after acute stress remains unclear. Here, we demonstrate that acute social isolation upregulates serotonin receptor 4 (5-HT4R) expression in the LHb. Electrophysiological analysis shows impaired long-term depression and facilitated long-term potentiation in isolated mice, which is restored by pharmacological activation of 5-HT4R. Behaviorally, group-housed mice show the typical social preference for novelty. On the other hand, isolated mice interact more with familiar mice than novel mice, which is restored by LHb-targeted 5-HT4R activation. These findings suggest that social isolation shifts social preference through 5-HT4R-mediated metaplasticity in the LHb. This study provides mechanistic insight into how acute social stress alters social behavior, with implications for social dysfunction in neuropsychiatric disorders.