Social cooperation is essential to animals' physical health and psychological state. However, the underlying molecular and neurobiological mechanisms remain poorly understood. Here, we established a novel model for systematically evaluating the cooperative behavior of mice for the task of water reward. Using this paradigm, we characterized cooperative de cits in isolated juvenile mice and the corrective effect of resocialization. Mechanistically, we found that the transcription factor early growth response 2 (Egr2)-dependent myelin maturation in the medial prefrontal cortex is necessary for the development of mice's cooperative behavior. Additionally, corticosterone levels in the serum and medial prefrontal cortex were elevated in the isolated mice, potentially contributing to Egr2 expression reduction. This work suggests targeting Egr2 could be targeted for preventing and treating social isolation-related neuropsychiatric disorders in the future.
Main TextSocial cooperation is a highly conserved and sophisticated behavior that exists from bacterial swarming, ants, bees, rodents, primates to humans 1 . Cooperation is crucial for social species to overcome tasks that a single individual cannot accomplish, and thus contributes to their physical health, survival, and reproduction 2,3 . Disruptions in social behaviors frequently occur in a variety of disorders in the central nervous system (CNS) including depression, autism, schizophrenia, bipolar disorder, obsessivecompulsive disorder, and Alzheimer's disease [4][5][6][7][8] . Recently, several studies investigated cooperative behavior in sh model species and rats with different types of reward tasks 9-12 . However, the detailed neurobiological and molecular mechanisms underlying cooperative behavior remain largely undetermined. Addressing these issues will help to further explore brain functions and nd potential therapeutic strategies for isolation-related neuropsychiatric disorders.
Establishing a paradigm for evaluating mice's cooperative abilityWe rst established a system in which two mice are induced to accomplish position tasks simultaneously to get water. The mouse was rst trained individually to complete the task and then get the water as a reward (Fig. 1b & Supplementary Video 1). After 7 consecutive days of training, all mice mastered to use this device to drink water, as re ected by the declining to latter attened curve for drinking latency, and the rising to latter attened curves for drinking number and drinking time (Fig. 1b, c). Subsequently, two trained mice were put into one cage, where the two mice could get water only if they accomplished the tasks simultaneously, a behavior we consider best explained by cooperation (Fig. 1d, Supplementary Video 2). Through the 5-day testing period, there was a consistent reduction in co-drinking latency, and consistent increases in co-drinking number and accumulated drinking time each day (Fig. 1e). This behavioral improvement could not be explained by stochastic co-occurrence, which should predict attened curves ...
