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Social isolation during the vulnerable period of adolescence contributes to the occurrence of psychiatric disorders and profoundly affects brain development and adult behavior. Although the impact of social isolation during adolescence on anxiety behaviors has been well studied, much less is known about the onset and underlying mechanisms of these behaviors. We observed that following 2 weeks, but not 1 week, of social isolation, adolescent mice exhibited anxiety behaviors. Strikingly, the mGluR5 protein levels in the amygdala increased concomitantly with anxiety behaviors, and both intraperitoneal administration and intra-basolateral amygdala (BLA) infusion of MPEP, a metabotropic glutamate receptor 5 antagonist, normalized anxiety behaviors. Furthermore, electrophysiological studies showed that 2 weeks of social isolation during adolescence facilitated pyramidal neuronal excitability in the BLA, which could be normalized by MPEP. Together, these results reveal a critical period in adolescence during which social isolation can induce anxiety behaviors and facilitate BLA pyramidal neuronal excitability, both of which are mediated by mGluR5, thus providing mechanistic insights into the onset of anxiety behaviors after social isolation during adolescence.

The CreERT2 recombinase system is an advanced method to temporally control site‐specific mutagenesis in adult rodents. In this process, tamoxifen is injected to induce Cre recombinase expression, and then, Cre recombinase can excise LoxP‐flanked DNA. However, tamoxifen is a nonselective estrogen receptor antagonist that may influence behavioral alterations. Therefore, we designed five different protocols (acute effects, chronic effects, chronic effects after social defeat model, chronic effects after learned helplessness model, chronic effects after isolation models) to explore whether tamoxifen affects mouse behavior. Researching the acute/chronic effects of tamoxifen, we found that tamoxifen could influence locomotor activity, anxiety and immobility time in the forced swimming test. Researching the chronic effects of tamoxifen after social defeat/learned helplessness/isolation models, we found that tamoxifen could also influence locomotor activity, social interaction and anxiety. Therefore, the effects of tamoxifen are more complex than previously reported. Our results show, for the first time, that tamoxifen affects behavior in mouse models. Meanwhile, we compare the effects of tamoxifen in different protocols. These results will provide important information when designing similar experiments.

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