Abstract：
Isolation of rodents throughout adolescence is known to induce many behavioral abnormalities which resemble neuropsychiatric disorders. Separately, this paradigm has also been shown to induce long-term metabolic changes consistent with a pre-diabetic state. Here, we investigate changes in central serotonin (5-HT) and glucagon-like peptide 1 (GLP-1) neurobiology that dually accompany behavioral and metabolic outcomes following social isolation stress throughout adolescence. We find that adolescent-isolation mice exhibit elevated blood glucose levels, impaired peripheral insulin signaling, altered pancreatic function, and fattier body composition without changes in bodyweight. These mice further exhibited disruptions in sleep and enhanced nociception. Using bulk and spatial transcriptomic techniques, we observe broad changes in neural 5-HT, GLP-1, and appetitive circuits. We find 5-HT neurons of adolescent-isolation mice to be more excitable, transcribe fewer copies of Glp1r (mRNA; GLP-1 receptor), and demonstrate resistance to the inhibitory effects of the GLP-1R agonist semaglutide on action potential thresholds. Surprisingly, we find that administration of semaglutide, commonly prescribed to treat metabolic syndrome, induced deficits in social interaction in group-housed mice and rescued social deficits in isolated mice. Overall, we find that central 5-HT circuitry may simultaneously influence mental well-being and metabolic health in this model, via interactions with GLP-1 and proopiomelanocortin circuitry.
摘要：
已知在整个青春期隔离啮齿动物会诱发许多行为异常，类似于神经精神疾病。分别,这种模式也被证明可以诱导与糖尿病前期状态一致的长期代谢变化.这里,我们调查了中枢5-羟色胺(5-HT)和胰高血糖素样肽1(GLP-1)神经生物学的变化,这些变化在整个青春期都伴随着社会隔离应激后的行为和代谢结局.我们发现青少年隔离小鼠表现出升高的血糖水平，外周胰岛素信号受损，改变胰腺功能，和更胖的身体成分没有变化的体重。这些小鼠进一步表现出睡眠中断和增强的伤害感受。使用批量和空间转录组技术，我们观察到神经5-HT的广泛变化，GLP-1和食欲回路。我们发现青春期隔离小鼠的5-HT神经元更容易兴奋，转录较少的Glp1r（mRNA；GLP-1受体）拷贝，并证明对GLP-1R激动剂司马鲁肽对动作电位阈值的抑制作用具有抗性。令人惊讶的是,我们发现司马鲁肽的管理，通常用于治疗代谢综合征，在群居小鼠中诱导社会互动缺陷，并在孤立小鼠中拯救社会缺陷。总的来说,我们发现，在这个模型中，中央5-HT电路可能同时影响心理健康和代谢健康，通过与GLP-1和前黑皮质素电路的相互作用。
