Chelini Gabriele, Fortunato-Asquini Tommaso, Cerilli Enrica, Monsorno Katia, Catena Benedetta, Dall'O' Ginevra Matilde, Paolicelli Rosa Chiara, Bozzi Yuri
Center for Mind/Brain Sciences, University of Trento, Piazza della Manifattura n.1, 38068, Rovereto, TN, Italy.
Department of Biomedical Sciences, University of Lausanne, Rue du Bugnon n.7, CH-1005, Lausanne, Switzerland.
Neurobiol Stress. 2025 Apr 22;36:100726. doi: 10.1016/j.ynstr.2025.100726. eCollection 2025 May.
The etiological complexity of psychiatric disorders arises from the dynamic interplay between genetic and environmental vulnerabilities. Among the environmental components, early-life adversities are a major risk factor for developing a psychiatric condition. Yet, the interaction between adversities early in life and genetic vulnerability contributing to psychopathology is poorly understood. To fill this gap, we took advantage of the ideally controlled conditions of a pre-clinical approach. We raised a mouse model with genetic predisposition for multiple psychiatric disorders (autism spectrum, schizophrenia, bipolar disorder), the mouse, with limited bedding and nesting (LBN), a well-established paradigm to induce early-life stress in rodents. These mice were compared to LBN-raised littermates, as well as parallel groups of and raised in standard conditions. Using a battery for behavioral phenotyping we show that early-life adverse experience shapes non-overlapping phenotypic landscapes based on genetic predisposition. Specifically, LBN-raised mice displayed a perseverative risk-taking behavior in the elevated plus maze. Interestingly, this trait was highly predictive of their success in social interaction, suggesting that the intrusion of anxiety into the social behavioral domain may contribute to extreme gain- or loss-of function in sociability. Finally, we show that LBN promotes hypertrophy of post-synaptic densities in the basolateral nucleus of the amygdala (BLA), but only in raised in LBN this is associated with microglia abnormalities. We conclude that the interplay between early-life adversities and haploinsufficiency alters emotion regulation in mice, putatively as a consequence of deficient synaptic scaling in the BLA.
精神疾病的病因复杂性源于遗传易感性和环境易感性之间的动态相互作用。在环境因素中，早期生活逆境是患精神疾病的主要风险因素。然而，人们对早期生活逆境与导致精神病理学的遗传易感性之间的相互作用了解甚少。为了填补这一空白，我们利用了临床前方法的理想控制条件。我们培育了一种对多种精神疾病（自闭症谱系障碍、精神分裂症、双相情感障碍）具有遗传易感性的小鼠模型，即 小鼠，通过有限的垫料和筑巢条件（LBN），这是一种在啮齿动物中诱导早期生活压力的成熟范式。将这些小鼠与在LBN条件下饲养的同窝小鼠进行比较，以及与在标准条件下饲养的 和 平行组进行比较。通过一系列行为表型分析，我们发现早期生活不良经历根据遗传易感性塑造了不重叠的表型格局。具体而言，在LBN条件下饲养的 小鼠在高架十字迷宫中表现出持续的冒险行为。有趣的是，这一特征高度预测了它们在社交互动中的成功，表明焦虑侵入社交行为领域可能导致社交能力的极端功能增强或丧失。最后，我们发现LBN促进杏仁核基底外侧核（BLA）中突触后密度的肥大，但只有在LBN条件下饲养的 小鼠中，这与小胶质细胞异常有关。我们得出结论，早期生活逆境与单倍体不足之间的相互作用改变了小鼠的情绪调节，推测这是BLA中突触缩放不足的结果。
