Nguyen Jennifer, Shimizu Kevin, Zlotnik Varvara, Nguyen Matthew N, Del Toro Sandra, Nguyen Michael T, Ronquillo Janet, Halladay Lindsay R
Department of Neuroscience, University of Arizona, Tucson, Arizona, USA.
bioRxiv. 2025 Apr 8:2025.04.08.647890. doi: 10.1101/2025.04.08.647890.
Understanding how genetic variability shapes responses to environmental and developmental factors is critical for advancing translational neuroscience. However, most preclinical studies rely on inbred mouse strains that do not capture the genetic complexity of human populations. One key area of translational research focuses on identifying the neural and behavioral consequences of early life trauma. Rodent models of childhood neglect, such as maternal separation with early weaning (MSEW), have been used in isogenic mouse strains like C57BL/6J (B6) to identify behavioral domains and neural loci of deficits stemming from exposure to MSEW. To understand how genetic diversity may contribute to the outcomes produced by MSEW, and thus inform future studies on the topic, we utilized the Jackson Laboratory Diversity Outbred (DO) line, a population derived from eight founder strains that exhibit broad genetic and phenotypic heterogeneity. We first compared MSEW effects on social behavior in DO mice versus B6 mice, because we have previously found social behavior deficits in B6 mice with a history of MSEW. Indeed, we established that MSEW incited social motivation deficits in DO mice, in a sex-specific manner. We then expanded our investigation of DO mice to test MSEW-related changes in anxiety-like behavior, fear learning and expression, and reward-seeking. Results revealed that MSEW produces distinct, sex-specific phenotypes: female DO mice displayed reduced social motivation and elevated anxiety-like behavior, while male DO mice showed attenuated CS-evoked fear expression and diminished reward-seeking behavior. Additionally, immunohistochemical analysis revealed increased Fos expression in the paraventricular nucleus of the hypothalamus (PVN) in MSEW-exposed DO mice, both at baseline and following acute stress. These findings highlight the importance of incorporating genetically diverse models to better capture the nuances of early life adversity-related outcomes relevant to human populations.
了解基因变异性如何塑造对环境和发育因素的反应对于推进转化神经科学至关重要。然而，大多数临床前研究依赖于近交系小鼠品系，这些品系无法捕捉人类群体的基因复杂性。转化研究的一个关键领域集中在确定早期生活创伤的神经和行为后果。童年期忽视的啮齿动物模型，如早期断奶的母婴分离（MSEW），已在C57BL/6J（B6）等近交系小鼠品系中用于识别因暴露于MSEW而产生的行为领域和缺陷的神经位点。为了了解基因多样性如何影响MSEW产生的结果，并为该主题的未来研究提供信息，我们利用了杰克逊实验室的多样性远交（DO）品系，这是一个源自八个创始品系的群体，表现出广泛的基因和表型异质性。我们首先比较了MSEW对DO小鼠和B6小鼠社交行为的影响，因为我们之前发现有MSEW病史的B6小鼠存在社交行为缺陷。事实上，我们确定MSEW以性别特异性方式引发了DO小鼠的社交动机缺陷。然后，我们扩大了对DO小鼠的研究，以测试与MSEW相关的焦虑样行为、恐惧学习和表达以及奖赏寻求方面的变化。结果显示，MSEW产生了独特的、性别特异性的表型：雌性DO小鼠表现出社交动机降低和焦虑样行为增加，而雄性DO小鼠表现出条件刺激诱发的恐惧表达减弱和奖赏寻求行为减少。此外，免疫组织化学分析显示，在基线和急性应激后，暴露于MSEW的DO小鼠下丘脑室旁核（PVN）中的Fos表达增加。这些发现强调了纳入基因多样化模型以更好地捕捉与人类群体相关的早期生活逆境相关结果细微差别的重要性。
