Across species, unpredictable patterns of maternal behavior are emerging as novel predictors of aberrant cognitive and emotional outcomes later in life. In animal models, exposure to unpredictable patterns of maternal behavior alters brain circuit maturation and cognitive and emotional outcomes. However, whether exposure to such signals in humans alters the development of brain pathways is unknown. In mother–child dyads, we tested the hypothesis that exposure to more unpredictable maternal signals in infancy is associated with aberrant maturation of corticolimbic pathways. We focused on the uncinate fasciculus, the primary fiber bundle connecting the amygdala to the orbitofrontal cortex and a key component of the medial temporal lobe–prefrontal cortex circuit. Infant exposure to unpredictable maternal sensory signals was assessed at 6 and 12 months. Using high angular resolution diffusion imaging, we quantified the integrity of the uncinate fasciculus using generalized fractional anisotropy (GFA). Higher maternal unpredictability during infancy presaged greater uncinate fasciculus GFA in children 9–11 years of age (n = 69, 29 female). In contrast to the uncinate, GFA of a second corticolimbic projection, the hippocampal cingulum, was not associated with maternal unpredictability. Addressing the overall functional significance of the uncinate and cingulum relationships, we found that the resulting imbalance of medial temporal lobe–prefrontal cortex connectivity partially mediated the association between unpredictable maternal sensory signals and impaired episodic memory function. These results suggest that unbalanced maturation of corticolimbic circuits is a mechanism by which early unpredictable sensory signals may impact cognition later in life.

SIGNIFICANCE STATEMENT Our prior work across species demonstrated that unpredictable patterns of maternal care are associated with compromised memory function. However, the neurobiological mechanisms by which this occurs in humans remain unknown. Here, we identify an association of exposure to unpredictable patterns of maternal sensory signals with the integrity of corticolimbic circuits involved in emotion and cognition using state-of-the-art diffusion imaging techniques and analyses. We find that exposure to early unpredictability is associated with higher integrity of the uncinate fasciculus with no effect on a second corticolimbic pathway, the cingulum. The resulting imbalance of corticolimbic circuit development is a novel mediator of the association between unpredictable patterns of maternal care and poorer episodic memory.

在整个物种中，不可预测的母体行为模式正在成为晚年异常认知和情感结果的新预测因子。在动物模型中，暴露于不可预测的母体行为模式会改变大脑回路的成熟度以及认知和情绪结果。然而，人类暴露于此类信号是否会改变大脑通路的发育尚不清楚。在母婴二元组中，我们检验了婴儿期接触更不可预测的母体信号与皮质边缘通路异常成熟相关的假设。我们专注于钩束，将杏仁核连接到眶额皮质的初级纤维束，以及内侧颞叶 - 前额皮质回路的关键组成部分。在 6 个月和 12 个月时评估婴儿暴露于不可预测的母体感觉信号。使用高角分辨率扩散成像，我们使用广义分数各向异性 (GFA) 量化了钩束的完整性。婴儿期较高的母体不可预测性预示着 9-11 岁儿童的钩束 GFA 较高（n = 69, 29 名女性）。与第二个皮质边缘投射（海马扣带回）的钩突相比，GFA 与母体的不可预测性无关。针对钩突和扣带关系的整体功能意义，我们发现由此产生的内侧颞叶-前额叶皮质连接失衡部分介导了不可预测的母体感觉信号与情景记忆功能受损之间的关联。这些结果表明，皮质边缘电路的不平衡成熟是一种机制，早期不可预测的感觉信号可能会通过这种机制影响生命后期的认知。

重要性声明我们之前跨物种的工作表明，不可预测的母体护理模式与记忆功能受损有关。然而，在人类中发生这种情况的神经生物学机制仍然未知。在这里，我们使用最先进的扩散成像技术和分析确定了暴露于不可预测的母体感觉信号模式与涉及情绪和认知的皮质边缘电路完整性之间的关联。我们发现，暴露于早期不可预测性与钩束的更高完整性有关，而对第二个皮质边缘通路，即扣带回没有影响。由此产生的皮质边缘电路发育不平衡是不可预测的孕产妇护理模式与较差的情景记忆之间关联的新中介。