Unstable Maternal Environment, Separation Anxiety, and Heightened CO2 Sensitivity Induced by Gene-by-Environment Interplay

BackgroundIn man, many different events implying childhood separation from caregivers/unstable parental environment are associated with heightened risk for panic disorder in adulthood. Twin data show that the occurrence of such events in childhood contributes to explaining the covariation between separation anxiety disorder, panic, and the related psychobiological trait of CO2 hypersensitivity. We hypothesized that early interference with infant-mother interaction could moderate the interspecific trait of response to CO2 through genetic control of sensitivity to the environment. MethodologyHaving spent the first 24 hours after birth with their biological mother, outbred NMRI mice were cross-fostered to adoptive mothers for the following 4 post-natal days. They were successively compared to normally-reared individuals for: number of ultrasonic vocalizations during isolation, respiratory physiology responses to normal air (20%O2), CO2-enriched air (6% CO2), hypoxic air (10%O2), and avoidance of CO2-enriched environments. ResultsCross-fostered pups showed significantly more ultrasonic vocalizations, more pronounced hyperventilatory responses (larger tidal volume and minute volume increments) to CO2-enriched air and heightened aversion towards CO2-enriched environments, than normally-reared individuals. Enhanced tidal volume increment response to 6%CO2 was present at 16–20, and 75–90 postnatal days, implying the trait's stability. Quantitative genetic analyses of unrelated individuals, sibs and half-sibs, showed that the genetic variance for tidal volume increment during 6%CO2 breathing was significantly higher (Bartlett χ = 8.3, p = 0.004) among the cross-fostered than the normally-reared individuals, yielding heritability of 0.37 and 0.21 respectively. These results support a stress-diathesis model whereby the genetic influences underlying the response to 6%CO2 increase their contribution in the presence of an environmental adversity. Maternal grooming/licking behaviour, and corticosterone basal levels were similar among cross-fostered and normally-reared individuals. ConclusionsA mechanism of gene-by-environment interplay connects this form of early perturbation of infant-mother interaction, heightened CO2 sensitivity and anxiety. Some non-inferential physiological measurements can enhance animal models of human neurodevelopmental anxiety disorders.研究背景：在人类中，诸多预示儿童时期与照料者分离/父母养育环境不稳定的不良事件，均与成年后罹患惊恐障碍（panic disorder）的风险升高显著相关。双生子研究数据表明，儿童时期此类不良事件的发生，有助于解释分离焦虑障碍（separation anxiety disorder）、惊恐发作以及与之相关的二氧化碳高敏感性（CO2 hypersensitivity）心理生物学特质之间的共变关系。本研究提出假说：早期母婴互动受到干扰，可通过调控机体对环境刺激的敏感性的遗传机制，调节对二氧化碳刺激的反应特质。 研究方法：将出生后最初24小时与亲生母亲共处的远交系NMRI小鼠，在出生后的前4天寄养于养母身边；随后将这些寄养小鼠与正常饲养的小鼠进行多维度比较，比较指标包括：隔离状态下的超声波发声次数、呼吸生理学对正常空气（20%O2）、富二氧化碳空气（6% CO2）、低氧空气（10%O2）的反应，以及对富二氧化碳环境的回避行为。 研究结果：与正常饲养小鼠相比，交叉寄养幼鼠的超声波发声次数显著更多，对富二氧化碳空气的过度通气反应更为显著（潮气量与每分通气量增幅更大），且对富二氧化碳环境的回避行为更强。在出生后16~20天以及75~90天时，幼鼠对6%CO2的潮气量增幅反应均显著增强，表明该反应特质具有稳定性。对无亲缘关系个体、同胞及半同胞的数量遗传学分析显示，在呼吸6%CO2时，交叉寄养组幼鼠的潮气量增幅遗传方差显著高于正常饲养组（巴特莱特χ=8.3，p=0.004），两组的遗传力（heritability）分别为0.37与0.21。上述结果支持应激-易感模型（stress-diathesis model），该模型指出，当个体遭遇环境逆境时，调控6%CO2反应的遗传因素的作用会显著增强。交叉寄养组与正常饲养组幼鼠的母鼠理毛/舔舐行为，以及基础皮质酮水平均无显著差异。 研究结论：母婴互动早期受到扰动的这种情形，可通过基因-环境交互作用（gene-by-environment interplay）的机制，与二氧化碳高敏感性升高及焦虑症状关联起来。部分非推论性生理指标可用于优化人类神经发育性焦虑障碍的动物模型。