Junod Anouchka, Opendak Maya, LeDoux Joseph E, Sullivan Regina M
Emotional Brain Institute, Nathan Kline Institute, Orangeburg, NY, United States.
Child and Adolescent Psychiatry, New York University School of Medicine, New York, NY, United States.
Front Behav Neurosci. 2019 Jun 25;13:130. doi: 10.3389/fnbeh.2019.00130. eCollection 2019.
Early life maltreatment by the caregiver constitutes a major risk factor for the development of later-life psychopathologies, including fear-related pathologies. Here, we used an animal model of early life maltreatment induced by the Scarcity-Adversity Model of low bedding (LB) where the mother is given insufficient bedding for nest building while rat pups were postnatal days (PN) 8-12. To assess effects of maltreatment on the expression of threat-elicited defensive behaviors, animals underwent odor-shock threat conditioning at three developmental stages: late infancy (PN18), adolescence (PN45) or adulthood (>PN75) and tested the next day with odor only presentations (cue test). Results showed that in typically developing rats, the response to threat increases with maturation, although experience with maltreatment in early infancy produced enhanced responding to threat in infancy and adulthood, but a decrease in maltreated adolescents. To better understand the unique features of this decreased threat responding in adolescence, c-Fos expression was assessed within the amygdala and ventromedial prefrontal cortex (vmPFC) associated with the cued expression of threat learning. Fos counts across amygdala subregions were lower in LB rats compared to controls, while enhanced c-Fos expression was observed in the vmPFC prelimbic cortex (PL). Correlational analysis between freezing behavior and Fos revealed freezing levels were correlated with CeA in controls, although more global correlations were detected in LB-reared rats, including the BA, LA, and CeA. Functional connectivity analysis between brain regions showed that LB reared rats exhibited more diffuse interconnectivity across amygdala subnuclei, compared the more heterogeneous patterns observed in controls. In addition, functional connectivity between the IL and LA switched from positive to negative in abused adolescents. Overall, these results suggest that in adolescence, the unique developmental decrease in fear expression following trauma is associated with distinct changes in regional function and long-range connectivity, reminiscent of pathological brain function. These results suggest that early life maltreatment from the caregiver perturbs the developmental trajectory of threat-elicited behavior. Indeed, it is possible that this form of trauma, where the infant's safety signal or "safe haven" (the caregiver) is actually the source of the threat, produces distinct outcomes across development.
早期生活中照顾者的虐待是后期心理病理学发展的主要风险因素，包括与恐惧相关的病理学。在此，我们使用了低垫料（LB）的稀缺-逆境模型诱导的早期生活虐待动物模型，在幼鼠出生后第8至12天，给予母亲不足的垫料用于筑巢。为了评估虐待对威胁引发的防御行为表达的影响，动物在三个发育阶段接受气味-电击威胁条件训练：婴儿后期（出生后第18天）、青春期（出生后第45天）或成年期（出生后第75天以上），并在第二天仅进行气味呈现测试（线索测试）。结果表明，在正常发育的大鼠中，对威胁的反应随着成熟而增加，尽管婴儿早期经历虐待会导致婴儿期和成年期对威胁的反应增强，但受虐待的青少年的反应会减少。为了更好地理解青春期这种威胁反应降低的独特特征，我们评估了杏仁核和腹内侧前额叶皮层（vmPFC）中与威胁学习的线索表达相关的c-Fos表达。与对照组相比，LB大鼠杏仁核各亚区域的Fos计数较低，而在vmPFC前边缘皮层（PL）中观察到c-Fos表达增强。冻结行为与Fos之间的相关性分析表明，对照组中冻结水平与中央杏仁核（CeA）相关，尽管在LB饲养的大鼠中检测到更广泛的相关性，包括基底外侧杏仁核（BA）、外侧杏仁核（LA）和CeA。脑区之间的功能连接分析表明，与对照组中观察到的更异质性模式相比，LB饲养的大鼠在杏仁核亚核之间表现出更弥散的互连性。此外，在受虐待的青少年中，岛叶（IL）和外侧杏仁核（LA）之间的功能连接从正相关转变为负相关。总体而言，这些结果表明，在青春期，创伤后恐惧表达的独特发育性降低与区域功能和长程连接的明显变化有关，这让人联想到病理性脑功能。这些结果表明，照顾者早期生活中的虐待扰乱了威胁引发行为的发育轨迹。事实上，这种形式的创伤，即婴儿的安全信号或“安全港”（照顾者）实际上是威胁的来源，可能在整个发育过程中产生不同的结果。
