Sgro Marissa, Kodila Zoe, Salberg Sabrina, Li Crystal N, Smith Madeleine J, Freeman James, Vlassopoulos Elaina, Harris Sydney, Shultz Sandy R, Yamakawa Glenn R, Noel Melanie, Mychasiuk Richelle
Department of Neuroscience, School of Translational Medicine, Monash University,Melbourne, Victoria, Australia.
Department of Neuroscience, School of Translational Medicine, Monash University,Melbourne, Victoria, Australia; Centre for Trauma and Mental Health Research, Vancouver Island University, Nanaimo, B.C., Canada.
J Pain. 2025 Mar;28:104762. doi: 10.1016/j.jpain.2024.104762. Epub 2024 Dec 25.
The perinatal period encompasses a critical window for neurodevelopment that renders the brain highly responsive to experience. Trauma, such as intimate partner violence (IPV) and early life stress/neglect, during this period negatively affects physical and mental health outcomes, including increasing ones risk for chronic pain. Although epigenetic programming likely contributes, the mechanisms that drive the relationship between perinatal trauma and adverse health outcomes, are not fully understood. Therefore, we explored the relationship between perinatal trauma (in utero exposure to IPV and/or early life neglect) and socio-emotional functioning, nociceptive sensitivity, and transcriptomic changes within the prefrontal cortex (PFC) and hypothalamus in dams and their adolescent offspring. Rat dams were randomly assigned to an IPV (i.e., combined mild traumatic brain injury and strangulation) or sham procedure during pregnancy. Following birth, offspring were subsequently assigned the early life neglect or control paradigm. In adolescence, offspring received a plantar incision or sham injury. Perinatal trauma altered nociception and emotional functioning in a sex-dependent manner when combined with the surgical procedure. We identified transcriptomic changes related to DNA transcription and expression within the PFC and hypothalamus of the dams. Examination of the offspring transcriptome highlighted impairment in immune regulation, dysfunction in stress-reactivity, as well as microglia activation. We also identified altered expression of genes associated with chronic pain. This demonstrates that perinatal trauma modifies offspring behaviour, including nociceptive sensitivity. We provide insight into the mechanisms that contribute to the chronification of pain, thereby informing future research targeted at the generation of prevention and therapeutic strategies. PERSPECTIVE: Perinatal trauma impaired cognitive, socio-emotional, and pain processing in offspring, while also inducing changes in gene expression, in both mothers and offspring. The findings highlight possible mechanisms responsible for intergenerational transmission of risk for chronic pain and provide targets for therapeutics which could potentially reverse perinatal-trauma induced epigenetic change.
围产期是神经发育的关键时期，在此期间大脑对经历高度敏感。在此期间，创伤，如亲密伴侣暴力（IPV）和早期生活压力/忽视，会对身心健康产生负面影响，包括增加慢性疼痛的风险。虽然表观遗传编程可能起作用，但围产期创伤与不良健康结果之间关系的驱动机制尚未完全了解。因此，我们探讨了围产期创伤（子宫内暴露于IPV和/或早期生活忽视）与社会情感功能、伤害感受敏感性以及母鼠及其青春期后代前额叶皮质（PFC）和下丘脑内的转录组变化之间的关系。将怀孕的母鼠随机分配接受IPV（即轻度创伤性脑损伤和勒颈联合）或假手术。出生后，后代随后被分配到早期生活忽视或对照范式。在青春期，后代接受足底切口或假损伤。围产期创伤与手术相结合时，会以性别依赖的方式改变伤害感受和情绪功能。我们确定了与母鼠PFC和下丘脑内DNA转录和表达相关的转录组变化。对后代转录组的检查突出了免疫调节受损、应激反应功能障碍以及小胶质细胞激活。我们还确定了与慢性疼痛相关基因的表达改变。这表明围产期创伤会改变后代行为，包括伤害感受敏感性。我们深入了解了导致疼痛慢性化的机制，从而为未来旨在制定预防和治疗策略的研究提供了信息。观点：围产期创伤损害了后代的认知、社会情感和疼痛处理能力，同时也在母亲和后代中诱导了基因表达的变化。这些发现突出了慢性疼痛风险代际传递的可能机制，并为可能逆转围产期创伤诱导的表观遗传变化的治疗提供了靶点。
