Bordes Joeri, Bajaj Thomas, Miranda Lucas, van Doeselaar Lotte, Brix Lea Maria, Narayan Sowmya, Yang Huanqing, Mitra Shiladitya, Kovarova Veronika, Springer Margherita, Kleigrewe Karin, Müller-Myhsok Bertram, Gassen Nils C, Schmidt Mathias V
Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany.
Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, Bonn Clinical Center, University of Bonn, 53127, Bonn, Germany.
Commun Biol. 2024 Dec 20;7(1):1684. doi: 10.1038/s42003-024-07396-8.
Early life stress (ELS) can negatively impact health, increasing the risk of stress-related disorders, such as post-traumatic stress disorder (PTSD). Importantly, PTSD disproportionately affects women, emphasizing the critical need to explore how sex differences influence the genetic and metabolic neurobiological pathways underlying trauma-related behaviors. This study uses the limited bedding and nesting (LBN) paradigm to model ELS and investigate its sex-specific effects on fear memory formation. Employing innovative unsupervised behavioral classification, the current study reveals distinct behavioral patterns associated with fear acquisition and retrieval in male and female mice following ELS. Females exposed to LBN display heightened active fear responses, contrasting with males. Furthermore, the study examined the crucial link between behavioral regulation and cellular metabolism in key brain regions involved in fear and stress processing. Sex-specific and stress-dependent alterations were observed in purine, pyrimidine, and glutamate metabolism within the basolateral amygdala, the dorsal hippocampus, and the ventral hippocampus. These findings provide crucial insights into the complex interplay between metabolic pathways, the neurobiological underpinnings of fear memory, and stress responses. Importantly, they emphasize the significance of considering sex-specific metabolic alterations when investigating stress-related disorders, opening potential avenues for the development of targeted interventions.
早期生活压力（ELS）会对健康产生负面影响，增加患创伤后应激障碍（PTSD）等与压力相关疾病的风险。重要的是，PTSD对女性的影响尤为严重，这凸显了探索性别差异如何影响创伤相关行为背后的遗传和代谢神经生物学途径的迫切需求。本研究采用有限垫料和筑巢（LBN）范式来模拟ELS，并研究其对恐惧记忆形成的性别特异性影响。通过创新的无监督行为分类，本研究揭示了ELS后雄性和雌性小鼠在恐惧获取和回忆方面的不同行为模式。暴露于LBN的雌性小鼠表现出更强的主动恐惧反应，这与雄性小鼠形成对比。此外，该研究还考察了参与恐惧和压力处理的关键脑区中行为调节与细胞代谢之间的关键联系。在基底外侧杏仁核、背侧海马体和腹侧海马体中观察到嘌呤、嘧啶和谷氨酸代谢存在性别特异性和应激依赖性改变。这些发现为代谢途径、恐惧记忆的神经生物学基础和应激反应之间的复杂相互作用提供了重要见解。重要的是，它们强调了在研究与压力相关的疾病时考虑性别特异性代谢改变的重要性，为开发针对性干预措施开辟了潜在途径。
