Ten-Blanco Marc, Ponce-Renilla María, Pereda-Pérez Inmaculada, Izquierdo-Luengo Cristina, Bressa Carlo, Zafra Olga, Tolón Rosa María, Berrendero Fernando
Neurobiology of Addictive Disorders and Anxiety Research Group, Institute of Life Sciences, Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223, Pozuelo de Alarcón, Madrid, Spain.
School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, BS8 1TD, United Kingdom.
Transl Psychiatry. 2025 Jun 10;15(1):195. doi: 10.1038/s41398-025-03400-9.
Exposure to traumatic life events may compromise physical and mental health of specific subjects. While some individuals extinguish fear appropriately, others exhibit an inefficient and persistent fear response, with remarkable differences between sexes. Understanding the heterogeneity in fear extinction responses is essential for elucidating the underlying mechanisms of fear-related disorders. We used a multidisciplinary approach analyzing the hypothalamic-pituitary-adrenal (HPA) axis tone, the microbiota composition, and the transcriptome of the amygdala (primary brain region involved in fear regulation) in adult male and female mice that were exposed to the Pavlovian fear conditioning and extinction paradigm. This model allowed us to stratify the mice population into two extreme phenotypic subgroups (resilient and susceptible), based on their individual fear extinction behavior. Characterization of some components of the HPA axis revealed strong disturbances in vulnerable males (e.g., increased hypothalamic CRF mRNA and corticosterone plasma levels), whereas softer changes were found in female animals. Several bacterial groups such as the genera Parvibacter, Alloprevotella and Limosilactobacillus and the family Christensenellaceae were enriched in the microbiota of resilient males, as well as relevant bacterial taxa enrichment was also observed in resilient (genus Muribaculum) and susceptible (family Eggerthellaceae) female mice. We also identified clear differences in the transcriptomic profile of the amygdala (31 differentially expressed genes) in male animals. These findings underscore the intricate involvement of multiple factors shaping the inter-individual variability of fear extinction response in a sex-dependent manner, thus paving the way for new potential targets for fear-related disorders.
经历创伤性生活事件可能会损害特定个体的身心健康。虽然有些人能适当地消除恐惧，但另一些人则表现出低效且持续的恐惧反应，两性之间存在显著差异。了解恐惧消退反应的异质性对于阐明恐惧相关障碍的潜在机制至关重要。我们采用多学科方法，分析了接受巴甫洛夫恐惧条件反射和消退范式的成年雄性和雌性小鼠的下丘脑 - 垂体 - 肾上腺（HPA）轴张力、微生物群组成以及杏仁核（参与恐惧调节的主要脑区）的转录组。该模型使我们能够根据小鼠个体的恐惧消退行为，将小鼠群体分为两个极端表型亚组（有恢复力的和易受影响的）。对HPA轴某些成分的表征显示，易受影响的雄性小鼠存在强烈干扰（如下丘脑CRF mRNA和血浆皮质酮水平升高），而雌性动物的变化则较轻微。一些细菌类群，如细小杆菌属、别普雷沃菌属、乳杆菌属和克里斯滕森菌科，在有恢复力的雄性小鼠的微生物群中富集，在有恢复力的（穆里杆菌属）和易受影响的（埃格特菌科）雌性小鼠中也观察到相关细菌分类群的富集。我们还在雄性动物的杏仁核转录组图谱中发现了明显差异（31个差异表达基因）。这些发现强调了多种因素以性别依赖的方式塑造恐惧消退反应个体间变异性的复杂参与，从而为恐惧相关障碍的新潜在靶点铺平了道路。
