Exploring individual differences in fear extinction in male and female mice: insights from HPA axis, microbiota, and transcriptomics
Abstract 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 f...
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Nature Publishing Group
2025-06-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03400-9 |
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| author | Marc Ten-Blanco María Ponce-Renilla Inmaculada Pereda-Pérez Cristina Izquierdo-Luengo Carlo Bressa Olga Zafra Rosa María Tolón Fernando Berrendero |
| author_facet | Marc Ten-Blanco María Ponce-Renilla Inmaculada Pereda-Pérez Cristina Izquierdo-Luengo Carlo Bressa Olga Zafra Rosa María Tolón Fernando Berrendero |
| author_sort | Marc Ten-Blanco |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-a2c1864ca5984c96b9eb67c3ecea3a00 |
| institution | Kabale University |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
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| series | Translational Psychiatry |
| spelling | doaj-art-a2c1864ca5984c96b9eb67c3ecea3a002025-08-20T03:45:32ZengNature Publishing GroupTranslational Psychiatry2158-31882025-06-0115111010.1038/s41398-025-03400-9Exploring individual differences in fear extinction in male and female mice: insights from HPA axis, microbiota, and transcriptomicsMarc Ten-Blanco0María Ponce-Renilla1Inmaculada Pereda-Pérez2Cristina Izquierdo-Luengo3Carlo Bressa4Olga Zafra5Rosa María Tolón6Fernando Berrendero7Neurobiology of Addictive Disorders and Anxiety Research Group, Institute of Life Sciences, Faculty of Experimental Sciences, Universidad Francisco de VitoriaNeurobiology of Addictive Disorders and Anxiety Research Group, Institute of Life Sciences, Faculty of Experimental Sciences, Universidad Francisco de VitoriaNeurobiology of Addictive Disorders and Anxiety Research Group, Institute of Life Sciences, Faculty of Experimental Sciences, Universidad Francisco de VitoriaNeurobiology of Addictive Disorders and Anxiety Research Group, Institute of Life Sciences, Faculty of Experimental Sciences, Universidad Francisco de VitoriaMicrobial Biotechnology Research Group, Institute of Life Sciences, Faculty of Experimental Sciences, Universidad Francisco de VitoriaMicrobial Biotechnology Research Group, Institute of Life Sciences, Faculty of Experimental Sciences, Universidad Francisco de VitoriaNeurobiology of Addictive Disorders and Anxiety Research Group, Institute of Life Sciences, Faculty of Experimental Sciences, Universidad Francisco de VitoriaNeurobiology of Addictive Disorders and Anxiety Research Group, Institute of Life Sciences, Faculty of Experimental Sciences, Universidad Francisco de VitoriaAbstract 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.https://doi.org/10.1038/s41398-025-03400-9 |
| spellingShingle | Marc Ten-Blanco María Ponce-Renilla Inmaculada Pereda-Pérez Cristina Izquierdo-Luengo Carlo Bressa Olga Zafra Rosa María Tolón Fernando Berrendero Exploring individual differences in fear extinction in male and female mice: insights from HPA axis, microbiota, and transcriptomics Translational Psychiatry |
| title | Exploring individual differences in fear extinction in male and female mice: insights from HPA axis, microbiota, and transcriptomics |
| title_full | Exploring individual differences in fear extinction in male and female mice: insights from HPA axis, microbiota, and transcriptomics |
| title_fullStr | Exploring individual differences in fear extinction in male and female mice: insights from HPA axis, microbiota, and transcriptomics |
| title_full_unstemmed | Exploring individual differences in fear extinction in male and female mice: insights from HPA axis, microbiota, and transcriptomics |
| title_short | Exploring individual differences in fear extinction in male and female mice: insights from HPA axis, microbiota, and transcriptomics |
| title_sort | exploring individual differences in fear extinction in male and female mice insights from hpa axis microbiota and transcriptomics |
| url | https://doi.org/10.1038/s41398-025-03400-9 |
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