Cuihong Jia, W. Drew Gill, Chiharu Lovins, Russell W. Brown , Theo Hagg
{"title":"Astrocyte focal adhesion kinase reduces passive stress coping by inhibiting ciliary neurotrophic factor only in female mice","authors":"Cuihong Jia, W. Drew Gill, Chiharu Lovins, Russell W. Brown , Theo Hagg","doi":"10.1016/j.ynstr.2024.100621","DOIUrl":null,"url":null,"abstract":"<div><p>Astrocytes have been implicated in stress responses and produce ciliary neurotrophic factor (CNTF), which we have shown in the mouse medial amygdala (MeA) to promote passive stress coping response only in females. Pharmacological inhibition of focal adhesion kinase (FAK) upregulates CNTF expression. Here, we found that inducible knockout of FAK in astrocytes or systemic treatment with an FAK inhibitor increased passive coping behavior, i.e., immobility, in an acute forced swim stress test in female, but not male, mice. Strikingly, four weeks of chronic unpredictable stress (CUS) did not further increase passive coping in female astrocytic FAK knockout mice, whereas it exacerbated it in female wildtype mice and male mice of both genotypes. These data suggest that astrocyte FAK inhibition is required for chronic stress-induced passive coping in females. Indeed, CUS reduced phospho-FAK and increased CNTF in the female MeA. Progesterone treatment after ovariectomy activated amygdala FAK and alleviated ovariectomy-induced passive coping in wildtype, but not astrocytic FAK knockout females. This suggests that progesterone-mediated activation of FAK in astrocytes reduces female stress responses. Finally, astrocytic FAK knockout or FAK inhibitor treatment increased CNTF expression in the MeA of both sexes, although not in the hippocampus. As mentioned, MeA CNTF promotes stress responses only in females, which may explain the female-specific role of astrocytic FAK inhibition. Together, this study reveals a novel female-specific progesterone-astrocytic FAK pathway that counteracts CNTF-mediated stress responses and points to opportunities for developing treatments for stress-related disorders in women.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":null,"pages":null},"PeriodicalIF":4.3000,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000171/pdfft?md5=b3c9f46d5085d9d0c7b70b4812056a13&pid=1-s2.0-S2352289524000171-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurobiology of Stress","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2352289524000171","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Astrocytes have been implicated in stress responses and produce ciliary neurotrophic factor (CNTF), which we have shown in the mouse medial amygdala (MeA) to promote passive stress coping response only in females. Pharmacological inhibition of focal adhesion kinase (FAK) upregulates CNTF expression. Here, we found that inducible knockout of FAK in astrocytes or systemic treatment with an FAK inhibitor increased passive coping behavior, i.e., immobility, in an acute forced swim stress test in female, but not male, mice. Strikingly, four weeks of chronic unpredictable stress (CUS) did not further increase passive coping in female astrocytic FAK knockout mice, whereas it exacerbated it in female wildtype mice and male mice of both genotypes. These data suggest that astrocyte FAK inhibition is required for chronic stress-induced passive coping in females. Indeed, CUS reduced phospho-FAK and increased CNTF in the female MeA. Progesterone treatment after ovariectomy activated amygdala FAK and alleviated ovariectomy-induced passive coping in wildtype, but not astrocytic FAK knockout females. This suggests that progesterone-mediated activation of FAK in astrocytes reduces female stress responses. Finally, astrocytic FAK knockout or FAK inhibitor treatment increased CNTF expression in the MeA of both sexes, although not in the hippocampus. As mentioned, MeA CNTF promotes stress responses only in females, which may explain the female-specific role of astrocytic FAK inhibition. Together, this study reveals a novel female-specific progesterone-astrocytic FAK pathway that counteracts CNTF-mediated stress responses and points to opportunities for developing treatments for stress-related disorders in women.
期刊介绍:
Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal.
Basic, translational and clinical research on the following topics as they relate to stress will be covered:
Molecular substrates and cell signaling,
Genetics and epigenetics,
Stress circuitry,
Structural and physiological plasticity,
Developmental Aspects,
Laboratory models of stress,
Neuroinflammation and pathology,
Memory and Cognition,
Motivational Processes,
Fear and Anxiety,
Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse),
Neuropsychopharmacology.