星形胶质细胞局灶粘附激酶仅通过抑制睫状神经营养因子降低雌性小鼠的被动压力应对能力

IF 4.3 2区 医学 Q1 NEUROSCIENCES Neurobiology of Stress Pub Date : 2024-03-11 DOI:10.1016/j.ynstr.2024.100621
Cuihong Jia, W. Drew Gill, Chiharu Lovins, Russell W. Brown , Theo Hagg
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摘要

星形胶质细胞与应激反应有关,并能产生睫状神经营养因子(CNTF)。我们在小鼠内侧杏仁核(MeA)中发现,只有雌性星形胶质细胞能促进被动应激反应。药物抑制局灶粘附激酶(FAK)可上调CNTF的表达。在这里,我们发现诱导性敲除星形胶质细胞中的FAK或用FAK抑制剂进行全身治疗可增加雌性小鼠在急性强迫游泳应激试验中的被动应对行为,即不动。令人吃惊的是,四周的慢性不可预测应激(CUS)并没有进一步增加雌性星形胶质细胞FAK基因敲除小鼠的被动应对行为,但却加剧了雌性野生型小鼠和雄性两种基因型小鼠的被动应对行为。这些数据表明,雌性小鼠慢性应激诱导的被动应对需要星形胶质细胞 FAK 抑制。事实上,CUS能减少雌性MeA的磷酸-FAK并增加CNTF。卵巢切除术后的黄体酮治疗激活了杏仁核FAK,缓解了野生型女性卵巢切除术诱导的被动应对,但没有缓解星形胶质细胞FAK基因敲除女性的被动应对。这表明,黄体酮介导的星形胶质细胞 FAK 激活可减轻女性的应激反应。最后,星形胶质细胞FAK敲除或FAK抑制剂处理增加了CNTF在两性MeA中的表达,尽管不是在海马中。如前所述,MeA CNTF只促进女性的应激反应,这可能解释了星形胶质细胞FAK抑制剂的女性特异性作用。总之,这项研究揭示了一种新的女性特异性黄体酮-星形胶质细胞FAK通路,它能抵消CNTF介导的应激反应,并为开发治疗女性应激相关疾病的方法提供了机会。
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Astrocyte focal adhesion kinase reduces passive stress coping by inhibiting ciliary neurotrophic factor only in female mice

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.

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来源期刊
Neurobiology of Stress
Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
9.40
自引率
4.00%
发文量
74
审稿时长
48 days
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.
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