Jia Cuihong, Gill W Drew, Lovins Chiharu, Brown Russell W, Hagg Theo
Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.
Neurobiol Stress. 2024 Mar 11;30:100621. doi: 10.1016/j.ynstr.2024.100621. eCollection 2024 May.
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.
星形胶质细胞与应激反应有关，并产生睫状神经营养因子（CNTF），我们已在小鼠内侧杏仁核（MeA）中证明，该因子仅在雌性小鼠中促进被动应激应对反应。局部粘着斑激酶（FAK）的药理学抑制可上调CNTF表达。在此，我们发现，在雌性而非雄性小鼠的急性强迫游泳应激试验中，星形胶质细胞中FAK的诱导性敲除或用FAK抑制剂进行全身治疗可增加被动应对行为，即不动。引人注目的是，四周的慢性不可预测应激（CUS）并未进一步增加雌性星形胶质细胞FAK敲除小鼠的被动应对行为，而在雌性野生型小鼠和两种基因型的雄性小鼠中却加剧了这种行为。这些数据表明，星形胶质细胞FAK抑制是雌性慢性应激诱导的被动应对所必需的。事实上，CUS降低了雌性MeA中的磷酸化FAK并增加了CNTF。卵巢切除术后进行孕酮治疗可激活杏仁核FAK，并减轻野生型而非星形胶质细胞FAK敲除雌性小鼠卵巢切除诱导的被动应对行为。这表明孕酮介导的星形胶质细胞中FAK的激活可降低雌性应激反应。最后，星形胶质细胞FAK敲除或FAK抑制剂治疗增加了两性MeA中的CNTF表达，尽管在海马体中未增加。如前所述，MeA中的CNTF仅在雌性中促进应激反应，这可能解释了星形胶质细胞FAK抑制的雌性特异性作用。总之，本研究揭示了一条新的雌性特异性孕酮-星形胶质细胞FAK途径，该途径可抵消CNTF介导的应激反应，并为开发女性应激相关疾病的治疗方法提供了机会。
