Sexually dimorphic CNTF/Ucn3 mechanism in fear extinction

项目概要 恐惧消退缺陷是创伤后应激障碍（PTSD）的一个标志，暴露疗法可以改善 恐惧灭绝。女性患 PTSD 的可能性是男性的两倍，但仍保持更强的治疗效果 暴露疗法，其机制尚不清楚。啮齿动物恐惧灭绝学习范式服务 作为暴露疗法的临床前模型。压力对创伤后应激障碍（PTSD）有重大影响，并会损害恐惧消退。 初步数据表明，慢性不可预测压力（CUS）会导致恐惧消退学习的缺陷 雌性小鼠。重要的是，睫状神经营养因子（CNTF）的敲除可以防止这种缺陷，揭示了 CNTF 在女性恐惧消退中的新抑制和有害作用。该提案也将包括男性。 我们最近的小鼠研究揭示了内侧杏仁核 (MeA) 中 CNTF 对压力的显着性别特异性影响 回应。 CUS 上调女性而非男性 MeA 中的 CNTF，从而促进应激反应。库斯 不会改变女性海马和下丘脑中的 CNTF 水平。这些数据表明女性—— CNTF 介导的特异性和 MeA 特异性应激效应。杏仁核，包括 MeA，具有强烈的 与恐惧学习有关。因此，慢性应激后 MeA CNTF 的性别特异性调节可能具有 性别对恐惧消退的影响。在大脑中，CNTF 由星形胶质细胞及其受体 CNTFRα 产生， 由星形胶质细胞和神经元表达。 CNTF 促进成人神经发生并具有神经保护作用。角色 CNTF 在杏仁核中的作用尚不清楚。初步数据显示，在女性而非男性中敲除 CNTF， 小鼠中神经肽尿皮质素 3 (Ucn3) 的表达增加，但 Ucn1 和 Ucn2 的表达并未降低 125 倍以上。 杏仁核。 Ucn3 激活其受体促肾上腺皮质激素释放因子受体 2 (CRF-R2)，已知 纠正压力引起的恐惧学习缺陷。 Ucn3主要在杏仁核的MeA中表达。我们的数据 结果表明，注射到 MeA 中的 CNTF 抗体会增加雌性小鼠的 Ucn3，而不会影响雄性小鼠。这个 表明女性特有的 CNTF 抑制的 MeA Ucn3 可能会导致恐惧消退缺陷。确实，CUS 雌性 MeA 中 Ucn3 减少，可能是由于 CNTF 增加。我们假设慢性压力诱发 CNTF 抑制雌性 MeA 中 Ucn3 的表达，导致恐惧消退学习受损。目标 1 将定义 MeA CNTF 对 Ucn3 表达和神经元活动的性别特异性影响。我们将研究的角色 MeA CNTF (1a) 和 CNTFRα (1b) 对 Ucn3 的调节作用。确认 CNTF 调控的 Ucn3 影响 CRF-R2 介导压力引起的恐惧学习缺陷的神经元，目标 1c 将测量 CRF-R2 阳性的活动 CUS 和 CNTF 的 MeA 内操作后 MeA 中的神经元。目标 2 将调查是否 慢性压力调节的 MeA CNTF (2a) 和 Ucn3 (2b) 介导每种性别的恐惧消退缺陷。目标 2c 将 直接定义了 MeA Ucn3 对慢性应激后 CNTF 介导的恐惧消退缺陷的作用。这个 该提案将在压力引起的恐惧的 MeA 中定义一种新的性别特异性 CNTF/Ucn3 机制 消退缺陷并使用干预策略来提高暴露疗法在 PTSD 中的疗效。

Project Summary Fear extinction deficit is a hallmark of post-traumatic stress disorder (PTSD) and exposure therapy improves fear extinction. Women are twice as likely to develop PTSD as men but maintain stronger treatment effects of exposure therapy, and the mechanism is not well understood. Rodent fear extinction learning paradigms serve as preclinical models of exposure therapy. Stress has a significant impact on PTSD and impairs fear extinction. Preliminary data show that chronic unpredictable stress (CUS) induces deficits in fear extinction learning in female mice. Importantly, knockout of ciliary neurotrophic factor (CNTF) prevented this deficit, revealing a novel inhibiting and detrimental role of CNTF in female fear extinction. This proposal will include males as well. Our recent mouse study reveals a striking sex-specific effect of CNTF in the medial amygdala (MeA) on stress responses. CUS upregulates CNTF in female, but not male, MeA, which promotes stress responses. CUS does not alter CNTF levels in the female hippocampus and hypothalamus. These data point to a female- specific and MeA-specific stress effect mediated by CNTF. The amygdala, including the MeA, is strongly associated with fear learning. Thus, sex-specific regulation of MeA CNTF following chronic stress may have a sex-specific effect on fear extinction. In the brain, CNTF is produced by astrocytes and its receptor, CNTFRα, is expressed by astrocytes and neurons. CNTF promotes adult neurogenesis and is neuroprotective. The role of CNTF in the amygdala is not known. Preliminary data show that knockout of CNTF in female, but not male, mice increased the neuropeptide urocortin 3 (Ucn3), but not the >125-fold lower Ucn1 and Ucn2 expression in the amygdala. Ucn3 activation of its receptor, corticotropin releasing factor receptor 2 (CRF-R2), is known to correct stress-induced fear learning deficits. Ucn3 is mainly expressed in the MeA of the amygdala. Our data show that CNTF antibodies injected in the MeA increased Ucn3 in female mice, while not affecting males. This suggests that female-specific CNTF-inhibited MeA Ucn3 might contribute to fear extinction deficit. Indeed, CUS reduced Ucn3 in female MeA, possibly due to increased CNTF. We hypothesize that chronic stress-induced CNTF inhibits Ucn3 expression in the female MeA, causing impaired fear extinction learning. Aim 1 will define the sex-specific effect of MeA CNTF on Ucn3 expression and neuronal activity. We will examine the role of MeA CNTF (1a) and CNTFRα (1b) in regulating Ucn3. To confirm CNTF-regulated Ucn3 affects CRF-R2 neurons that mediate stress-induced fear learning deficit, aim 1c will measure the activity of CRF-R2-positive neurons in the MeA following CUS and intra-MeA manipulation of CNTF. Aim 2 will investigate whether chronic stress-regulated MeA CNTF (2a) and Ucn3 (2b) mediate fear extinction deficits in each sex. Aim 2c will directly define the role of MeA Ucn3 on CNTF-mediated fear extinction deficit following chronic stress. This proposal will define a novel sex-specific CNTF/Ucn3 mechanism in the MeA underlying stress-induced fear extinction deficits and use an intervention strategy to improve the efficacy of exposure therapy in PTSD.