Sexually dimorphic CNTF/Ucn3 mechanism in fear extinction

项目摘要 恐惧消退缺陷是创伤后应激障碍(PTSD)的标志，暴露疗法改善了 恐惧消失了。女性患创伤后应激障碍的可能性是男性的两倍，但仍保持着更强的治疗效果 暴露疗法，其机制尚不清楚。啮齿动物对灭绝的恐惧学习范式服务于 作为暴露疗法的临床前模型。压力对创伤后应激障碍有重大影响，并削弱恐惧消退。 初步数据显示，慢性不可预测的压力(CUS)会导致大鼠恐惧消退学习的缺陷 雌性老鼠。重要的是，睫状神经营养因子(CNTF)的敲除可以防止这种缺陷，揭示了一种 CNTF在女性恐惧消退中的新抑制和有害作用。这项提议也将包括男性。 我们最近的小鼠研究显示，杏仁内侧核(Mea)CNTF对应激有显著的性别特异性效应。 回应。CuS上调女性的CNTF，但不上调男性的CNTF，从而促进应激反应。CUS 不会改变女性海马体和下丘脑中的CNTF水平。这些数据指向一名女性- CNTF介导的特异性和MeA特异性应激效应。杏仁核，包括Mea，是强烈的 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， 是由星形胶质细胞和神经元表达的。CNTF促进成人神经发生，具有神经保护作用。角色 杏仁核中CNTF的含量尚不清楚。初步数据显示，CNTF在女性中被敲除，而在男性中没有， 小鼠增加神经肽Ucn3(Ucn3)，但不能使Ucn1和Ucn2的表达降低125倍 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)是已知的 纠正压力导致的恐惧学习缺陷。UCN3主要在杏仁核中央表达。我们的数据 结果表明，注射在mea中的CNTF抗体增加了雌性小鼠的Ucn3，而不影响雄性小鼠。这 提示女性特异性CNTF抑制的mea Ucn3可能与恐惧消退缺陷有关。事实上，CUS 女性MEA中Ucn3降低，可能是由于CNTF增加所致。我们假设慢性压力引起的 CNTF抑制Ucn3在女性MEA中的表达，导致恐惧消退学习受损。目标1将定义 MeA CNTF对Ucn3表达和神经元活性的性别特异性影响。我们将研究这一角色 MeA CNTF(1a)和CNTFRα(1b)对UCN3的调节作用。确认CNTF调节的UCN3对CRF-R2的影响 介导应激诱导的恐惧学习障碍的神经元，Aim 1c将测量CRF-R2阳性的活性 CUS和MEA内CNTF处理后MeA内的神经元。AIM 2将调查 慢性应激调节的mea、CNTF(2a)和Ucn3(2b)在性别间调节恐惧消退缺陷。AIM 2c将 直接确定mea Ucn3在CNTF介导的慢性应激后恐惧消退缺陷中的作用。这 该提案将在应激诱导的恐惧中定义一种新的性别特异性CNTF/Ucn3机制 消除创伤后应激障碍，并使用干预策略来提高创伤后应激障碍暴露疗法的疗效。

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.