Sexually dimorphic CNTF/Ucn3 mechanism in fear extinction

CNTF/Ucn3性别二态性恐惧消退机制

• 批准号: 10738916
• 负责人: Cuihong Jia
• 金额: $ 41.25万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738916
• 关键词: Adult; Affect; Amygdaloid structure; Antibodies; Area; Astrocytes; Behavior; Behavioral; Blood capillaries; Brain; C57BL/6 Mouse; CRF receptor type 2; Cell Nucleus; Chronic; Chronic stress; Ciliary Neurotrophic Factor; Corticotropin-Releasing Hormone Receptors; Cues; Data; Disease; Environmental Impact; Exclusion; Extinction; FOS gene; Female; Freezing; Fright; Gene Expression; Genetic; Grant; Hippocampus; Human; Hypothalamic structure; Immediate-Early Genes; Immunofluorescence Immunologic; Impairment; Injections; Intervention; Knock-out; Learning; Lesion; Link; Measures; Medial; Mediating; Molecular; Motor Activity; Mus; National Institute of Mental Health; Nervous System; Neurons; Neuropeptides; Pathway interactions; Peptides; Peripheral; Post-Traumatic Stress Disorders; Pre-Clinical Model; Proteins; Publishing; Recording of previous events; Regulation; Resistance; Risk Factors; Rodent; Role; Specificity; Stress; Testing; Therapeutic; Training; Trauma; Travel; Western Blotting; Woman; adult neurogenesis; biological adaptation to stress; clinically relevant; conditioned fear; improved; insight; learning extinction; mRNA Expression; male; men; neuroprotection; neutralizing antibody; novel; pharmacologic; prevent; receptor; response; sex; sexual dimorphism; stress reduction; stress related disorder; stressor; treatment effect; urocortin; Adult; Affect; Amygdaloid structure; Antibodies; Area; Astrocytes; Behavior; Behavioral; Blood capillaries; Brain; C57BL/6 Mouse; CRF receptor type 2; Cell Nucleus; Chronic; Chronic stress; Ciliary Neurotrophic Factor; Corticotropin-Releasing Hormone Receptors; Cues; Data; Disease; Environmental Impact; Exclusion; Extinction; FOS gene; Female; Freezing; Fright; Gene Expression; Genetic; Grant; Hippocampus; Human; Hypothalamic structure; Immediate-Early Genes; Immunofluorescence Immunologic; Impairment; Injections; Intervention; Knock-out; Learning; Lesion; Link; Measures; Medial; Mediating; Molecular; Motor Activity; Mus; National Institute of Mental Health; Nervous System; Neurons; Neuropeptides; Pathway interactions; Peptides; Peripheral; Post-Traumatic Stress Disorders; Pre-Clinical Model; Proteins; Publishing; Recording of previous events; Regulation; Resistance; Risk Factors; Rodent; Role; Specificity; Stress; Testing; Therapeutic; Training; Trauma; Travel; Western Blotting; Woman; adult neurogenesis; biological adaptation to stress; clinically relevant; conditioned fear; improved; insight; learning extinction; mRNA Expression; male; men; neuroprotection; neutralizing antibody; novel; pharmacologic; prevent; receptor; response; sex; sexual dimorphism; stress reduction; stress related disorder; stressor; treatment effect; urocortin

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.

项目摘要 恐惧扩展赤字是创伤后应激障碍（PTSD）和暴露疗法的标志。 恐惧延伸。女性发展为PTSD的可能性是男性的两倍，但保持了更强的治疗效果 暴露疗法和机制尚不清楚。啮齿动物恐惧扩展学习范式服务 作为暴露疗法的临床前模型。压力对PTSD有重大影响，并损害恐惧的扩大。 初步数据表明，慢性不可预测的压力（CUS）在恐惧扩展学习中引起防御 雌鼠。重要的是，睫状神经营养因子（CNTF）的敲除可以防止这种防御 CNTF在女性恐惧扩展中的新颖抑制和有害作用。该建议还将包括男性。 我们最近的小鼠研究揭示了CNTF对内侧杏仁核（MEA）对压力的惊人性别特异性作用 回答。 CUS上调女性而非男性MEA的CNTF，这会促进压力反应。 cus 不会改变雌性海马和下丘脑的CNTF水平。这些数据指向女性 CNTF介导的特异性和MEA特异性应力效应。包括MEA在内的杏仁核强烈 与恐惧学习有关。那就是慢性压力后对MEA CNTF的性别特异性调节可能具有 对恐惧延伸的性别特定影响。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 杏仁核中的CNTF尚不清楚。初步数据表明，女性而非男性的CNTF敲除 小鼠增加了神经肽尿素素3（UCN3），但在UCN1和UCN2表达中却不增加125倍 杏仁核。其受体的UCN3激活，皮质激素释放因子受体2（CRF-R2）已知已知 正确的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 表明在MEA中注入的CNTF抗体增加了雌性小鼠的UCN3，同时不影响雄性。这 表明抑制了女性特异性CNTF的MEA UCN3可能会导致恐惧的赤字。确实，cus 雌性MEA的UCN3降低，由于CNTF增加而可能。我们假设慢性应激诱导 CNTF抑制雌性MEA中的UCN3表达，从而导致恐惧扩展学习受损。 AIM 1将定义 MEA CNTF对UCN3表达和神经元活性的性别特异性作用。我们将研究 在调节UCN3中，MEA CNTF（1A）和CNTFRα（1B）。确认CNTF调节的UCN3会影响CRF-R2 介导压力引起的恐惧学习防御的神经元，AIM 1C将测量CRF-R2阳性的活性 CUS和MEA内部操纵CNTF后MEA中的神经元。 AIM 2将调查是否 慢性应激调节的MEA CNTF（2a）和UCN3（2b）介导恐惧的扩展在每个性别中定义。 AIM 2C会 直接定义了MEA UCN3在慢性应激后CNTF介导的恐惧扩展不足的作用。这 提案将定义一种新颖的性别特异性CNTF/UCN3机制，其基础应力引起的恐惧 灭绝不足并使用干预策略来提高PTSD暴露疗法的效率。