Sexually dimorphic CNTF/Ucn3 mechanism in fear extinction

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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.