Ciliary neurotrophic factor (CNTF) is produced by astrocytes which have been implicated in regulating stress responses. We found that CNTF in the medial amygdala (MeA) promotes despair or passive coping, i.e., immobility in an acute forced swim stress, in female mice, while having no effect in males. Neutralizing CNTF antibody injected into the MeA of wildtype females reduced activation of downstream STAT3 (Y705) 24 and 48 h later. In concert, the antibody reduced immobility in the swim test in females and only after MeA injection, but not when injected in the central or basolateral amygdala. Antibody injected into the male MeA did not affect immobility. These data reveal a unique role of CNTF in female MeA in promoting despair or passive coping behavior. Moreover, 4 weeks of chronic unpredictable stress (CUS) increased immobility in the swim test and reduced sucrose preference in wildtype CNTF+/+, but not CNTF-/- littermate, females. Following CUS, 10 min of restraint stress increased plasma corticosterone levels only in CNTF+/+ females. In males, the CUS effects were present in both genotypes. Further, CUS increased CNTF expression in the MeA of female, but not male, mice. CUS did not alter CNTF in the female hippocampus, hypothalamus and bed nucleus of stria terminalis. This suggests that MeA CNTF has a female-specific role in promoting CUS-induced despair or passive coping, behavioral anhedonia and neuroendocrine responses. Compared to CNTF+/+ mice, CNTF-/- mice did not show differences in CUS-induced anxiety-like behavior and sensorimotor gating function as measured by elevated T-Maze, open field and pre-pulse inhibition of the acoustic startle response. Together, this study reveals a novel CNTF-mediated female-specific mechanism in stress responses and points to opportunities for developing treatments for stress-related disorders in women.
Keywords: Anhedonia; BLA, basolateral amygdala; BNST, bed nucleus of stria terminalis; CNTF, ciliary neurotrophic factor; CRF, corticotropin releasing factor; CUS, chronic unpredictable stress; CeA, central amygdala; Chronic unpredictable stress; HPA, hypothalamic-pituitary-adrenal; Hyp, hypothalamus; IL-6, interleukin-6; LIF, leukemia inhibitory factor; MeA, medial amygdala; Neuroendocrine response; Neutralizing antibody; PAG, periaqueductal grey; PTSD, post-traumatic stress disorder; PVN, paraventricular nucleus; Passive stress-coping; Stereotaxic injection; TNF, tumor necrosis factor; mPFC, medial prefrontal cortex.
© 2022 The Authors.