Effects And Mechanism Of Phoenixin-14 On Anxiety And Cognitive Behavior In Mice

Phoenixin(PNX) is a recently discovered neuropeptide shown to be involved in regulating reproductive system and pain, and its receptor has not been reported so far. Phoenixin(PNX-14), one of the endogenous active isoforms, is an amidated neuropeptide. PNX-14 is widely distributed in brain and periphery regions,which was reported to involve in regulating GnRH receptor expression and GnRH secretion. Studies showed that GnRH could regulate brain responses to anxiety. Foremore, both GnRH receptor and GnRH are reported to involve in the regulation of learning and memory processes. However, the role of PNX-14 in anxiety and cognition were largely unclear. Here, we firstly investigated that the effects of PNX-14 in anxiety-related behavior in adult mice via the open field and elevated plus maze. PNX-14 was administered intracerebroventricularly(i.c.v.) in different doses(5, 10, 25 and 50 nmol), and the drug could dose-dependently induce anxiolytic effects. Then this anxiolytic action was presented after PNX-14 injected into the anterior hypothalamic area(AHA), while PNX-14 infused into the amygdala did not exert anxiolytic effects. GnRH receptor antagonist(Cetrorelix) could significantly antagonize the anxiolytic effects of PNX-14, while Atosiban,a competitive vasopressin/oxytocin receptor antagonist could not. Moreover, PNX-14 could significantly lower the core temperature and the effect could be blocked by Cetrorelix. Additionally, the AHA infusion of PNX-14(5 nmol) increased the expression level of the GnRH mRNA in the hypothalamus and plasma concentrations of GnRH. Similarly, i.c.v. injection of PNX-20 also reduced the core temperature and exerted anxiolytic effects.Taken together, centrally injected PNX-14 generates anxiolytic effects in mice, through the activation of the AHA GnRH system.Then, we investigated the role of PNX-14 in memory processes, and determined whether PNX-14 could mitigate memory impairment induced by Aβ1-42 in mice, using novel object recognition(NOR) and object location recognition(OLR) tasks. Our results reveal that i.c.v. injection of PNX-14(25 nmol) immediately after training not only facilitated memory formation, but also prolonged memory retention in both tasks. Then these memory-enhancing effects also were presented after PNX-14 infused into the hippocampus. Moreover, these memory-improving effects of PNX-14 could be blocked by GnRH receptor antagonist(Cetrorelix). Meanwhile,we found that these memory-improving effects of PNX-14 have nothing to do with locomotor activity.Additionally, we found that i.c.v. injection of PNX-14 reversed the memory impairment induced by Aβ1-42. To sum up, our present results indicate that PNX-14 facilitates memory formation and prolongs memory retentionthrough activation of the GnRH receptor, and mitigates the memory-impairing effects of Aβ1-42, suggesting that PNX-14 may be a potential drug for enhancing memory and treating Alzheimer’s disease.