Effect Of Cortistatin-14 On Learning And Memory And Depression-Like Behavior In Mice

Cortistatin-14?CST-14?,a recently discovered cyclic neuropeptide,shares high structural homology with somatostain-14,so it can bind to all receptors?SSTRs?of somatostatin.Besides,it can also bind to the Ghrelin receptor to exert biological activity and co-exit with GABA in the cortex and hippocampus.In the hippocampus,CST-14 inhibits CA1 neuronal pyramidal cell firing.However,its role of CST-14 in cognitive is still not clarified.The first aim of our study was to elucidate the role of CST-14 signaling in consolidation and reconsolidation of recognition memory in mice,using novel object recognition task.The results showed that central CST-14 induced impairment of long-term and short-term recognition memory,indicating memory consolidation impairment effect.Similarly,we found that CST-14 did not impaired long-term and short-term reconsolidation recognition memory.To further investigate the underlying mechanisms of CST-14 in memory process,we used cyclosomatostatin?c-SOM,a non-selective SST₁–₅ receptor antagonist?,Cyanamid154806?a selective SST₂receptor antagonist?,ODN-8?a selective SST₃ receptor antagonist?,[D-Lys³]GHRP-6?a selective Ghrelin receptor antagonist?,Picrotoxin?PTX,a GABA_A receptor antagonist?,and Sacolfen?a GABA_B receptor antagonist?to research its effects in recognition.Our results firstly indicated that the memory-impairing effects of CST-14were significantly reversed by c-SOM,Cyanamid154806,[D-Lys³]GHRP-6,PTX and Sacolfen,but not ODN-8,suggesting that the blockage of recognition memory consolidation induced by CST-14 involves SST₂,Ghrelin and GABA system.The present study provides a potential strategy to regulate memory processes,providing new evidence that reconsolidation is not a simple reiteration of consolidation.Since recent studies have reported the role and mechanism of Ghrelin-like antidepressants.Besides,the localization of SSTRs and Ghrelin receptors in brain has prompted us to speculate that CST-14 may play a role in the control of depression processes.Here,we tested the behavioral effects of CST-14 in a variety of classical rodent models of depression[forced swimming test?FST?,tail suspension test?TST?and novelty-suppressed feeding test?NSFT?].In the models of depression,CST-14produced antidepressant-like effects,and did not altered locomotor activity levels.We also found that CST-14 mRNA and BDNF mRNA were significantly decreased in the hippocampus and cortex after mice exposed to stress,these data indicated that ICV administration of CST-14 produce rapid antidepressant effects.Similarly,the following mechanism is discussed.The results showed that these antidepressant-like effects were significantly reversed by[D-Lys³]GHRP-6,but not c-SOM.Meanwhile,the effects of some neurotransmitter blockers indicated that only GABA_A system,but not CRF₁ receptor,?/?-adrenergic receptor,was involved in the antidepressant effect of CST-14.The effects of the p-mTOR inhibitor?Rapamycin?,the PI3K/Akt inhibitor?LY294002?and the p-ERK1/2 inhibitor?U0126?suggesting that the ERK/mTOR or PI3K/Akt/mTOR signaling pathway was not involved in the antidepressant effects of CST-14.Furthermore,in view of the damaged memory effect of CST-14,co-administration of CST-14 and NPS?Neuropeptide S,a neuropeptide enhanced memory?produced antidepressant effect without impairing memory.Interestingly,intranasal administration of CST-14 led to reducing depressive-like behavior,and near-infrared fluorescent imaging experiments showed bio-distribution in brain after intranasal infusion of Cy7.5-CST-14.Taken all together,the results of present study point to a role for CST-14 in the modulation of depression processes via the Ghrelin and GABA_A receptor,and suggest cortistation may represent a novel strategy for the treatment of depression disorders.