A Critical Role Of NPAS4 In PTSD-like Behavior

Objective: In this study, the single prolonged stress(SPS) animal model as the main model of PTSD.To explore the role of NPAS4 in PTSD-like behavior and its molecular signaling pathways by overexpression of NPAS4,drug intervention of SSRIs and behavioral epigenetic modulation.Methods:(1) Open field test and elevated plus maze are used to tset anxiety behavior in rats;(2) Using unconditioned stimulus to test the change of the rats fear memory;(3) Using fear extinction to measuring the freezing time of SPS rats;(4) By intraperitoneal injection of fluoxetine to detect brain regions NPAS4 protein levels change;(5) Brain injection LV-NPAS4-RNAi detect NPAS4 protein levels change.Results:(1) The anxiety levels was significantly increased 14 days after SPS compared with the no-SPS; The analysis of the Western blot data using one-way ANOVA revealed that NPAS4 expression in the IL was significantly increased 14 days after SPS compared with the group no-SPS, but not Pr L.Also, the anxiety levels was significantly increased 1days after SPS compared with the no-SPS, no significant differences were found in the Pr L and IL of NPAS4 expression.(2) Before SPS injecting LV-NPAS4-RNAi in the IL produced an early-onset of PTSD-like behaviors. The analysis of the Western blot data using one-way ANOVA revealed that NPAS4 expression descraesed in the two groups of rats received LV-NPAS4-RNAi or LV-GFP;(3) Groups of anxiety characterized by intraperitoneal of fluoxetine:both SPS and injected fluoxetine compared with only injected fluoxetine or saline had no significant differences,but compared with the group of both SPS and injected saline found descreaded;(4) BDNF、GAD-67、GABA-A、GABA-B、Glu R1 and Glu R2 were increased 1 day after SPS compared with the control,while GABA-B and Glu R2 had no significant differences 14 days after SPS compared with the control;(5) After a month of Physical environment enrichment,the NPAS4 protein level compared with the normal and SPS increased,while no significant differences were found compared with other groups.Conclusion:(1) Single prolonged stress-induced delayed onset of PTSD-like behaviors was associated with decreased infralimbic NPAS4 levels;(2) InfralimbicNPAS4 knockdown produced an early-onset of PTSD-like behaviors;(3) Up-regulation of NPAS4 prevented the development of PTSD-like behaviors;(4) Overexpression of NPAS4 prevented the stress-induced PTSD-like behavior via restoring GABAergic tone;(5) Behavioral epigenetic modulation of NPAS4 expression protected the rats from the PTSD-like behavior.