Neuropeptide Senhances Acquisition And Consolidation Of Spatial Memory, And Renovates Impaired Acquisition Of Memory By Ketamine In Mice

Memory is a higher brain function in humans and animals, which is divided into three different stages:acquisition, consolidation and retrieval. Memory acquisition occurs as the beginning of the memory, when humans and animals are to obain knowledge and experience. During consolidation, when the memorized experience is consolidated, which can last from minutes to days, this memory is moved from a labile to a more fixed state. Retrieval, in which the memorized experience is assessed and recruited. Each stage has different sensitivities to behavioral and pharmacological interventions. Neuropeptide S (NPS) is a newly identified neuromodulator located in the brainstem and regulates various biological functions by selectively activating the NPS receptors (NPSR). NPSR mRNA is significantly expressed in the major input and output regions of the hippocampal formation including the subiculum, the presubiculum, the parasubiculum, the lateralentorhinal and endopiriform cortex suggesting that NPS-NPSR system would be involved in the regulation of memory. The effects of NPS on the memory acquisition, consolidation and retrieval are unclear so far, though several studies have reported NPS could promote spatial memory. The present study was designed to detect the effects of NPS-NPSR system on the spatial memory in both of the normal mice and impaired memory by keamine-treated mice, and the potential mechanism of NPS-NPSR system in memory regulation.MethodsIn memory acquisition test, Morris water maze (MWM) was employed to detect the escape latency to find the underwater platform for8trails following intracerebroventricular (ICV) injection NPS (0.01-1nmol) or saline in mice or ketamine-treated mice. The test of memory consolidation was performed24h after8trails training and then recived a ICV injection of NPS (0.01-0.5nmol) or saline in mice or ketamine-treated mice to detect the spent time in the target quadrant in which platform had been removed from MWM. The memory retrieval test was carried out intracerebroventricularly injection NPS (0.01-0.5nmol) or saline in mice or ketamine-treated mice24h after8trails training to detect the spent time in the target quadrant in which platform had been removed from MWM.[D-Val5]NPS was ICV injected with or without0.5nmol of NPS into mice to identify whether NPSR antagonist blocks the effect of NPS on spatial memory. C-Fos immunohistochemistry was used to marked the active neurons in the memory-related brain regions following NPS administration.Results1. The memory acquisition test demonstrated that NPS (0.1-1nmol) significantly reduced the escape latency to find underwater platform (P＜0.05) in mice. The effect of NPS at dose of0.5and1nmol on the escape latency was not different suggesting that the dose of0.1nmol is effective, and the dose of0.5nmol is maximum effective for NPS enhancing memory acquisition. NPS (0.01-0.5nmol) did not alter swimming velocity compared with saline suggesting that NPS promoting memory acquisition is not due to increase swimming speed.2. In the memory consolidation test, we found that0.5nmol of NPS significantly increased the duration of mice in the target quadrant (P＜0.001). However,0.01and0.1nmol of NPS-induced time in the target quadrant was not different from saline-treated mice, suggesting that0.5nmol of NPS effectively enhances consolidation of spatial memory.3. In the memory retrieval test, NPS (0.01-0.5nmol) showed no difference in spent time in target quadrant compared to saline-treated mice indicating that NPS is not affect on retrieval of spatial memory.4. In order to get rid of the influence of vision and motor coordination over NPS memory regualtion, visible platform test showed no difference in escape latency to find the visible platform between NPS and saline administrations suggesting that NPS enhances momory acquisition and consolidation in mice without attribution of vision and motor coordination.5. When co-injection of40nmol of [D-Val5]NPS with0.5nmol NPS, the effect of NPS on spatial memory was blocked (P<0.05), suggesting that NPS enhances spatial memory via selective action on NPSR.6. NPS (0.5nmol, ICV) induced an increase in the number of Fos-ir neurons in hippocampus including S, Prs, Pas, CA1, CA3and DG (P＜0.001). The evidence demonstrates that NPS promotes memory through activation of hippocampal neurons.7. The memory acquisition test demonstrated ketamine (50mg/kg, IP)-treated mice prolonged the escape latency to underwater platform compared to saline-treated mice (P＜0.05). NPS (0.5nmol, ICV) administration significantly shortened the escape latency to find underwater platform in ketamine-treated mice. The results indicate NPS renovates ketamine-induced memory impairment.8. The memory consolidation test showed no difference in the spent time in target quadrant between ketamined-treated and saline-treated mice, and between ketamine+NPS and ketamine+saline groups (P＞0.05), suggesting that ketamine does not impaired memeory consolidation, and NPS has no effect on memory consolidation in ketamine-treated mice.Conclusions:NPS enhances acquisition and consolidation of spatial memory through NPSR to activate hippocampal neurons in mice. NPS renovates ketamine-induced memory impaiment.