體能運動與NMDA受體部分活化劑調節母體免疫激活小鼠引起的精神異常模型

Abstract

母體免疫激活（MIA）對後代大腦發育有負向的傳導，導致神經化學因子異常和產生精神疾病行為。由於MIA子代中N-甲基-D-天冬氨酸受體（NMDAR）功能低下可能是精神疾病的重要病因。精神疾病患者的症狀改善也顯示與其海馬迴的結構和功能改變有正向影響。長期以來，許多精神疾病研究指出海馬迴一直扮演關鍵角色。體能運動能刺激成年的海馬迴而引起神經新生現象，支持在海馬迴功能的神經與精神疾病發生之間建立關聯。本研究旨在評估NMDAR調節劑和運動是否可以減緩由MIA引起的子代成年期間精神疾病之行為障礙。使用產前感染模型，在胚胎第12-17天（E12至E17）給予懷孕的ICR小鼠雙鏈RNA聚核糖肌苷酸 - 聚核糖酸[Poly（i：c）]或生理食鹽水6天。後代（P70-84）每天以腹腔注射給予NMDAR調節劑（100mg / kg）或體能運動兩週。成年子代進行活動性運動，社會互動，刻板行為和急性束縛壓力誘發的行為反應測試。並且應用流式細胞儀技術測定成年子代周邊血液的細胞表面標記物的表達水平。在活動力運動測試（LMT）中，與控制組相比，MIA子代在開闊場地行走的總距離相似。MIA子代在成人階段比起控制組，表現出較少的社會互動現象但在刻板挖掘的大理石埋藏實驗無明顯變化。此外，來自MIA成年後代的周邊血液中CD11b+細胞表達更高水平的巨噬細胞活化標記CD86和主要組織相容性複合體II類（MHC II類，I-A / I-E）。 NMDAR調節劑的慢性給藥和體能運動兩週減緩了由MIA誘導的社交缺陷，但在刻板動作挖掘中沒有明顯變化。此外，NMDAR調節劑在急性束縛壓力中，體能運動緩解了MIA子代的社交活動障礙，而不是減少活動量和重複性挖掘。這項工作提出了膳食補充NMDAR調節劑或運動，能成功的減緩MIA子代精神障礙有關的社交異常行為，為此打開了新的途徑。

Maternal immune activation (MIA) during pregnancy negatively transforms offspring brain development, resulting in neurochemical abnormalities and neuropsychiatric disorder behaviors. Since hypofunction of N-methyl-D-aspartate receptors (NMDARs) in offspring after MIA may be a convergence point for psychiatric symptoms. Improvements in the behavioral symptoms in psychosis are associated with positive changes in hippocampal structure and function as shown in patients with chronic schizophrenia, because hippocampus has been demonstrated for its critical involvement in many mental diseases. Physical exercise that stimulates adult hippocampal neurogenesis may improve the neuropsychological symptoms. This study was undertaken to evaluate whether NMDAR modulator and exercise could reduce MIA-induced behavioral impairments in the adult offspring. Using a prenatal infection model, the pregnant ICR mice were administrated with double-stranded RNA polyinosinic:polycytidylic acid [Poly(i:c)] or saline on embryonic days 12-17 (E12 to E17) for six days. The offspring (P70-84) were given (i.p.) daily with NMDAR modulator (100 mg/kg) and physical exercise for two weeks. Adult offspring were tested for spontaneous locomotion, social interaction, stereotyped behavior, and restraint stress induced behavioral responses. The expressing levels of cell surface markers from adult offspring peripheral blood were also determined by flow cytometry. In spontaneous locomotion test (LMT), MIA offspring traveled a similar total distance in open field compared with their control groups. MIA offspring at adult stage exhibited a less social interaction. Their stereotypic digging and marble burying performance was not different to control offspring. Moreover, peripheral blood CD11b+ cells from MIA adult offspring expressed a higher levels of activation markers, CD86 and major histocompatibility complex class II (MHC class II, I-A/I-E). Subchronic administration of NMDAR modulator and physical exercise for two weeks attenuated the social interaction deficits, but not stereotypic digging induced by MIA. Moreover, NMDAR modulator alleviated the social interaction deficits, but did not alter locomotion and stereotypic digging in MIA offspring after acute restraint stress. This work raises the possibility that dietary supplementation with NMDAR modulator or physical exercise may open new avenues for a successful attenuation of behavioral alterations relevant to psychiatric disorder about sociality in the adult MIA offspring.