Experimental Laboratory of Translational Neuroscience and Otolaryngology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium; Bio-Imaging Lab, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Bio-Imaging Lab, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Behav Brain Res. 2019 May 17;364:303-316. doi: 10.1016/j.bbr.2019.02.040. Epub 2019 Feb 23.
Immune activation during pregnancy is an important risk factor for schizophrenia. Brain dysconnectivity and NMDA receptor (NMDAR) hypofunction have been postulated to be central to schizophrenia pathophysiology. The aim of this study was to investigate resting-state functional connectivity (resting-state functional MRI-rsfMRI), microstructure (diffusion tension imaging-DTI) and response to NMDAR antagonist (pharmacological fMRI-phMRI) using multimodal MRI in offspring of pregnant dams exposed to immune challenge (maternal immune activation-MIA model), and determine whether these neuroimaging readouts correlate with schizophrenia-related behaviour.
Pregnant rats were injected with Poly I:C or saline on gestational day 15. The maternal weight response was assessed. Since previous research has shown behavioural deficits can differ between MIA offspring dependent on the maternal response to immune stimulus, offspring were divided into three groups: controls (saline, n = 11), offspring of dams that gained weight (Poly I:C WG, n = 12) and offspring of dams that lost weight post-MIA (Poly I:C WL, n = 16). Male adult offspring were subjected to rsfMRI, DTI, phMRI with NMDAR antagonist, behavioural testing and histological assessment.
Poly I:C WL offspring exhibited increased functional connectivity in default mode-like network (DMN). Poly I:C WG offspring showed the most pronounced attenuation in NMDAR antagonist response versus controls. DTI revealed no differences in Poly I:C offspring versus controls. Poly I:C offspring exhibited anxiety.
MIA offspring displayed a differential pathophysiology depending on the maternal response to immune challenge. While Poly I:C WL offspring displayed hypersynchronicity in the DMN, altered NMDAR antagonist response was most pronounced in Poly I:C WG offspring.
怀孕期间的免疫激活是精神分裂症的一个重要危险因素。脑连接中断和 NMDA 受体 (NMDAR) 功能低下被认为是精神分裂症病理生理学的核心。本研究旨在通过多模态 MRI 研究母体免疫激活（MIA 模型）下怀孕母鼠后代的静息态功能连接（静息态功能 MRI-rsfMRI）、微观结构（扩散张力成像-DTI）和对 NMDAR 拮抗剂的反应，并确定这些神经影像学指标是否与精神分裂症相关行为相关。
在妊娠第 15 天给怀孕的大鼠注射 Poly I:C 或生理盐水。评估母体体重反应。由于先前的研究表明，MIA 后代的行为缺陷可能因母体对免疫刺激的反应而异，因此将后代分为三组：对照组（生理盐水，n=11）、体重增加的母鼠后代（Poly I:C WG，n=12）和 MIA 后体重减轻的母鼠后代（Poly I:C WL，n=16）。雄性成年后代进行 rsfMRI、DTI、NMDAR 拮抗剂的 phMRI、行为测试和组织学评估。
Poly I:C WL 后代表现出默认模式样网络 (DMN) 中功能连接的增加。Poly I:C WG 后代与对照组相比，NMDAR 拮抗剂反应的抑制最为明显。DTI 显示 Poly I:C 后代与对照组之间没有差异。Poly I:C 后代表现出焦虑。
根据母体对免疫挑战的反应，MIA 后代表现出不同的病理生理学。虽然 Poly I:C WL 后代的 DMN 表现出过度同步，但 Poly I:C WG 后代的 NMDAR 拮抗剂反应最为明显。
