Gene expression profiling of the nucleus accumbens and dorsolateral striatum in a two-hit model combining maternal immune activation and peripubertal stress in rats

Substance use disorders are more prevalent in schizophrenia, worsening its course and prognosis. Here, we used a double-hit rat model, combining maternal immune activation (MIA) and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioral alterations. We injected lipopolysaccharide (LPS) or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to unpredictable stress during adolescence. When rats reached adulthood, we studied their cocaine addiction-like behavior, impulsivity and conditioning processes, and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration but PUS reduced cocaine intake, an effect that was reversed by MIA. MIA increased motivation for cocaine and revearsed the effects of PUS during extended access. Incubation of seeking was unaffected. Neither hit alone nor their combination impacted pavlovian or instrumental learning or impulsiveness. At the brain level, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum. When combined, both hits altered the structure and function of the dorsal striatum increasing its volume and interferring with glutamatergic dynamics. MIA alone had no effect on the gene expression of the nucleus accumbens but, when combined with PUS, modulated specific genes that could account for the decreased cocaine intake. PUS had a profund effect on the dorsal striatal transcriptome however, this was obliterated when PUS occurred in animals with MIA. These results describe a complex interplay between MIA and stress on neurodevelopment and in the susceptibility to develop cocaine addiction.精神分裂症患者的物质使用障碍患病率更高，且会加重其病程与预后。本研究采用结合母体免疫激活（Maternal Immune Activation, MIA）与青春期前应激（Peripubertal Stress, PUS）的双打击大鼠模型，探究可卡因成瘾及其潜在的神经行为改变。我们于妊娠第15、16天向孕鼠注射脂多糖（Lipopolysaccharide, LPS）或生理盐水，随后令其子代雄性大鼠在青春期接受不可预知应激刺激。待大鼠进入成年期后，通过磁共振成像（Magnetic Resonance Imaging, MRI）、正电子发射计算机断层扫描（Positron Emission Computed Tomography, PET）与RNA测序（RNAseq）技术，评估其类可卡因成瘾行为、冲动性、条件反射过程以及脑结构与功能的多项特征。研究发现，MIA可促进可卡因自身给药行为的习得，而PUS则会降低可卡因摄取量，且该抑制效应可被MIA逆转；在延长给药时段下，MIA可增强可卡因觅药动机，并抵消PUS的作用。觅药行为的孵育效应未受上述处理影响。单一打击或二者联合均未对巴甫洛夫式学习、工具性学习或冲动性产生显著影响。在脑结构层面，PUS可降低海马体积并激活背侧下托；二者联合则会改变背侧纹状体的结构与功能，使其体积增大并干扰谷氨酸能动力学。单独的MIA对伏隔核的基因表达无显著影响，但当与PUS联合时，可调控特定基因的表达，这或许能解释可卡因摄取量降低的现象。PUS对背侧纹状体转录组具有深远影响，然而该效应在同时经历MIA的个体中被完全消除。本研究结果揭示了MIA与应激在神经发育及可卡因成瘾易感性间存在复杂的交互作用。