Allergic inflammation during pregnancy increases risk for a diagnosis of neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) in the offspring. Previously, we found a model of such inflammation, allergy-induced maternal immune activation (MIA), produced symptoms analogous to those associated with neurodevelopmental disorders in rats, including reduced juvenile play behavior, hyperactivity, and cognitive inflexibility. These behaviors were preceded by perinatal changes in microglia colonization and phenotype in multiple relevant brain regions. Given the role that microglia play in synaptic patterning as well as evidence for altered synaptic architecture in neurodevelopmental disorders, we investigated whether allergic MIA altered the dynamics of dendritic spine patterning throughout key regions of the rat forebrain across neurodevelopment. Adult virgin female rats were sensitized to the allergen, ovalbumin, with alum adjuvant, bred, and allergically challenged on gestational day 15. Brain tissue was collected from male and female offspring on postnatal days (P) 5, 15, 30, and 100–120 and processed for Golgi-Cox staining. Mean dendritic spine density was calculated for neurons in brain regions associated with cognition and social behavior, including the medial prefrontal cortex (mPFC), basal ganglia, septum, nucleus accumbens (NAc), and amygdala. Allergic MIA reduced dendritic spine density in the neonatal (P5) and juvenile (P15) mPFC, but these mPFC spine deficits were normalized by P30. Allergic inflammation reduced spine density in the septum of juvenile (P30) rats, with an interaction suggesting increased density in males and reduced density in females. MIA-induced reductions in spine density were also found in the female basal ganglia at P15, as well as in the NAc at P30. Conversely, MIA-induced increases were found in the NAc in adulthood. While amygdala dendritic spine density was generally unaffected throughout development, MIA reduced density in both medial and basolateral subregions in adult offspring. Correlational analyses revealed disruption to amygdala-related networks in the neonatal animals and cortico-striatal related networks in juvenile and adult animals in a sex-specific manner. Collectively, these data suggest that communication within and between these cognitive and social brain regions may be altered dynamically throughout development after prenatal exposure to allergic inflammation. They also provide a basis for future intervention studies targeted at rescuing spine and behavior changes via immunomodulatory treatments.

怀孕期间的过敏性炎症会增加后代诊断出注意力缺陷/多动障碍 (ADHD) 和自闭症谱系障碍 (ASD) 等神经发育障碍的风险。以前，我们发现了这种炎症模型，即过敏诱导的母体免疫激活 (MIA)，产生的症状类似于与大鼠神经发育障碍相关的症状，包括幼年游戏行为减少、多动和认知僵化。在这些行为之前，多个相关大脑区域的小胶质细胞定植和表型发生了围产期变化。鉴于小胶质细胞在突触模式中的作用以及神经发育障碍中突触结构改变的证据，我们研究了过敏性 MIA 是否改变了整个大鼠前脑神经发育关键区域的树突棘模式动力学。成年处女雌性大鼠使用明矾佐剂对过敏原卵清蛋白敏感，在妊娠第 15 天进行繁殖和过敏性攻击。在出生后第 5、15、30 和 100 天（P）从雄性和雌性后代收集脑组织– 120 并进行高尔基-考克斯染色处理。计算了与认知和社会行为相关的脑区神经元的平均树突棘密度，包括内侧前额叶皮层 (mPFC)、基底神经节、隔膜、伏隔核 (NAc) 和杏仁核。过敏性 MIA 降低了新生儿 (P5) 和幼年 (P15) mPFC 的树突棘密度，但这些 mPFC 脊柱缺陷被 P30 标准化。过敏性炎症降低了幼年 (P30) 大鼠隔膜的脊柱密度，相互作用表明雄性大鼠密度增加而雌性大鼠密度降低。在 P15 的女性基底神经节以及 P30 的 NAc 中也发现了 MIA 诱导的脊柱密度降低。相反，MIA 诱导成年后 NAc 增加。虽然杏仁核树突棘密度在整个发育过程中通常不受影响，但 MIA 降低了成年后代内侧和基底外侧子区域的密度。相关分析显示新生动物的杏仁核相关网络和幼年动物和成年动物的皮质-纹状体相关网络以性别特异性方式受到破坏。总的来说，这些数据表明，在产前暴露于过敏性炎症后，这些认知和社交大脑区域内部和之间的交流可能会在整个发育过程中发生动态变化。它们还为未来旨在通过免疫调节治疗挽救脊柱和行为改变的干预研究提供了基础。