早产相关损伤重塑小脑发育与行为
Prematurity insults remodel cerebellar development and behaviour
早产存活者常出现运动和社会认知障碍，这提示小脑发育发生了改变，但其潜在机制仍知之甚少。一个关键挑战在于，早产涉及多种相互重叠的围产期损伤，这些损伤共同作用于发育中的大脑，使得难以区分它们各自的影响。在此，我们在小鼠中模拟了两种主要的早产相关损伤：母体免疫激活（MIA）和新生儿缺氧（Hx）。通过控制发生时间和顺序，我们明确了这些损伤如何在快速成熟期塑造小脑的组装过程。与人体组织的比较分析证实，这些损伤重现了人类早产小脑的关键特征，从而确立了该模型用于剖析特定损伤结局的转化效度。行为学和运动学表型分析揭示了分化的运动和社会表型，我们将其追溯至损伤特异性的小脑重塑。缺氧同时损害了内颗粒层中颗粒细胞的成熟以及投射至浦肯野细胞的主要兴奋性传入，这一环路状态表现为运动执行受损以及刻板、感觉脱离的社会探究行为。相比之下，母体免疫激活扩大了颗粒细胞祖细胞层并降低了浦肯野细胞树突复杂性，该表型保留了社会偏好，但重组了社会探究的运动学结构。当缺氧发生在母体免疫激活之后时，它作用于这一已被致敏的底物，产生了一种独特的状态：先前炎症所建立的特征被颗粒细胞增殖停滞、进行性线粒体功能障碍以及异常、过度互动的社会探究所叠加。总之，这些发现将早产相关损伤重新定义为受损伤身份和顺序共同塑造的小脑重编程事件，将不同的机制底物与分化的神经发育结局联系起来。
把母体免疫激活与新生儿缺氧分开并组合操纵，说明 insult 的种类和先后顺序对应不同的小脑环路重塑与行为表型。
Preterm survivors often develop motor and socio-cognitive impairments that implicate altered cerebellar development, yet the underlying mechanisms remain poorly understood. A key challenge is that prematurity involves overlapping perinatal insults that converge on the developing brain, making their individual effects difficult to disentangle.Here, we model two major prematurity-associated insults, maternal immune activation (MIA) and neonatal hypoxia (Hx), in mice. By controlling timing and sequence, we define how these insults shape cerebellar assembly during rapid maturation. Comparative analysis with human tissue confirmed that these insults recapitulate key features of the human preterm cerebellum, establishing the translational validity of this model for dissecting insult-specific outcomes.Behavioral and kinematic profiling revealed divergent motor and social phenotypes, which we traced to insult-specific cerebellar remodelling. Hypoxia compromised both granule cell maturation in the internal granule layer and the principal excitatory afferents to Purkinje cells, a circuit state that manifested as impaired motor execution and stereotyped, sensory-disengaged social investigation. Maternal immune activation, by contrast, expanded the granule cell progenitor layer and reduced Purkinje cell dendritic complexity, a phenotype that preserved social preference but reorganized the kinematic structure of social investigation. When hypoxia followed maternal immune activation, it acted on this primed substrate to produce a distinct state in which the features established by prior inflammation were compounded by granule cell proliferative arrest, progressive mitochondrial dysfunction, and aberrant, hyper-interactive social investigation.Together, these findings reframe prematurity-associated insults as cerebellar reprogramming events shaped by both the identity and sequence of insults, linking distinct mechanistic substrates to divergent neurodevelopmental outcomes
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来源：Brain · academic.oup.com