Severe stress exposure causes the loss of dendritic spines on cortical pyramidal neurons and induces psychiatric-like symptoms in rodent models. These effects are strongest following early-life stress and are most persistent on apical dendrites. However, the long-term impacts and temporal effects of stress exposure on the human brain remain poorly understood. Using a novel postmortem cohort of psychiatric cases with severe stress experienced in childhood, adulthood, or no severe stress, and matched controls, we aimed to determine the impact of stress timing on pyramidal neuron structure in the human orbitofrontal cortex (OFC). We performed Golgi Cox staining and manually measured the morphology and density of over 22,000 dendritic spines on layer-specific pyramidal neuron apical dendrites. We also quantified glucocorticoid receptor mRNA and protein as a marker of stress dysregulation. Both childhood and adulthood stress were associated with large reductions in mature mushroom spine density (up to 56% loss) in both the superficial (II/III) and deeper layers (V) of the OFC. However, childhood stress caused more substantial reductions to both total and mature mushroom spines. No difference in glucocorticoid receptor mRNA and protein were seen between groups, although both negatively correlated with total spine density within the whole cohort. These findings indicate that severe stress, especially when experienced during childhood, persistently affects the fine morphological properties of neurons in the human OFC. This may impact on cell connectivity in this brain area, and at least partly explain the social and emotional symptoms that originate in the OFC in psychiatric disorders.

严重的压力暴露会导致皮质锥体神经元上的树突棘丧失，并在啮齿动物模型中诱发类似精神病的症状。这些作用在生命早期应激后最强，并且对根尖树突最持久。但是，人们对应力暴露对人脑的长期影响和暂时影响知之甚少。我们使用了新型的事后队列研究，即在儿童期，成年期或没有严重压力下经历过严重压力的精神病学病例，并采用相匹配的对照，我们旨在确定压力时机对人眶额皮质（OFC）锥体神经元结构的影响。我们进行了高尔基·考克斯（Golgi Cox）染色，并手动测量了层特异性锥体神经元根尖突上22,000多个树突棘的形态和密度。我们还量化了糖皮质激素受体的mRNA和蛋白作为压力失调的标志。儿童期和成年期压力都与OFC浅表层（II / III）和深层（V）的成熟蘑菇脊柱密度大大降低（损失高达56％）有关。但是，童年时期的压力导致香菇刺的总数和成熟度都有较大幅度的下降。两组之间糖皮质激素受体的mRNA和蛋白均无差异，尽管两者均与整个队列中的总脊柱密度呈负相关。这些发现表明，严重的压力，特别是在儿童时期经历的压力，会持续影响人类OFC中神经元的精细形态学特性。这可能会影响该大脑区域的细胞连接，