Major illnesses, including heart attack and sepsis, can cause cognitive impairments, depression, and progressive memory decline that persist long after recovery from the original illness. In rodent models of sepsis or subchronic immune challenge, memory deficits also persist for weeks or months, even in the absence of ongoing neuroimmune activation. This raises the question of what mechanisms in the brain mediate such persistent changes in neural function. Here, we used RNA-sequencing as a large-scale, unbiased approach to identify changes in hippocampal gene expression long after a subchronic immune challenge previously established to cause persistent memory impairments in both males and females. We observed enduring dysregulation of gene expression three months after the end of a subchronic immune challenge. Surprisingly, there were striking sex differences in both the magnitude of changes and the specific genes and pathways altered, where males showed persistent changes in both immune- and plasticity-related genes three months after immune challenge, whereas females showed few such changes. In contrast, females showed striking differential gene expression in response to a subsequent immune challenge. Thus, immune activation has enduring and sex-specific consequences for hippocampal gene expression and the transcriptional response to subsequent stimuli. Together with findings of long-lasting memory impairments after immune challenge, these data suggest that illnesses can cause enduring vulnerability to, cognitive decline, affective disorders, and memory impairments via dysregulation of transcriptional processes in the brain.

中文翻译：

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亚慢性免疫挑战后海马基因表达的持久和性别特异性变化。

重大疾病，包括心脏病发作和败血症，可导致认知障碍、抑郁和进行性记忆力下降，这些疾病在从原始疾病恢复后仍会持续很长时间。在败血症或亚慢性免疫挑战的啮齿动物模型中，即使没有持续的神经免疫激活，记忆缺陷也会持续数周或数月。这就提出了一个问题，即大脑中的什么机制介导了神经功能的这种持续变化。在这里，我们使用 RNA 测序作为一种大规模、无偏见的方法来识别海马基因表达的变化，这是在先前确定的亚慢性免疫挑战导致男性和女性持续性记忆障碍后很长一段时间内发生的变化。我们在亚慢性免疫挑战结束三个月后观察到基因表达持续失调。出奇，在变化的幅度以及改变的特定基因和途径方面存在显着的性别差异，其中男性在免疫挑战三个月后显示出免疫和可塑性相关基因的持续变化，而女性几乎没有这种变化。相比之下，女性在随后的免疫挑战中表现出显着的差异基因表达。因此，免疫激活对海马基因表达和对后续刺激的转录反应具有持久和性别特异性的影响。连同免疫挑战后长期记忆障碍的发现，这些数据表明，疾病可通过大脑转录过程失调导致持久的脆弱性、认知能力下降、情感障碍和记忆障碍。