Background

Information processing in cortical cell microcircuits involves regulation of excitatory pyramidal (PYR) cells by inhibitory somatostatin- (SST), parvalbumin-, and vasoactive intestinal peptide–expressing interneurons. Human postmortem and rodent studies show impaired PYR cell dendritic morphology and decreased SST cell markers in major depressive disorder or after chronic stress. However, knowledge of coordinated changes across microcircuit cell types is virtually absent.

Methods

We investigated the transcriptomic effects of unpredictable chronic mild stress (UCMS) on distinct microcircuit cell types in the medial prefrontal cortex (cingulate regions 24a, 24b, and 32) in mice. C57BL/6 mice, exposed to UCMS or control housing for 5 weeks, were assessed for anxiety- and depressive-like behaviors. Microcircuit cell types were laser microdissected and processed for RNA sequencing.

Results

UCMS induced predicted elevations in behavioral emotionality in mice. DESeq2 analysis revealed unique differentially expressed genes in each cell type after UCMS. Presynaptic functions, oxidative stress response, metabolism, and translational regulation were differentially dysregulated across cell types, whereas nearly all cell types showed downregulated postsynaptic gene signatures. Across the cortical microcircuit, we observed a shift from a distributed transcriptomic coordination across cell types in control mice toward UCMS-induced increased coordination between PYR, SST, and parvalbumin cells and a hub-like role for PYR cells. Finally, we identified a microcircuit-wide coexpression network enriched in synaptic, bioenergetic, and oxidative stress response genes that correlated with UCMS-induced behaviors.

Conclusions

These findings suggest cell-specific deficits, microcircuit-wide synaptic reorganization, and a shift in cells regulating the cortical excitation–inhibition balance, suggesting increased coordinated regulation of PYR cells by SST and parvalbumin cells.

中文翻译：

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慢性压力导致协调的皮层微电路细胞型转录组变化与改变的信息处理一致

背景

皮层细胞微电路中的信息处理涉及通过抑制性生长抑素（SST）、小白蛋白和血管活性肠肽表达中间神经元调节兴奋性锥体（PYR）细胞。人类死后和啮齿动物研究表明，在重度抑郁症或慢性应激后，PYR 细胞树突形态受损和 SST 细胞标志物减少。然而，几乎不存在跨微电路单元类型的协调变化的知识。

方法

我们研究了不可预测的慢性轻度应激 (UCMS) 对小鼠内侧前额叶皮层（扣带回 24a、24b 和 32）中不同微电路细胞类型的转录组学影响。C57BL/6 小鼠，暴露于 UCMS 或控制住房 5 周，评估焦虑和抑郁样行为。对微电路细胞类型进行激光显微切割和处理以进行 RNA 测序。

结果

UCMS 诱导小鼠行为情绪的预测升高。DESeq2 分析揭示了 UCMS 后每种细胞类型中独特的差异表达基因。突触前功能、氧化应激反应、代谢和翻译调节在不同细胞类型之间存在差异性失调，而几乎所有细胞类型都显示出下调的突触后基因特征。在整个皮层微电路中，我们观察到对照小鼠从跨细胞类型的分布式转录组协调转变为 UCMS 诱导的 PYR、SST 和小白蛋白细胞之间的协调增加以及 PYR 细胞的枢纽样作用。最后，我们确定了一个微电路范围内的共表达网络，该网络富含与 UCMS 诱导的行为相关的突触、生物能量和氧化应激反应基因。

结论

这些发现表明细胞特异性缺陷、微电路范围内的突触重组和调节皮质兴奋-抑制平衡的细胞发生变化，表明 SST 和小白蛋白细胞对 PYR 细胞的协调调节增加。