Abstract：
The infralimbic (IL) cortex dysfunction has been implicated in major depressive disorder (MDD), yet the precise cellular and molecular mechanisms remain poorly understood. In this study, we investigated the role of layer V pyramidal neurons in a mouse model of MDD induced by repeated lipopolysaccharide (LPS) administration. Our results demonstrate that three days of systemic LPS administration induced depressive-like behavior and upregulated mRNA levels of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-β (TGF-β) in the IL cortex. Electrophysiological recordings revealed a significant decrease in the intrinsic excitability of layer V pyramidal neurons in the IL following systemic LPS exposure. Importantly, chemogenetic activation of IL pyramidal neurons ameliorated LPS-induced depressive-like behavior. Additionally, LPS administration significantly increased microglial activity in the IL, as evidenced by a greater number of Ionized calcium binding adaptor molecule-1 (IBA-1)-positive cells. Morphometric analysis further unveiled enlarged soma, decreased branch numbers, and shorter branch lengths of microglial cells in the IL cortex following LPS exposure. Moreover, the activation of pyramidal neurons by clozapine-N-oxide increased the microglia branch length but did not change branch number or cytosolic area. These results collectively suggest that targeted activation of pyramidal neurons in the IL cortex mitigates microglial response and ameliorates depressive-like behaviors induced by systemic LPS administration. Therefore, our findings offer potential therapeutic targets for the development of interventions aimed at alleviating depressive symptoms by modulating IL cortical circuitry and microglial activity.
摘要：
下边缘（IL）皮质功能障碍与重度抑郁症（MDD）有关，然而，精确的细胞和分子机制仍然知之甚少。在这项研究中,我们研究了V层锥体神经元在重复脂多糖（LPS）诱导的MDD小鼠模型中的作用。我们的研究结果表明，3天的全身LPS给药诱导抑郁样行为和上调的白细胞介素-1β（IL-1β）的mRNA水平，肿瘤坏死因子-α（TNF-α），和转化生长因子-β（TGF-β）在IL皮质。电生理记录显示，全身LPS暴露后，IL中V层锥体神经元的内在兴奋性显着降低。重要的是,IL锥体神经元的化学遗传激活改善了LPS诱导的抑郁样行为。此外,LPS显著增加IL中的小胶质细胞活性，如更大量的离子化钙结合衔接子分子-1(IBA-1)阳性细胞所证明的。形态学分析进一步揭示了增大的躯体，分支数量减少，LPS暴露后IL皮质中小胶质细胞的分支长度较短。此外，氯氮平-N-氧化物对锥体神经元的激活增加了小胶质细胞的分支长度，但没有改变分支数量或胞质面积。这些结果共同表明，IL皮质中锥体神经元的靶向激活减轻了小胶质细胞反应，并改善了全身LPS给药诱导的抑郁样行为。因此,我们的研究结果为开发旨在通过调节IL皮质回路和小胶质细胞活性来缓解抑郁症状的干预措施提供了潜在的治疗靶点.
