Department of Anesthesiology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
Department of Anesthesiology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
J Neuroinflammation. 2023 Oct 5;20(1):227. doi: 10.1186/s12974-023-02910-x.
Some patients show persistent cognitive decline for weeks, months or even years after surgery, which seriously affects their long-term prognosis and quality of life. However, most previous basic studies have focused mainly on the mechanisms of early postoperative cognitive decline, whereas cognitive decline in the longer term after surgery is less well-understood. The subgranular zone of the dentate gyrus exhibits life-long neurogenesis, supporting hippocampus-dependent learning and memory.
The aim of this study was to investigate whether adult hippocampal neurogenesis (AHN) involves in cognitive decline later following surgery and to further explore the roles of CD8 + T lymphocytes infiltrating the hippocampal parenchyma after surgery in this pathological process. Cognitive function was examined in adult mice that underwent laparotomy combined with partial hepatectomy, and the results showed that cognitive decline persisted in mice who underwent surgery during the first postoperative month, even though there was a trend toward continuous improvement over time. Significantly decreased numbers of DCX + cells, BrdU + cells, and BrdU + /DCX + cells were observed on day 8 after surgery, and a significantly decreased number of NeuN + /BrdU + cells was observed on day 28 after surgery, which indicated inhibition of AHN. After surgery, T lymphocytes, the majority of which were CD8 + T cells, infiltrated the hippocampus and secreted Interferon-γ (IFN-γ). Depletion of CD8 + T cells could inhibit the increase of IFN-γ synthesis, improve hippocampal neurogenesis, and improve postoperative cognitive function. Hippocampal microinjection of IFN-γ neutralizing antibody or adeno-associated virus to knock down IFN-γ receptor 1 (IFNGR1) could also partially attenuate the inhibition of AHN and improve postoperative cognitive function.
These results demonstrate that postoperative infiltration of CD8 + T cells into the hippocampus and subsequent secretion of IFN-γ contribute to the inhibition of AHN and cognitive decline later following surgery.
一些患者在手术后数周、数月甚至数年内仍持续出现认知能力下降，严重影响其长期预后和生活质量。然而，大多数之前的基础研究主要集中在术后早期认知能力下降的机制上，而对术后较长时间的认知能力下降了解较少。齿状回的颗粒下层区具有终生的神经发生能力，支持海马依赖性学习和记忆。
本研究旨在探讨成年海马神经发生（AHN）是否参与手术后的认知能力下降，并进一步探讨手术后浸润海马实质的 CD8+T 淋巴细胞在这一病理过程中的作用。对接受剖腹术联合部分肝切除术的成年小鼠进行了认知功能检查，结果显示，即使术后时间延长，认知能力仍持续下降。术后第 8 天观察到 DCX+细胞、BrdU+细胞和 BrdU+/DCX+细胞数量明显减少，术后第 28 天观察到 NeuN+/BrdU+细胞数量明显减少，提示 AHN 受到抑制。手术后，T 淋巴细胞（大部分为 CD8+T 细胞）浸润海马并分泌干扰素-γ（IFN-γ）。CD8+T 细胞耗竭可抑制 IFN-γ 合成增加，改善海马神经发生，改善术后认知功能。海马内注射 IFN-γ 中和抗体或腺相关病毒敲低 IFN-γ 受体 1（IFNGR1）也可部分减轻 AHN 抑制，改善术后认知功能。
这些结果表明，手术后 CD8+T 细胞浸润海马并随后分泌 IFN-γ，导致 AHN 抑制和术后较长时间的认知能力下降。
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