Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Oklahoma City Veterans Affairs Health Care System, Oklahoma City, Oklahoma.
Am J Physiol Gastrointest Liver Physiol. 2022 Feb 1;322(2):G223-G233. doi: 10.1152/ajpgi.00307.2021. Epub 2021 Dec 8.
Cognitive behavioral therapy (CBT) improves the quality of life for patients with brain-gut disorders; however, the underlying mechanisms of CBT remain to be explored. Previously, we showed that environmental enrichment (EE), an experimental paradigm that mirrors positive behavioral intervention, ameliorates chronic stress-induced visceral hypersensitivity in a rodent model via mechanisms involving altered activity in the central nucleus of amygdala (CeA). In the present study, we investigated whether microglia-mediated synaptic plasticity in the CeA is a potential mechanism underlying the protective effects of EE against stress-induced visceral hypersensitivity. We stereotaxically implanted corticosterone (CORT) micropellets onto the dorsal margin of the CeA shown previously to induce colonic hypersensitivity. Animals were housed in EE cages or standard cages for 14 days after CORT implantation. Visceral sensitivity was assessed via visceromotor behavioral response to colorectal distension. Microglial morphology, microglia-mediated synaptic engulfment, and the expression of synaptic pruning-related signals complement component 1q (C1q), complement component 3 (C3), and C3 receptor (C3R) were measured using immunofluorescence and RNAscope assay. We found that housing CORT implanted rats in EE cages for 14 days attenuated visceral hypersensitivity in both male and female rats as compared with control rats maintained in standard housing. EE reduced CORT-induced microglial remodeling and microglia-mediated synaptic pruning with reduced C1q and CR3, but not C3, expression. Our data suggest that exposure to EE is sufficient to ameliorate stress-induced visceral pain via reducing amygdala microglia-modulated neuronal plasticity. Clinical studies show that cognitive behavioral therapy (CBT) is effective in ameliorating visceral pain in patient with irritable bowel syndrome (IBS), yet the underlying mechanisms remain unexplored. By using environmental enrichment (EE), an experimental paradigm that mirrors positive behavioral intervention, we demonstrated that microglia-mediated synaptic plasticity in the CeA explains, plays a role, at least in part, in the positive effects of EE to reduce visceral hypersensitivity.
认知行为疗法（CBT）可提高脑肠疾病患者的生活质量；然而，CBT 的潜在机制仍有待探索。之前，我们发现环境富集（EE），一种模拟积极行为干预的实验范式，可通过改变杏仁中央核（CeA）中的活动来改善慢性应激诱导的内脏高敏性，在一种啮齿动物模型中。在本研究中，我们研究了 CeA 中微胶质细胞介导的突触可塑性是否是 EE 对应激诱导的内脏高敏性的保护作用的潜在机制。我们立体定向地将皮质酮（CORT）微球植入 CeA 的背缘，如前所述，这会导致结肠高敏性。动物在 CORT 植入后在 EE 笼或标准笼中饲养 14 天。通过对结直肠扩张的内脏运动行为反应评估内脏敏感性。使用免疫荧光和 RNAscope 测定法测量小胶质细胞形态、小胶质细胞介导的突触吞噬作用以及突触修剪相关信号补体成分 1q（C1q）、补体成分 3（C3）和 C3 受体（C3R）的表达。我们发现，将 CORT 植入大鼠饲养在 EE 笼中 14 天可减轻雄性和雌性大鼠的内脏高敏性，与标准饲养的对照大鼠相比。EE 减少了 CORT 诱导的小胶质细胞重塑和小胶质细胞介导的突触修剪，减少了 C1q 和 CR3 的表达，但 C3 表达没有减少。我们的数据表明，暴露于 EE 足以通过减少杏仁核小胶质细胞调节的神经元可塑性来改善应激诱导的内脏疼痛。临床研究表明，认知行为疗法（CBT）可有效改善肠易激综合征（IBS）患者的内脏疼痛，但潜在机制仍未得到探索。通过使用环境富集（EE），一种模拟积极行为干预的实验范式，我们证明了 CeA 中的小胶质细胞介导的突触可塑性解释了、至少部分发挥了 EE 降低内脏高敏性的积极作用。
