Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China; National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, 100191 Beijing, China.
Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No. 2018RU006), Peking University, Beijing 100191, China.
Behav Brain Res. 2023 Feb 15;439:114230. doi: 10.1016/j.bbr.2022.114230. Epub 2022 Nov 25.
Large amount of zinc (100 µM even up to 300 µM) is released from the nerve terminals in response to high frequency neuronal stimulation in certain brain regions including hippocampus and amygdala. However, its precise pharmacological effect is poorly understood. Here, we investigated the role of extracellular zinc (endogenous zinc) and exogenous zinc in memory formation using contextual fear conditioning (CFC) model. Male Sprague Dawley rats were trained for fear conditioning followed by in vivo microdialysis for collection of microdialysate samples from CA1 and CA3 regions of hippocampus and basolateral amygdala (BLA). Extracellular zinc chelator CaEDTA, BDNF scavenger TrkB-Fc, exogenous 7,8-DHF and matrix metalloproteinases (MMP) inhibitor were infused into the CA1 and CA3 regions of hippocampus and BLA after CFC. Different doses of exogenous zinc hydroaspartate were administered intraperitoneally immediately after CFC. We found that CFC increased the level of extracellular zinc in the hippocampus and BLA. Infusing the CaEDTA, TrkB-Fc and MMP inhibitor into the CA1 and CA3 regions of hippocampus and BLA disrupted the fear memory formation. Furthermore, administration of TrKB agonist 7,8-DHF reversed the inhibitory effect of CaEDTA on fear memory formation, suggesting that extracellular zinc may regulate fear memory formation via the BDNF-TrKB pathway. We also found that high dose of exogenous zinc hydroaspartate supplementation increased extracellular zinc levels in brain and enhanced fear memory formation. Altogether, these findings indicate that extracellular zinc may participate in formation of contextual fear memory through MMP-BDNF-TrkB pathway in the hippocampus and BLA.
大量的锌（即使是 100μM 甚至 300μM）会从神经末梢释放出来，以响应包括海马体和杏仁核在内的某些大脑区域的高频神经元刺激。然而，其确切的药理作用仍知之甚少。在这里，我们使用情境恐惧条件反射（CFC）模型研究了细胞外锌（内源性锌）和外源性锌在记忆形成中的作用。雄性 Sprague Dawley 大鼠接受恐惧条件反射训练，然后进行体内微透析，从海马体 CA1 和 CA3 区以及杏仁核基底外侧区（BLA）采集微透析样本。在 CFC 后，将细胞外锌螯合剂 CaEDTA、BDNF 清除剂 TrkB-Fc、外源性 7,8-DHF 和基质金属蛋白酶（MMP）抑制剂注入海马体 CA1 和 CA3 区以及 BLA。在 CFC 后立即给予不同剂量的外源性锌氢氧化物腹腔内注射。我们发现 CFC 增加了海马体和 BLA 中细胞外锌的水平。将 CaEDTA、TrkB-Fc 和 MMP 抑制剂注入海马体 CA1 和 CA3 区以及 BLA 会破坏恐惧记忆的形成。此外，给予 TrKB 激动剂 7,8-DHF 可逆转 CaEDTA 对恐惧记忆形成的抑制作用，表明细胞外锌可能通过 BDNF-TrKB 途径调节恐惧记忆的形成。我们还发现，外源性锌氢氧化物的高剂量补充会增加大脑中的细胞外锌水平并增强恐惧记忆的形成。总之，这些发现表明细胞外锌可能通过海马体和 BLA 中的 MMP-BDNF-TrKB 途径参与情境恐惧记忆的形成。
