Background Latent inhibition (LI) reflects an adaptive form of learning impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified. Methods Accordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus to signal a pending footshock. We employed 2 mechanistically distinct LTD inhibitors, the Tat-GluA23Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, or the selective glutamate n-methyl-d-aspartate receptor 2B antagonist, Ro25-6981, administered prior to the acquisition of 2-way conditioned avoidance with or without tone pre-exposure. Results Systemic LTD blockade with the Tat-GluA23Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in conditional stimulus-preexposed rats compared with normal conditioning in non-preexposed controls. Systemic Ro25-6981 had no significant effects. Brain region–specific microinjections of the Tat-GluA23Y peptide into the nucleus accumbens, medial prefrontal cortex, or central or basolateral amygdala demonstrated that disruption of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis in the central amygdala also potentiated the LI effect. Conclusions These data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory.

中文翻译：

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长期抑郁的破坏会增强潜在的抑制：杏仁核中央核的关键作用


背景 潜在抑制（LI）反映了某些形式的精神疾病中学习障碍的适应性形式。谷氨酸受体活性与 LI 有关，但突触可塑性的潜在作用仍未明确。方法 因此，本研究探讨了长期抑郁 (LTD) 在 LI 中的可能作用，该 LI 是由大鼠事先暴露于听觉刺激，随后用作条件刺激，发出即将发生的足部电击信号。我们采用了 2 种机制不同的 LTD 抑制剂，即 Tat-GluA23Y 肽，可阻断含 GluA2 的谷氨酸 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体的内吞作用，或选择性谷氨酸 n-甲基-d-天冬氨酸受体 2B 拮抗剂 Ro25-6981，在有或没有音调预暴露的情况下获得双向条件性回避之前施用。结果 与非预暴露对照组的正常条件反射相比，Tat-GluA23Y 肽的全身性 LTD 阻断通过进一步损害条件刺激预暴露大鼠的条件回避获得来增强 LI 效应。全身性Ro25-6981没有显着影响。将 Tat-GluA23Y 肽脑区域特异性显微注射到伏隔核、内侧前额叶皮质或中央或基底外侧杏仁核中，表明谷氨酸 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体内吞作用受到破坏。中央杏仁核也增强了 LI 效应。结论 这些数据揭示了中央杏仁核 LTD 在 LI 中的一个以前未知的作用，它是认知灵活性的关键调节因素，需要对以前不相关的刺激做出反应，而这些刺激通过强化而变得有意义。 这些发现可能与我们对 LI 及其在精神分裂症等疾病状态中的改变的机制理解相关，同时进一步阐明 LTD 在学习和记忆中的作用。