Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
Int J Neuropsychopharmacol. 2021 Jul 23;24(7):580-591. doi: 10.1093/ijnp/pyab011.
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.
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.
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.
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.
潜伏抑制（LI）反映了一种适应性学习形式，在某些精神疾病中受到损害。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。
因此，本研究探讨了长时程压抑（LTD）在大鼠先前暴露于听觉刺激后，作为随后信号即将到来的足底电击的条件刺激，诱导 LI 中的可能作用。我们使用了两种机制上不同的 LTD 抑制剂，即 Tat-GluA23Y 肽，它阻断包含 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 2 种条件性回避获得之前，或有或无音调预暴露时给予。
Tat-GluA23Y 肽系统 LTD 阻断通过进一步损害条件刺激预暴露大鼠的条件性回避获得，从而增强了 LI 效应，与正常非预暴露对照组相比。系统给予 Ro25-6981 没有显著影响。Tat-GluA23Y 肽在伏隔核、内侧前额叶皮质、中央或基底外侧杏仁核中的脑区特异性微注射显示，中央杏仁核中谷氨酸 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体内吞作用的破坏也增强了 LI 效应。
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，作为对先前无关刺激的认知灵活性的关键介导物，这些刺激通过强化获得意义。这些发现不仅对我们对 LI 的机制理解具有重要意义，而且对精神分裂症等疾病状态下 LI 的改变也具有重要意义，同时进一步阐明了 LTD 在学习和记忆中的作用。
