Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR 5292, University Lyon 1, Lyon 69366, France.
Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, 91190 Gif-sur-Yvette, France.
Neurobiol Learn Mem. 2021 Jul;182:107446. doi: 10.1016/j.nlm.2021.107446. Epub 2021 Apr 27.
Interval timing, the ability to encode and retrieve the memory of intervals from seconds to minutes, guides fundamental animal behaviors across the phylogenetic tree. In Pavlovian fear conditioning, an initially neutral stimulus (conditioned stimulus, CS) predicts the arrival of an aversive unconditioned stimulus (US, generally a mild foot-shock) at a fixed time interval. Although some studies showed that temporal relations between CS and US events are learned from the outset of conditioning, the question of the memory of time and its underlying neural network in fear conditioning is still poorly understood. The aim of the present study was to investigate the role of the dorsal striatum in timing intervals in odor fear conditioning in male rats. To assess the animal's interval timing ability in this paradigm, we used the respiratory frequency. This enabled us to detect the emergence of temporal patterns related to the odor-shock time interval from the early stage of learning, confirming that rats are able to encode the odor-shock time interval after few training trials. We carried out reversible inactivation of the dorsal striatum before the acquisition session and before a shift in the learned time interval, and measured the effects of this treatment on the temporal pattern of the respiratory rate. In addition, using intracerebral microdialysis, we monitored extracellular dopamine level in the dorsal striatum throughout odor-shock conditioning and in response to a shift of the odor-shock time interval. Contrary to our initial predictions based on the existing literature on interval timing, we found evidence suggesting that transient inactivation of the dorsal striatum may favor a more precocious buildup of the respiratory frequency's temporal pattern during the odor-shock interval in a manner that reflected the duration of the interval. Our data further suggest that the conditioning and the learning of a novel time interval were associated with a decrease in dopamine level in the dorsal striatum, but not in the nucleus accumbens. These findings prompt a reassessment of the role of the striatum and striatal dopamine in interval timing, at least when considering Pavlovian aversive conditioning.
间隔时间计时，即编码和提取从秒到分钟的时间间隔记忆的能力，指导着整个进化树中的基本动物行为。在巴甫洛夫式的恐惧条件作用中，最初的中性刺激（条件刺激，CS）预测厌恶的非条件刺激（US，通常是轻微的足部电击）在固定的时间间隔内到达。尽管一些研究表明，CS 和 US 事件之间的时间关系是从条件作用开始就被学习到的，但恐惧条件作用中时间记忆及其潜在的神经网络问题仍未得到很好的理解。本研究的目的是研究背侧纹状体在雄性大鼠气味恐惧条件作用中的时间间隔计时中的作用。为了评估动物在这个范式中的间隔计时能力，我们使用呼吸频率。这使我们能够从学习的早期阶段检测与气味-电击时间间隔相关的时间模式的出现，从而证实大鼠在经过几次训练试验后能够编码气味-电击时间间隔。我们在获得阶段之前和学习的时间间隔发生变化之前可逆地失活背侧纹状体，并测量该处理对呼吸率时间模式的影响。此外，使用脑室内微透析，我们在气味-电击条件作用过程中和对气味-电击时间间隔的变化作出反应时监测背侧纹状体中的细胞外多巴胺水平。与我们基于关于间隔时间计时的现有文献的最初预测相反，我们有证据表明，背侧纹状体的短暂失活可能有利于在气味-电击间隔期间更早期地建立呼吸频率的时间模式，方式反映了间隔的持续时间。我们的数据进一步表明，条件作用和新时间间隔的学习与背侧纹状体中多巴胺水平的降低有关，但与伏隔核无关。这些发现促使我们重新评估纹状体和纹状体多巴胺在间隔时间计时中的作用，至少在考虑到巴甫洛夫式的厌恶条件作用时是如此。
