Bast Tobias, Zhang Wei-Ning, Feldon Joram
Behavioral Neurobiology Laboratory, Swiss Federal Institute of Technology Zurich, Schwerzenbach, Switzerland.
Hippocampus. 2003;13(6):657-75. doi: 10.1002/hipo.10115.
Consistent with the importance of the hippocampus in learning more complex stimulus relations, but not in simple associative learning, the dorsal hippocampus has commonly been implicated in classical fear conditioning to context, but not to discrete stimuli, such as a tone. In particular, a specific and central role in contextual fear conditioning has been attributed to mechanisms mediated by dorsal hippocampal N-methyl-D-aspartate (NMDA)-type glutamate receptors. The present study characterized the effects of blockade or tonic stimulation of dorsal hippocampal NMDA receptors by bilateral local infusion of the noncompetitive NMDA receptor antagonist MK-801 (dizocilpine maleate; 6.25 microg/side) or of NMDA (0.7 microg/side), respectively, on classical fear conditioning to tone and context in Wistar rats. Freezing was used to measure conditioned fear. Regardless of whether conditioning was conducted with tone-shock pairings or unsignaled footshocks (background or foreground contextual conditioning), both NMDA and MK-801 infusion before conditioning resulted in reduced freezing during subsequent exposure to the conditioning context. Freezing during subsequent tone presentation in a new context, normally resulting from conditioning with tone-shock pairings, was not impaired by MK-801 but was strongly reduced by NMDA infusion before conditioning; this freezing was also reduced by NMDA infusion before tone presentation (in an experiment involving NMDA infusions before conditioning and subsequent tone presentation to assess the role of state-dependent learning). It was assessed whether unspecific infusion effects (altered sensorimotor functions, state dependency) or infusion-induced dorsal hippocampal damage contributed to the observed reductions in conditioned freezing. Our data suggest that formation of fear conditioning to context, but not tone, requires NMDA receptor-mediated mechanisms in the dorsal hippocampus. As indicated by the effects of NMDA, some dorsal hippocampal processes may also contribute to fear conditioning to tone. The role of the dorsal hippocampus and local NMDA receptor-mediated processes in fear conditioning to tone and context is discussed in comparison with ventral hippocampal processes.
与海马体在学习更复杂刺激关系而非简单联想学习中的重要性相一致,背侧海马体通常与对情境的经典恐惧条件反射有关,而与对离散刺激(如音调)的恐惧条件反射无关。特别是,背侧海马体N-甲基-D-天冬氨酸(NMDA)型谷氨酸受体介导的机制在情境恐惧条件反射中具有特定的核心作用。本研究通过分别双侧局部注射非竞争性NMDA受体拮抗剂MK-801(马来酸氯氮平;6.25微克/侧)或NMDA(0.7微克/侧)来阻断或强直刺激背侧海马体NMDA受体,研究其对Wistar大鼠对音调及情境的经典恐惧条件反射的影响。采用僵立来测量条件性恐惧。无论条件反射是通过音调-电击配对还是无信号电击(背景或前景情境条件反射)进行,在条件反射前注射NMDA和MK-801均会导致随后暴露于条件反射情境时僵立减少。在新情境中随后呈现音调时的僵立,通常由音调-电击配对条件反射引起,不受MK-801影响,但在条件反射前注射NMDA会使其显著减少;在音调呈现前注射NMDA(在一项涉及条件反射前注射NMDA及随后音调呈现以评估状态依赖性学习作用的实验中)也会减少这种僵立。评估了非特异性注射效应(改变感觉运动功能、状态依赖性)或注射引起的背侧海马体损伤是否导致了观察到的条件性僵立减少。我们的数据表明,对情境而非音调的恐惧条件反射的形成需要背侧海马体中NMDA受体介导的机制。如NMDA的作用所示,一些背侧海马体过程可能也有助于对音调的恐惧条件反射。将背侧海马体及局部NMDA受体介导的过程在对音调和情境的恐惧条件反射中的作用与腹侧海马体过程进行了比较讨论。
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