Beck C H, Fibiger H C
Department of Psychology, University of Alberta, Edmonton, Canada.
J Neurosci. 1995 Jan;15(1 Pt 2):709-20. doi: 10.1523/JNEUROSCI.15-01-00709.1995.
The synthesis of Fos, the protein product of the immediate early gene c-fos, was used to map metabolically some of the neural substrates of conditioned fear in the rat. Analysis of the behaviors emitted by the rats during the test session provided strong evidence that the conditioning procedure was effective. Exposure to the environment in which they had previously received footshock significantly increased the number of Fos-like immunoreactive neurons in nearly 50 brain regions, both cortical and subcortical. Among the structures showing the most dramatic increases in fear-induced c-fos expression were the cingulate, piriform, infralimbic, and retrosplenial cortices, the anterior olfactory nucleus, claustrum, endopiriform nucleus, nucleus accumbens shell, lateral septal nucleus, various amygdalar nuclei, paraventricular thalamic nucleus, ventral lateral geniculate nucleus, the ventromedial, lateral, and dorsal hypothalamic nuclei, the ventral tegmental area, and the supramammillary area. These data demonstrate that a relatively simple classical conditioning procedure activates a large number of widely dispersed cortical and subcortical structures. Some of the structures showing increased c-fos expression have important autonomic functions and may therefore have reflected centrally mediated changes in blood pressure and respiration produced by the anxiogenic stimuli. In a second experiment, the effects of pretreatment with the anxiolytic drug diazepam (2.5, 5.0, or 10 mg/kg) were evaluated. The benzodiazepine produced dose-related decreases in the frequency of crouching (freezing) elicited by the aversively conditioned contextual cues. Diazepam also produced dose-related decreases in conditioned stress-induced c-fos expression in all but one structure, the effects being statistically significant in 38 of 60 sampled structures. Diazepam dose dependently increased fear-induced c-fos expression in the central nucleus of the amygdala. There was considerable regional variability with respect to sensitivity to diazepam, the retrosplenial cortex and the supramammillary area being the only two structures to show decreases after the lowest dose of diazepam. In contrast, the entorhinal cortex, nucleus accumbens core, ventromedial and posterior hypothalamic nuclei, median raphe, and locus coeruleus were particularly resistant to diazepam, all failing to show statistically significant decreases in conditioned fear-induced c-fos expression even at the highest dose. The extent to which diazepam decreased conditioned stress-induced c-fos expression was unrelated to previous estimates of benzodiazepine receptor density in the sampled structures.
即刻早期基因c-fos的蛋白质产物Fos的合成，被用于在大鼠中对条件性恐惧的一些神经基质进行代谢图谱绘制。对测试过程中大鼠发出的行为进行分析，提供了有力证据表明条件化程序是有效的。暴露于它们先前接受过足部电击的环境中，显著增加了近50个脑区（包括皮质和皮质下区域）中Fos样免疫反应性神经元的数量。在恐惧诱导的c-fos表达增加最为显著的结构中，有扣带回、梨状皮质、边缘下皮质和压后皮质、前嗅核、屏状核、内梨状核、伏隔核壳、外侧隔核、各种杏仁核、室旁丘脑核、腹外侧膝状核、腹内侧、外侧和背侧下丘脑核、腹侧被盖区和乳头体上区。这些数据表明，一个相对简单的经典条件化程序能激活大量广泛分布的皮质和皮质下结构。一些显示c-fos表达增加的结构具有重要的自主神经功能，因此可能反映了由致焦虑刺激引起的血压和呼吸中枢介导的变化。在第二个实验中，评估了用抗焦虑药物地西泮（2.5、5.0或10mg/kg）预处理的效果。苯二氮䓬类药物使厌恶条件化情境线索引发的蹲伏（僵住）频率呈剂量依赖性降低。地西泮还使除一个结构外的所有结构中条件性应激诱导的c-fos表达呈剂量依赖性降低，在60个采样结构中的38个结构中，这种效应具有统计学意义。地西泮剂量依赖性地增加杏仁核中央核中恐惧诱导的c-fos表达。关于对地西泮的敏感性存在相当大的区域差异，压后皮质和乳头体上区是仅有的两个在最低剂量地西泮后显示降低的结构。相比之下，内嗅皮质、伏隔核核心、腹内侧和下丘脑后核、中缝正中核和蓝斑对 地西泮特别耐药，即使在最高剂量下，所有这些结构在条件性恐惧诱导的c-fos表达中也未显示出统计学显著降低。地西泮降低条件性应激诱导的c-fos表达的程度与先前对采样结构中苯二氮䓬受体密度的估计无关。
