Girotti M, Pace T W W, Gaylord R I, Rubin B A, Herman J P, Spencer R L
Department of Psychology, Muenzinger Building, Room D244, University of Colorado, UCB 345, Boulder, CO 80309, USA.
Neuroscience. 2006;138(4):1067-81. doi: 10.1016/j.neuroscience.2005.12.002. Epub 2006 Jan 23.
Rats repeatedly exposed to restraint show a reduced hypothalamic-pituitary-adrenal axis response upon restraint re-exposure. This hypothalamic-pituitary-adrenal axis response habituation to restraint does not generalize to other novel stressors and is associated with a decrease in stress-induced c-fos expression in a number of stress-reactive brain regions. We examined whether habituation to repeated restraint is also associated with adaptation of immediate early gene expression in brain regions that process and relay primary sensory information. These brain regions may not be expected to show gene expression adaptation to repeated restraint because of their necessary role in experience discrimination. Rats were divided into a repeated restraint group (five 1-hour daily restraint sessions) and an unstressed group (restraint naïve). On the sixth day rats from each group were either killed with no additional stress experience or at 15, 30 or 60 min during restraint. Immediate early gene expression (corticotrophin-releasing hormone heteronuclear RNA, c-fos mRNA, zif268 mRNA) was determined by in situ hybridization. A reduction in stress-induced hypothalamic-pituitary-adrenal axis hormone secretion (plasma corticosterone and adrenocorticotropic hormone) and immediate early gene expression levels in the paraventricular nucleus of the hypothalamus, the lateral septum and the orbital cortex was observed in repeated restraint as compared with restraint naïve animals. This reduction was already evident at 15 min of restraint. Unexpectedly, we also found in repeated restraint rats a reduction in restraint-induced c-fos expression in primary sensory-processing brain areas (primary somatosensory cortex, and ventroposteriomedial and dorsolateral geniculate nuclei of thalamus). The overall levels of hippocampal mineralocorticoid receptor heteronuclear RNA or glucocorticoid receptor mRNA were not decreased by repeated restraint, as may occur in response to severe chronic stress. We propose that repeated restraint leads to a systems-level adaptation whereby re-exposure to restraint elicits a rapid inhibitory modulation of primary sensory processing (i.e. sensory gating), thereby producing a widespread attenuation of the neural response to restraint.
反复遭受束缚的大鼠在再次暴露于束缚时，下丘脑-垂体-肾上腺轴反应会减弱。这种下丘脑-垂体-肾上腺轴对束缚的反应习惯化不会扩展到其他新的应激源，并且与多个应激反应性脑区中应激诱导的c-fos表达减少有关。我们研究了对反复束缚的习惯化是否也与处理和传递初级感觉信息的脑区中即时早期基因表达的适应性有关。由于这些脑区在经验辨别中具有必要作用，因此预计它们不会表现出对反复束缚的基因表达适应性。将大鼠分为反复束缚组（每天进行5次1小时的束缚实验）和未受应激组（从未经历过束缚）。在第6天，每组大鼠要么在没有额外应激经历的情况下处死，要么在束缚期间的15、30或60分钟时处死。通过原位杂交测定即时早期基因表达（促肾上腺皮质激素释放激素异核RNA、c-fos mRNA、zif268 mRNA）。与未经历过束缚的动物相比，反复束缚的大鼠在应激诱导的下丘脑-垂体-肾上腺轴激素分泌（血浆皮质酮和促肾上腺皮质激素）以及下丘脑室旁核、外侧隔区和眶皮质中的即时早期基因表达水平降低。这种降低在束缚15分钟时就已很明显。出乎意料的是，我们还发现反复束缚的大鼠在初级感觉处理脑区（初级体感皮层、丘脑腹后内侧核和背外侧膝状核）中束缚诱导的c-fos表达减少。反复束缚并未使海马盐皮质激素受体异核RNA或糖皮质激素受体mRNA的总体水平降低，而这在对严重慢性应激的反应中可能会发生。我们提出，反复束缚会导致系统水平的适应性变化，即再次暴露于束缚会引发对初级感觉处理（即感觉门控）的快速抑制性调节，从而广泛减弱对束缚的神经反应。
