Lkhagvasuren B, Oka T, Nakamura Y, Hayashi H, Sudo N, Nakamura K
Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Neuroscience. 2014 Jul 11;272:34-57. doi: 10.1016/j.neuroscience.2014.04.047. Epub 2014 May 4.
The anxiolytic diazepam selectively inhibits psychological stress-induced autonomic and behavioral responses without causing noticeable suppression of other central performances. This pharmacological property of diazepam led us to the idea that neurons that exhibit diazepam-sensitive, psychological stress-induced activation are potentially those recruited for stress responses. To obtain neuroanatomical clues for the central stress circuitries, we examined the effects of diazepam on psychological stress-induced neuronal activation in broad brain regions. Rats were exposed to a social defeat stress, which caused an abrupt increase in body temperature by up to 2°C. Pretreatment with diazepam (4mg/kg, i.p.) attenuated the stress-induced hyperthermia, confirming an inhibitory physiological effect of diazepam on the autonomic stress response. Subsequently, the distribution of cells expressing Fos, a marker of neuronal activation, was examined in 113 forebrain and midbrain regions of these rats after the stress exposure and diazepam treatment. The stress following vehicle treatment markedly increased Fos-immunoreactive (IR) cells in most regions of the cerebral cortex, limbic system, thalamus, hypothalamus and midbrain, which included parts of the autonomic, neuroendocrine, emotional and arousal systems. The diazepam treatment significantly reduced the stress-induced Fos expression in many brain regions including the prefrontal, sensory and motor cortices, septum, medial amygdaloid nucleus, medial and lateral preoptic areas, parvicellular paraventricular hypothalamic nucleus, dorsomedial hypothalamus, perifornical nucleus, tuberomammillary nucleus, association, midline and intralaminar thalami, and median and dorsal raphe nuclei. In contrast, diazepam increased Fos-IR cells in the central amygdaloid nucleus, medial habenular nucleus, ventromedial hypothalamic nucleus and magnocellular lateral hypothalamus. These results provide important information for elucidating the neural circuitries that mediate the autonomic and behavioral responses to psychosocial stressors.
抗焦虑药物地西泮能选择性抑制心理应激诱导的自主神经和行为反应，而不会对其他中枢功能造成明显抑制。地西泮的这一药理学特性使我们想到，那些表现出对地西泮敏感、心理应激诱导激活的神经元可能就是参与应激反应的神经元。为了获取中枢应激回路的神经解剖学线索，我们研究了地西泮对广泛脑区中心理应激诱导的神经元激活的影响。将大鼠暴露于社会挫败应激中，这会导致体温突然升高多达2°C。地西泮（4mg/kg，腹腔注射）预处理可减轻应激诱导的体温过高，证实了地西泮对自主神经应激反应具有抑制性生理作用。随后，在应激暴露和地西泮处理后，检查了这些大鼠113个前脑和中脑区域中表达Fos（一种神经元激活标记物）的细胞分布。给予赋形剂处理后的应激显著增加了大脑皮质、边缘系统、丘脑、下丘脑和中脑大多数区域中Fos免疫反应性（IR）细胞，这些区域包括自主神经、神经内分泌、情绪和觉醒系统的部分区域。地西泮处理显著降低了许多脑区应激诱导的Fos表达，这些脑区包括前额叶、感觉和运动皮质、隔区、杏仁内侧核、视前内侧和外侧区、下丘脑室旁核小细胞部、下丘脑背内侧核、穹窿周核、乳头体核、丘脑联合核、中线核和板内核，以及中缝正中核和背核。相反，地西泮增加了杏仁中央核、缰内侧核、下丘脑腹内侧核和下丘脑外侧大细胞部中Fos-IR细胞。这些结果为阐明介导对心理社会应激源的自主神经和行为反应的神经回路提供了重要信息。
