Kubota Osamu, Hattori Kotaro, Hashimoto Kenji, Yagi Takeshi, Sato Toshio, Iyo Masaomi, Yuasa Shigeki
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Brain Res Mol Brain Res. 2004 Nov 4;130(1-2):149-60. doi: 10.1016/j.molbrainres.2004.07.018.
Fyn-tyrosine-kinase-deficient mice exhibit increased fearfulness. To elucidate the neural mechanisms of their emotional defects, we compared fyn(-/-) and fyn(+/-) mice by behavioral analysis of conditioned fear and by functional neuroanatomical analysis of the distribution of highly responsive neurons associated with conditioned fear. The mice were exposed to the auditory conditioned stimulus paired with electric shock as the unconditioned stimulus. After the fear conditioning, auditory stimulus-induced freezing behavior was enhanced in fyn(-/-) mice. When the occurrence of c-Fos-immunoreactive neurons in the brain of fear-conditioned mice was examined following exposure to the auditory stimulus, a significant increase in immunoreactive neurons was found in the amygdala, hypothalamus, and midbrain of both genotypes. The occurrence of conditioned-fear-dependent c-Fos-immunoreactive neurons was enhanced in the central, medial, cortical, and basomedial amygdaloid subdivisions, the hypothalamic nuclei, and the midbrain periaqueductal gray of the fyn(-/-) mice in comparison with the fyn(+/-) mice. However, remarkably, the occurrence of conditioned-fear-dependent c-Fos-immunoreactive neurons was very low in the basolateral and lateral amygdaloid subdivisions of the fyn(-/-) mice, in striking contrast to a significant increase in c-Fos-immunoreactive neurons in these subdivisions in the fyn(+/-) mice. These findings suggest that the increased excitability of the specific amygdaloid subdivisions including the central nucleus, and of the projection targets such as the hypothalamus and midbrain in fyn(-/-) mice, is directly related to the enhanced fear response, and that the decreased excitability in the basolateral and lateral amygdaloid subdivisions is involved in the defective control of the neural circuit for emotional expression in this mutant.
Fyn酪氨酸激酶缺陷型小鼠表现出更高的恐惧性。为了阐明其情绪缺陷的神经机制，我们通过条件性恐惧的行为分析以及对与条件性恐惧相关的高反应性神经元分布进行功能性神经解剖分析，对fyn(-/-)和fyn(+/-)小鼠进行了比较。将小鼠暴露于与电击（作为非条件刺激）配对的听觉条件刺激下。恐惧条件训练后，fyn(-/-)小鼠中听觉刺激诱发的僵住行为增强。在暴露于听觉刺激后，检查恐惧条件训练小鼠大脑中c-Fos免疫反应性神经元的出现情况，发现两种基因型小鼠的杏仁核、下丘脑和中脑中免疫反应性神经元均显著增加。与fyn(+/-)小鼠相比，fyn(-/-)小鼠的中央、内侧、皮质和基底内侧杏仁核亚区、下丘脑核以及中脑导水管周围灰质中，依赖条件性恐惧的c-Fos免疫反应性神经元的出现增加。然而，值得注意的是，fyn(-/-)小鼠的基底外侧和外侧杏仁核亚区中依赖条件性恐惧的c-Fos免疫反应性神经元的出现非常低，这与fyn(+/-)小鼠这些亚区中c-Fos免疫反应性神经元的显著增加形成鲜明对比。这些发现表明，fyn(-/-)小鼠中包括中央核在内的特定杏仁核亚区以及如下丘脑和中脑等投射靶点的兴奋性增加，与恐惧反应增强直接相关，并且基底外侧和外侧杏仁核亚区的兴奋性降低与该突变体中情绪表达神经回路的控制缺陷有关。
