Center for the Study of Emotion and Attention

描述（由申请人提供）：我们在恐惧增强惊吓试验中发现，双侧杏仁核内侧核（Me）局部输注吗啡完全阻断条件性恐惧的表达，而中枢核（Ce）、基底外侧核（Bla）或尾壳核输注相当剂量的吗啡则没有效果。吗啡注入到Me的影响被完全逆转的共同注入纳洛酮到Me。此外，局部注入纳洛酮到Me完全阻止吗啡，全身给予，从阻断恐惧增强惊吓。局部输注μ或δ选择性阿片受体激动剂具有与吗啡相似的作用。目前还不清楚为什么将吗啡局部注入Me可以如此有效地阻断恐惧增强的惊吓，因为我们还没有发现Me的损伤可以阻断恐惧增强的惊吓。虽然已经报道了Me投射到Ce，但我们认为这种明显的投射可能是由于示踪剂扩散到Ce中，因为我们没有发现使用敏感的顺行示踪剂生物素化葡聚糖离散输注到Me中的从Me到Ce的投射。相反，Me大量投射到终纹的前内侧床核（BNSTam），即后中间BNSTpi），下丘脑腹内侧（VMH）。因为BNST对Ce的投射很重，事实上最重的是Ce从Me到BNST再到Ce的投射的输出部分，很可能参与了由吗啡与Me受体结合激活的抑制回路。或者，其他脑区也可能参与了这种假定的恐惧抑制回路。为了评估这一点，我们将吗啡注入Me，然后使用Fos蛋白作为神经元激活的标志物的免疫细胞化学分析大脑。局部注入吗啡到ME导致Fos的增加在ME，腹侧隔核和邻近地区的BNST，之间的边界上的Ce和Bla的闰细胞团，和腹侧下托。因为这些区域中的一些与恐惧的抑制有关，我们相信我们可能已经进入了一个与恐惧抑制有关的神经元网络。因此，我们将确定BNST，腹侧下托，外侧隔，下丘脑腹内侧和闰细胞的作用，在局部给予吗啡的抗焦虑作用到我，以及抗焦虑作用的吗啡，丁螺环酮和地西泮给予全身。我们还将评估Me中的阿片受体、Bla中的神经肽Y（NPY）细胞和Bla中的GABA以及上述各种脑区在恐惧增强惊吓的消退和条件抑制中的作用。最后，我们将在麻醉大鼠中使用11 T磁体中的fMRI和血压测量来进行气味介导的恐惧保持、消退和条件抑制的脑成像

DESCRIPTION (provided by applicant): We have found in the fear potentiated startle test that bilateral local infusion of morphine into the medial nucleus of the amygdala (Me) completely blocks the expression of conditioned fear whereas infusion of comparable doses into the central (Ce), basolateral (Bla) or caudate-putamen had no effect. The effects of morphine infused into the Me were completely reversed by co-infusion of naloxone into the Me. Moreover, local infusion of naloxone into the Me completely prevented morphine, given systemically, from blocking fear potentiated startle. Local infusion of mu or delta selective opiate agonists had similar effects to morphine. At the present time it is not clear why local infusion of morphine into the Me so effectively blocks fear potentiated startle because we have not found that lesions of the Me block fear potentiated startle. Although the Me has been reported to project to the Ce we believe this apparent projection probably resulted from spread of the tracer into the Ce, because we have not found projections from the Me to the Ce using discrete infusion of the sensitive anterograde tracer biotinylated dextran into the Me. Instead, the Me projects heavily to anteriomedial bed nucleus of the stria terminalis (BNSTam) the posterior intermediate BNSTpi), and the ventromedial hypothalamus (VMH). Because the BNST projects heavily to the Ce, in fact most heavily to the output division of the Ce projections from the Me to the BNST and then to the Ce could well be involved in an inhibitory circuit activated by morphine binding to receptors in the Me. Alternatively, other brain areas might also participate in this putative fearinhibition circuit. To evaluate this, we infused morphine into the Me and then analyzed the brain using immunocytochemistry for Fos protein as a marker of neuronal activation. Local infusion of morphine into the ME led to increases in Fos in the Me, ventral lateral septal nucleus and adjacent areas of the BNST, the intercalated cell mass on the border between the Ce and Bla, and the ventral subiculum. Because some of these areas have been implicated in the inhibition of fear we believe we may have tapped into a neuronal network involved in the inhibition of fear. Hence, we will determine the role of the BNST, ventral subiculum, lateral septum, ventromedial hypothalamus and intercalated cells in the anxiolytic effects of morphine given locally into the Me, as well as the anxiolytic effects of morphine, buspirone and diazepam given systemically. We wll also evaluate the role of opiate receptors in the Me, neuropeptide Y (NPY) cells in the Bla and GABA in the Bla, as well as various brain areas identified above, in extinction and conditioned inhibition of fear potentiated startle. Finally, we will carry out brain imaging of odor-mediated fear retention, extinction, and conditioned inhibition in anesthetized rats usingfMRI in an 11 T magnet measured with blood pressure