Anatomy and Pharmacology of Fear-Potentiated Startle

这是对1990年最后一次竞争性审查的10年期优异奖的竞争性续展。因为 在我最近搬到埃默里大学后，由于拨款转移和实验室建设的延误，我收到了一封- 延长一年，这就解释了为什么这个申请是在这个时候提交的。的总体目标 这个项目是用恐惧强化惊吓来理解参与条件性恐惧的神经系统。 作为一种措施进行测试。过去10年的进展主要集中在杏仁核及其直接投射到 声学惊吓通路的关键部分。在本应用程序中，我们将评估 中脑网状结构，靠近上丘深白色层的边缘(深 SC/我)，在恐惧中加强了惊吓。我们还将测试恐惧是否增强了激活后的惊吓结果 在CEA(外侧CEA)的侧部含有GABA的神经元，然后抑制GABA 在内侧CEA含有投射神经元，从而抑制深SC/Me，导致 增加了惊吓。在之前的资助期间，我们发现CREB(cAMP反应)的过度表达 元素结合蛋白)显著增加了恐惧的条件反射。在这里，我们建议更准确地本地化 在杏仁基底外侧核(Bla)，CREB的过度表达将促进恐惧条件反射 病毒载体基因转移。我们还发现实验性消光(在不存在的情况下呈现灯光 恐惧条件反射后的休克)导致对抑制作用至关重要的gen基因的表达上调。 神经递质甘氨酸和GABA。在这里，我们将确定阻止(局部APS或 BLA中的MAP激酶抑制剂)或易化(系统地或直接给入BLA的D-环丝氨酸)将改变 Gen基因表达上调。我们还发现，恐惧条件反射诱导了几个基因的内部和传入 杏仁核。在这里，我们将确定阻断(局部APS或MAPK抑制剂)的治疗是否 BLA)或促进获得(HSV-CREB)恐惧增强的惊吓将阻断或促进基因表达 杏仁核等区域。最后，我们将使用我们开发的歧视程序来确定或 GABA拮抗剂或使海马、隔核、终纹床核或额叶失活 大脑皮质会影响辨别、抑制和概括。这项工作与人类的焦虑有关 疾病和承诺阐明在形成和消除恐惧和焦虑的关键事件。

This is a competing renewal for a 10-year MERIT Award competitively reviewed last in 1990. Because of delays in grant transfer and lab construction after my recent move to Emory University, I received a one- year extension,which accounts for why this application is being submitting at this time. The overall goals of this project are to understand neural systems involved in conditioned fear using the fear potentiated startle test as a measure. Progress over the last 10 years has focused on the amygdala and its direct projection to a critical part of the acoustic startle pathway. In this application we will evaluate the role of the mesencephalic reticular formation, near the border of the deep white layers of the superior colliculus (deep SC/Me), in fear potentiated startle. We will also test whether fear potentiated startle results from activation of GABA containing neurons in the lateral division of the CeA (lateral CeA), which then inhibit GABA containing projection neurons in the medial CeA, thereby disinhibiting the deep SC/Me, leading to an increase in startle. During the prior grant period we found that over-expression of CREB (cAMP response element binding protein) dramatically increased fear conditioning. Here we propose to localize more exactly within the basolateral amygdala (Bla) where over-expression of CREB will facilitate fear conditioning using viral vector gene transfer. We also found that experimental extinction (presentation of lights in the absence of shock following fear conditioning) led to an upregulation of gephyrin mRNA, critical for the inhibitory neurotransmitters glycine and GABA. Here we will determine whether treatments that block (local APS or Map kinase inhibitors in Bla) or facilitate (D-cyclpserine given systemically or directly into Bla) will alter gephyrin mRNA upregulation. We also found fear conditioning induced several genes within and afferent to the amygdala. Here we will determine whether treatments that block (local APS or Map kinase inhibitors in Bla) or facilitate acquisition (HSV-CREB) of fear potentiated startle will block or facilitate gene expression in amygdala and other areas. Finally, we will employ a discrimination procedure we developed to determine or GABA antagonists or inactivation of the hippocampus, septal nucleus, bed nucleus stria terminalis or frontal cortex will affect discrimination, inhibition and generalization. The work is relevant to human anxiety disorders and promises to elucidate critical events in the formation and elimination of fear and anxiety.