Anatomy and Pharmacology of Fear-Potentiated Startle

这是对1990年最后一次竞争性审查的10年MERIT奖的竞争性更新。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，我收到了一份- 一年的延长，这就是为什么这个应用程序是在这个时候提交。的总目标 这个项目是了解神经系统参与条件性恐惧使用恐惧增强惊吓 测试作为衡量标准。在过去的10年里，研究的重点是杏仁核及其对大脑的直接投射。 声音惊吓路径的关键部分在本应用程序中，我们将评估 中脑网状结构，靠近上级丘的深白色层的边界（深 SC/Me），在恐惧增强惊吓中。我们还将测试恐惧增强惊吓是否是激活的结果 在CeA的外侧分裂（外侧CeA）中含有GABA的神经元，然后抑制GABA 含有投射神经元在内侧CeA，从而解除抑制深SC/Me，导致 增加惊吓。在之前的研究期间，我们发现CREB的过度表达（cAMP反应） 元素结合蛋白）显著增加恐惧条件反射。在这里，我们建议更准确地定位 在基底外侧杏仁核（Bla）中，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，实验消光（在没有光的情况下， 恐惧条件反射后的休克）导致桥蛋白mRNA的上调，这对抑制 神经递质甘氨酸和GABA。在这里，我们将确定是否治疗阻断（局部APS或 在Bla中的MAP激酶抑制剂）或促进（全身给予或直接给予Bla的D-环丝氨酸）将改变 桥蛋白mRNA表达上调。我们还发现恐惧条件反射诱导了几个基因， 杏仁核在这里，我们将确定是否治疗阻断（局部APS或MAP激酶抑制剂， Bla）或促进获得（HSV-CREB）的恐惧增强惊吓将阻断或促进基因表达， 杏仁核和其他区域。最后，我们将采用我们开发的歧视程序来确定或 GABA拮抗剂或海马、隔核、终纹床核或额叶 皮层将影响辨别、抑制和概括。这项工作与人类的焦虑有关 障碍和承诺，以阐明关键事件的形成和消除恐惧和焦虑。

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.