Anatomy and Pharmacology of Fear-Potentiated Startle

描述（由申请人提供）：这个项目的总体目标是通过恐惧增强惊吓测试来了解与条件性恐惧有关的神经系统。过去十年的研究进展主要集中在杏仁核及其直接投射到声惊吓通路的关键部分上。在这个应用中，我们将评估中脑网状结构在恐惧增强惊吓中的作用，中脑网状结构靠近上丘深部白色层的边界（深部SC/Me）。我们还将测试恐惧增强的惊吓是否源于CeA侧分裂（侧CeA）中含有GABA的神经元的激活，然后抑制内侧CeA中含有GABA的投射神经元，从而解除对深部SC/Me的抑制，导致惊吓增加。在先前的资助期间，我们发现CREB （cAMP反应元件结合蛋白）的过度表达显著增加了恐惧条件反射。在这里，我们建议更准确地定位在基底外侧杏仁核（Bla）内，CREB的过表达将促进使用病毒载体基因转移的恐惧调节。我们还发现，实验消失（在恐惧条件反射后没有电击的情况下呈现灯光）导致gephyrin mRNA的上调，这对抑制性神经递质甘氨酸和GABA至关重要。在这里，我们将确定阻断（Bla中的局部AP5或Map激酶抑制剂）或促进（系统或直接给予Bla的d -环丝氨酸）的治疗是否会改变gephyrin mRNA的上调。我们还发现恐惧条件反射诱导了杏仁核内部和传入的几个基因。在这里，我们将确定阻断（Bla中的局部AP5或Map激酶抑制剂）或促进获得（HSV-CREB）恐惧增强惊吓的治疗是否会阻断或促进杏仁核和其他区域的基因表达。最后，我们将采用我们开发的鉴别程序来确定GABA拮抗剂或海马、间隔核、床纹状核或额叶皮质的失活是否会影响鉴别、抑制和泛化。这项工作与人类焦虑症有关，并有望阐明恐惧和焦虑形成和消除的关键事件。

DESCRIPTION (provided by applicant): 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 up regulation of gephyrin mRNA, critical for the inhibitory neurotransmitters glycine and GABA. Here we will determine whether treatments that block (local AP5 or Map kinase inhibitors in Bla) or facilitate (D-cycloserine 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 AP5 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.