Rodent models of anxiety disorder treatment

描述(由申请人提供)：巴甫洛夫恐惧条件反射是人类焦虑症和学习的重要模型。消除，即恐惧条件反射的逐渐逆转，同样是行为疗法的明确模式，行为疗法是精神病学中最有效的治疗方法之一。消除恐惧也是主动抑制性学习的一个重要范例，它似乎依赖于杏仁核中的NMDA受体。尽管它很重要，但导致物种灭绝的分子和细胞底物在很大程度上仍未得到研究。这笔赠款的目的是探索恐惧条件反射消退的分子和生理基础。我推测，灭绝可能与其他形式的长期学习和依赖NMDA受体的突触可塑性有许多共同的机制。然而，与其他形式的学习的不同将特别具有信息量，因为它们可能表明特定的灭绝机制。我的初步研究发现了两个这样的差异。首先，集中训练比临时分布训练更有效地产生灭绝。我们的数据表明，消亡是由两种相反的行为过程造成的，一种是提醒的敏化效应，另一种是长期暴露在条件刺激下的减弱效应。我们还发现，条件性恐惧的消退，而不是获得或表达，依赖于L型电压门控钙通道(LVGCC)。我现在建议1)优化小鼠的实验方案，最大限度地分离无强化条件刺激后恐惧条件反射的减弱(消退)或敏化；2)使用全身和脑内给药来剖析这两个过程；3)探索在杏仁核产生依赖于LVGCC的突触变化的方案；以及4)使用药物将这种LVGCC-LTP与行为消退联系起来。特别是，该项目将探索神经递质和第二信使的作用，这些信使已经与世代灭绝有关，包括肾上腺素能和多巴胺能、胆碱能和GABA能系统以及MAP激酶。我的目标是从事基础神经科学研究的学术生涯，有可能将其迅速转化为精神治疗。我计划追求这一目标，重点研究恐惧条件作用的消退，作为精神治疗的一个重要的同源模型，并发展药理学和生理学技能，以最大限度地提高我对这种现象进行分子和细胞解剖的能力。

DESCRIPTION (provided by applicant): Pavlovian fear conditioning is an important model both of human anxiety disorders and of learning. Extinction, the gradual reversal of fear conditioning, is similarly the explicit model for behavior therapy, one of the most effective treatments in psychiatry. Extinction of fear is also an important paradigm of active inhibitory learning that appears to depend on NMDA receptors in the amygdala. Despite its importance, the molecular and cellular substrates of extinction remain largely unstudied. The goal of this grant is to explore the molecular and physiological bases of the extinction of fear conditioning. I hypothesize that extinction may share many mechanisms with other forms of long-lasting learning and NMDA-receptor dependent synaptic plasticity. However, differences from other forms of learning will be especially informative, since they may suggest mechanisms specific to extinction. My preliminary studies have identified two such differences. First, massed training is more effective in generating extinction than is temporally distributed training. Our data suggest that extinction results from two opposing behavioral processes, a sensitizing effect of reminders, and a weakening effect of longer exposures to the conditional stimulus. We have also found that extinction, but not acquisition or expression, of conditional fear depends on L-type voltage-gated calcium channels (LVGCC). I now propose 1) To optimize protocols in mice to maximally isolate the weakening (extinction) or sensitization of fear conditioning following presentations of unreinforced conditioned stimuli; 2) To dissect these two processes using systemic and intracerebral drug administration; 3) To explore protocols that generate LVGCC-dependent synaptic changes in amygdala; and 4) To use drugs to correlate such LVGCC-LTP with behavioral extinction. In particular, the project will explore the roles of neurotransmitters and second messengers that have already been implicated in the generation extinction, including adrenergic and dopaminergic, cholinergic and GABAergic systems, and MAP kinase. My goal is an academic career in fundamental neuroscience research with potential for rapid translational application to psychiatric treatment. I plan to pursue this goal focusing on the study of extinction of fear conditioning as an important homologous model of psychiatric treatment, and to develop the pharmacological and physiological skills to maximize my ability to perform a molecular and cellular dissection of this phenomenon.