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障碍和学习的重要模型。消失，恐惧条件反射的逐渐逆转，类似于行为疗法的明确模式，这是精神病学中最有效的治疗方法之一。恐惧的消除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。尽管其重要性，灭绝的分子和细胞底物仍在很大程度上未被研究。这项拨款的目的是探索恐惧条件反射消失的分子和生理基础。我推测，灭绝可能与其他形式的持久学习和nmda受体依赖的突触可塑性有许多共同的机制。然而，与其他学习形式的差异将特别有用，因为它们可能表明灭绝的特定机制。我的初步研究发现了两个不同之处。首先，大规模训练比时间分布训练更有效地产生灭绝。我们的数据表明，消退是由两个相反的行为过程导致的，一个是提醒的敏感效应，另一个是长时间暴露在条件刺激下的弱化效应。我们还发现，条件恐惧的消退，而不是获得或表达，取决于l型电压门控钙通道（LVGCC）。我现在建议1)优化小鼠实验方案，最大限度地隔离未强化条件刺激后恐惧条件反射的减弱（消失）或增敏；2)通过全身给药和脑内给药来剖析这两个过程；3)探讨杏仁核中lvgc依赖性突触变化的机制；4)利用药物将lvgc - ltp与行为消失联系起来。特别是，该项目将探索已经涉及代灭绝的神经递质和第二信使的作用，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，并有可能快速转化应用于精神病学治疗。我计划追求这一目标，专注于研究恐惧消退条件反射作为精神治疗的重要同源模型，并发展药理学和生理学技能，以最大限度地提高我对这一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.