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。灭绝，恐惧条件反射的逐渐逆转，同样是行为疗法的明确模型，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。尽管它的重要性，分子和细胞基板的灭绝仍然在很大程度上未被研究。这项资助的目标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共享许多机制。然而，与其他学习形式的差异将特别有意义，因为它们可能暗示灭绝的特定机制。我的初步研究发现了两个这样的差异。首先，大规模训练在产生灭绝方面比时间分布训练更有效。我们的数据表明，灭绝的结果，从两个相反的行为过程，一个敏感的提醒效果，和较长时间暴露于条件刺激的削弱效果。我们还发现，条件性恐惧的消退，而不是获得或表达，取决于L型电压门控钙通道（LVGCC）。我现在提出：1）优化小鼠实验方案，以最大限度地隔离未强化条件刺激后恐惧条件反射的减弱（消退）或敏化; 2）使用全身和脑内药物给药来剖析这两个过程; 3）探索在杏仁核中产生LVGCC依赖性突触变化的方案; 4）使用药物将LVGCC-LTP与行为消退联系起来。特别是，该项目将探索已经涉及一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。我的目标是在基础神经科学研究的学术生涯，具有快速转化应用于精神病治疗的潜力。我计划追求这个目标，专注于研究恐惧条件反射的消退作为精神病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.