Long-term kindling as an animal model to study the neural mechanisms of fear-mediated behaviour

我们研究的一般目的是研究伴随恐惧敏化的行为和神经变化。所有的动物在新奇的或有威胁的情况下都会有可怕的反应。这些反应大多是适应性的，因为它们是为了保护动物免受伤害。然而，恐惧可以被敏感化，从而最终导致不适应的行为反应。因此，动物所经历的恐惧程度可以从我们认为的“正常”到我们认为的“病态”。利用杏仁核点燃的老鼠，我们开发了一种动物模型，使我们能够系统地研究恐惧行为的敏感性。点燃是一个过程，通过每天的脑电刺激导致运动癫痫的逐渐发展和加剧。除了诱发癫痫的作用，点火还会使负责恐惧行为表现的大脑回路变得敏感。被点燃的老鼠表现出恐惧的行为，当老鼠受到更多的刺激时，这种行为的强度会增加。因此，点火为研究恐惧行为的敏化提供了一个极好的机会，并将恐惧行为的变化与大脑中的神经变化联系起来。本申请中提出的研究的具体目标是调查一个被称为海马体的大脑区域在恐惧敏感化中的作用。我们有证据表明，引火引起的恐惧可能是由海马功能障碍引起的。为了验证这一观点，我们将评估点燃对由海马体介导的行为任务的影响。我们还将研究点燃是否会改变海马细胞的形态和电生理特征。最后，我们将确定引燃引起的恐惧是否可以通过环境丰富来减少，以及这些有益的影响是否通过海马体内的神经变化发生。我们的实验结果将提供有关恐惧介导行为的神经基础的基本信息，并将迅速加速我们对治疗以极端恐惧为特征的疾病的新疗法的进展。

The general purpose of our research is to study the behavioral and neural changes concomitant with fear sensitization. All animals respond fearfully in novel or threatening situations. Most of these responses are adaptive in that they serve to protect animals from harm. However, fear can be sensitized so that it eventually results in behavioral responses that are maladaptive. Accordingly, the level of fear experienced by an animal can range from what we would consider "normal" to what we would consider "pathological". Using amygdala-kindled rats, we have developed an animal model that permits us to systematically study the sensitization of fearful behavior. Kindling is a process by which daily administration of electrical brain stimulations results in the gradual development and intensification of motor seizures. In addition to its epileptogenic effects, kindling also sensitizes brain circuits responsible for behavioral manifestations of fear. Kindled rats display fearful behavior that increases in magnitude as the rats receive a greater number of stimulations. Kindling thus provides an excellent opportunity to study the sensitization of fearful behavior, and to correlate changes in fearful behavior with neural changes in the brain.       The specific objective of the research proposed in this application is to investigate the role of a brain region called the hippocampus in the sensitization of fear. We have evidence to suggest that kindling-induced fear might result from hippocampal dysfunction. To test this idea, we will assess the effect of kindling on behavioral tasks that are mediated by the hippocampus. We will also investigate whether kindling alters the morphological and electrophysiological characteristics of cells in the hippocampus. Finally, we will determine whether kindling-induced fear can be reduced by environmental enrichment, and whether these beneficial effects occur via neural changes within the hippocampus. The results of our experiments will provide fundamental information about the neural basis of fear-mediated behavior and should rapidly accelerate our progression toward new therapies for treating disorders characterized by extreme fear.