Neural Substrates of Phasic versus Sustained Fear

描述（由申请人提供）：巴甫洛夫恐惧条件反射已被广泛用于在实验室动物中重现焦虑样状态并探索其神经基质。主要基于这些类型的研究结果，神经回路模型已经开发并广泛采用。大多数情况下，这些范例涉及配对简短的刺激，如灯光或音调与脚电击。然而，在过去的几年里，我积累了证据表明，当老鼠接受训练和测试时，使用更长时间的刺激（即，分钟，而不是秒），目前的模式是不够的。在这些数据的基础上，我提出了一个扩展的模型，重点关注床核的终纹（BNST）和应激相关肽促肾上腺皮质激素释放因子（CRF）。非常简单地说，该模型假设，从杏仁核到BNST的神经元投射与持续但非短期的恐惧反应密切相关，并且这些通路中的神经传递由CRF门控。提出了一系列的实验，测试来自这个模型的具体预测。目标1中的实验评估了杏仁核到BNST投射对长持续时间与短持续时间恐惧的贡献。目标2中的实验评估CRF受体对长时间与短时间恐惧的贡献。目的3中的实验评估CRF和持续威胁线索对BNST中谷氨酸释放的影响，以及这种释放对杏仁核的依赖性。所使用的主要技术是脑内药物输注，永久性和可逆性失活选定的脑区，并测量细胞外谷氨酸在不同的脑区，使用微透析和高压液相色谱法（HPLC）。这些研究的结果将有助于更全面地了解恐惧的神经基础，这是开发新的更有效的治疗焦虑症（如PTSD和GAD）的关键一步。此外，随着BNST和CRF越来越多地涉及其他几种心理健康和行为问题，如抑郁症，药物渴望，戒断引起的焦虑和慢性疼痛的情绪后果，从这些研究中获得的数据可能与广泛的临床重要现象有关。 公共卫生相关性：持续的恐惧和焦虑反应是一个重要的临床问题。最近的研究表明，短时间的恐惧反应的神经基板可能是不同的，从那些更持久的恐惧反应。本文提出的实验旨在进一步探索这些差异。

DESCRIPTION (provided by applicant): Pavlovian fear conditioning has been widely used to reproduce anxiety-like states in laboratory animals and explore their neural substrates. Based largely on the results from these types of studies, a neural circuit model has been developed and widely adopted. Most often, these paradigms involve pairing brief stimuli such as lights or tones with footshock. Over the last several years, however, I have amassed evidence that when rats are trained and tested using longer duration stimuli (i.e., minutes as opposed to seconds), the current model is inadequate. On the basis of those data, I proposed an expanded model that focuses attention on the bed nucleus of the stria terminalis (BNST) and the stress-related peptide corticotropin releasing factor (CRF). Very briefly, the model posits that glutamatergic projections from the amygdala to the BNST are critically involved in sustained but not short-duration fear responses, and that neural transmission in these pathways is gated by CRF. A series of experiments are proposed which test specific predictions derived from this model. Experiments in Aim 1 evaluate the contribution to long- vs. short-duration fear of amygdala-to-BNST projections. Experiments in Aim 2 evaluate the contribution of CRF receptors to long- vs. short- duration fear. Experiments in Aim 3 evaluate the effect of CRF and sustained threat cues on glutamate release in the BNST, and the dependency of this release on the amygdala. The major techniques used are intra-cerebral drug infusion, permanent and reversible inactivation of selected brain regions, and the measurement of extracellular glutamate in different brain areas using microdialysis and high-pressure liquid chromatography (HPLC). The results from these studies will contribute to a more complete understanding of the neural bases of fear, which is a key step in developing new and more effective treatments for anxiety disorders such as PTSD and GAD. Moreover, as the BNST and CRF have been increasingly implicated in several other mental health and behavioral problems such as depression, drug craving, withdrawal-induced anxiety, and the emotional consequences of chronic pain, the data derived from these studies will likely be relevant to a broad range of clinically important phenomena. PUBLIC HEALTH RELEVANCE: Persistent fear and anxiety responses are a significant clinical problem. Recent studies indicate that the neural substrates of short-duration fear responses may be different from those of more sustained fear responses. The experiments proposed herein are meant to further explore these differences.