Neural Substrates of Phasic versus Sustained Fear

描述(申请人提供)：巴甫洛夫恐惧条件作用已被广泛用于在实验动物身上复制类似焦虑的状态并探索它们的神经基础。在很大程度上基于这些类型的研究结果，一个神经电路模型已经被开发并被广泛采用。大多数情况下，这些范例包括将短暂的刺激(如灯光或音调)与脚部电击配对。然而，在过去的几年里，我积累了一些证据，表明当使用更长持续时间的刺激(即几分钟而不是几秒)来训练和测试老鼠时，目前的模型是不够的。在这些数据的基础上，我提出了一个关注终纹床核(BNST)和应激相关肽促肾上腺皮质激素释放因子(CRF)的扩展模型。简而言之，该模型假设，从杏仁核到BNST的谷氨酸能投射与持续但不是短期的恐惧反应密切相关，这些通路中的神经传递受到CRF的控制。提出了一系列实验，以检验从该模型得出的特定预测。目标1中的实验评估了杏仁核到BNST的投射对长期和短期恐惧的贡献。目标2中的实验评估了CRF受体对长期恐惧和短期恐惧的贡献。目的3的实验评估CRF和持续威胁线索对BNST谷氨酸释放的影响，以及这种释放对杏仁核的依赖性。使用的主要技术包括脑内药物输注，选定脑区的永久和可逆灭活，以及使用微透析和高压液相色谱(HPLC)测量不同脑区的细胞外谷氨酸。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、更有效的焦虑障碍治疗方法的关键一步，如创伤后应激障碍和广泛性焦虑。此外，由于BNST和CRF越来越多地与其他几种精神健康和行为问题有关，如抑郁、药物渴求、戒断诱导的焦虑和慢性疼痛的情感后果，这些研究得出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大的临床问题。最近的研究表明，短期恐惧反应的神经基础可能与更持久的恐惧反应不同。这里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.