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再现实验动物的焦虑状态并探索其神经基质。基于这些类型的研究结果，神经回路模型已经发展并被广泛采用。大多数情况下，这些范例包括将短暂的刺激（如灯光或音调）与脚震配对。然而，在过去的几年里，我积累的证据表明，当老鼠被训练和测试时，使用更长的持续时间刺激（即，几分钟而不是几秒钟），目前的模型是不充分的。在这些数据的基础上，我提出了一个扩展模型，将注意力集中在终纹床核（BNST）和应激相关肽促肾上腺皮质激素释放因子（CRF）上。简而言之，该模型假设从杏仁核到BNST的谷氨酸能投射在持续但不是短时间的恐惧反应中起关键作用，并且这些途径中的神经传递是由CRF控制的。提出了一系列实验来验证从该模型得出的具体预测。目的1的实验评估了对杏仁核-脑基底核投射的长时间恐惧和短时间恐惧的贡献。目的2的实验评估了CRF受体对长时间和短时间恐惧的影响。目的3的实验评估了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。使用的主要技术是脑内药物输注，选择脑区域永久和可逆失活，以及使用微透析和高压液相色谱（HPLC）测量不同脑区域的细胞外谷氨酸。这些研究的结果将有助于更全面地了解恐惧的神经基础，这是开发新的和更有效的治疗焦虑症的关键一步，如创伤后应激障碍和广泛性焦虑症。此外，由于BNST和CRF越来越多地与其他一些心理健康和行为问题有关，如抑郁症、药物渴求、戒断性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相关。

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.