Functional Organization of the Bed Nucleus of the Stria Terminalis

终纹床核的功能组织

• 批准号: 8404086
• 负责人: DENIS PARE
• 金额: $ 38.75万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8404086
• 关键词: Address; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Automobile Driving; Bilateral; Boxing; Brain Stem; Brain region; Cells; Cues; Data; Dependovirus; Diffuse; Disease; Fiber Optics; Fright; Functional disorder; Glutamates; Human; Hypothalamic structure; In Vitro; Individual; Infusion procedures; Label; Lead; Learning; Light; Location; Methods; Minority; Neurons; Neurotransmitters; Outcome; Output; Pattern; Phenotype; Physiological; Physiology; Process; Property; Rattus; Research; Role; Sensory; Site; Specificity; Stimulus; Stimulus Generalization; Structure of terminal stria nuclei of preoptic region; Testing; Time; Variant; Viola; Virus; Work; arm; base; biocytin; cell type; conditioned fear; experience; extracellular; improved; in vivo; neglect; neurochemistry; optogenetics; research study; response

DESCRIPTION (provided by applicant): Our general objective is to characterize the functional organization of the bed nucleus of the stria terminalis (BNST), a brain region involved in anxiety but about which little is known. In the process, we aim to shed light on the mechanisms underlying fear generalization, a hallmark of anxiety disorders. It is commonly believed that BNST generates long lasting anxiety-like states in response to diffuse contingencies but that it is not involved in the expression of learned fear responses to discrete sensory cues, the latter depending on the amygdala. In contrast, our previous work indicates that BNST activity contributes to cued fear in two ways: by prolonging fear responses long after the threatening stimulus has ended (temporal generalization of fear) and by allowing different (safe) cues to also trigger fear (stimulus generalization of fear). Since experiencing fright long after the threa has passed or in response to safe stimuli are hallmarks of anxiety disorders, understanding how BNST contributes to fear generalization is an issue of considerable translational significance. Thus, this proposal will examine how BNST, via its reciprocal connections with the amygdala and projections to brainstem fear effectors, contributes to the generalization of learned fear responses. However, before addressing this question, we need to improve our understanding of the basic physiological organization of BNST. Indeed, BNST is known to contain multiple physiological cell types, expressing different neurotransmitters, and projecting to various sites that influence fear expression. However, how these various properties correlate with each other is unknown. Thus in Aims #1-2, we will first strive to obtain a morpho-physiological wiring diagram of BNST by combining patch recordings of retrogradely labeled BNST cells in vitro, biocytin labeling, photic uncaging of glutamate, and post-hoc immunofluoerescence for GABAergic and glutamatergic markers. As a result, will be able to assign cells recorded in vivo (Aim #3) to locations in this circuit based on their physiology. In Aim #3, guided by the data obtained in Aims #1-2, we will perform extracellular recordings of rat BNST and amygdala neurons. The rats will be subjected to a differential fear conditioning paradigm that reproduces the inter-individual variations in fear responding seen in humans. The projection site of recorded cells will be identified by antidromic invasion. By relating the unit data with inter-individual variations in fear responding, we will formulate testable predictions regarding the mechanisms underlying the temporal and stimulus generalization of fear. Last, in Aim #4, we will test these predictions by selectively inhibiting or activating particular BNST or amygdala outputs using in vivo optogenetic inhibition or stimulation. Given that similar networks underlie fear learning in animals and humans, the proposed studies might shed light on the pathophysiology of anxiety disorders. PUBLIC HEALTH RELEVANCE: The ability to associate fear responses to new stimuli or circumstances on the basis of experience is necessary for survival. On the other hand, excessive fear can lead to a pernicious cycle of avoidance that gradually spreads and intensifies, as seen in anxiety disorders. Much data suggest that research on fear learning mechanisms constitutes our best hope of understanding anxiety disorders. Indeed, similar networks underlie fear learning in animals and humans (Phelps & LeDoux '05). Moreover, these networks show abnormal activity patterns in humans with anxiety disorders (Bremner '08). Thus, to shed light on the pathophysiology of these disorders, we must further our understanding of fear learning networks. This proposal aims to do just that, focusing on the bed nucleus of the stria terminalis (BNST), a relatively neglected, yet critical, node in the fear circuit. !

描述（由申请人提供）：我们的总体目标是描述终纹床核（BNST）的功能组织，这是一个与焦虑有关的大脑区域，但对此知之甚少。在此过程中，我们的目标是揭示恐惧泛化的潜在机制，这是焦虑症的一个标志。人们普遍认为，BNST 会产生持久的类焦虑状态，以应对分散的突发事件，但实际上 不参与对离散感觉线索的习得恐惧反应的表达，后者取决于杏仁核。相比之下，我们之前的工作表明，BNST 活动通过两种方式促成暗示恐惧：在威胁性刺激结束后很长时间内延长恐惧反应（恐惧的时间泛化），并允许不同的（安全）线索也引发恐惧（刺激泛化）的恐惧）。由于在威胁过去很长时间后经历恐惧或对安全刺激做出反应是焦虑症的标志，因此了解 BNST 如何促进恐惧泛化是一个具有相当大转化意义的问题。因此，该提案将研究 BNST 如何通过其与杏仁核的相互联系以及对脑干恐惧效应器的预测，促进习得恐惧反应的泛化。然而，在解决这个问题之前，我们需要加深对BNST基本生理组织的理解。事实上，已知 BNST 含有多种生理细胞类型，表达不同的神经递质，并投射到影响恐惧表达的各个部位。然而，这些不同的属性如何相互关联尚不清楚。因此，在目标 #1-2 中，我们将首先通过结合体外逆行标记 BNST 细胞的贴片记录、生物胞素标记、谷氨酸的光解笼和 GABA 能和的事后免疫荧光来努力获得 BNST 的形态生理接线图。谷氨酸能标记。因此，将能够根据细胞的生理学将体内记录的细胞（目标#3）分配到该回路中的位置。在目标#3 中，以目标#1-2 中获得的数据为指导，我们将对大鼠 BNST 和杏仁核神经元进行细胞外记录。老鼠将接受差异化的恐惧条件反射范式，该范式再现了人类恐惧反应的个体间差异。记录的细胞的投射位点将通过逆向入侵来识别。通过将单位数据与恐惧反应的个体间差异联系起来，我们将针对恐惧的时间和刺激泛化的潜在机制制定可测试的预测。最后，在目标#4中，我们将通过使用体内光遗传学抑制或刺激选择性抑制或激活特定的 BNST 或杏仁核输出来测试这些预测。鉴于类似的网络是动物和人类恐惧学习的基础，拟议的研究可能会揭示焦虑症的病理生理学。 公共卫生相关性：根据经验将恐惧反应与新刺激或环境联系起来的能力对于生存是必要的。另一方面，过度的恐惧可能导致恶性的回避循环，并逐渐蔓延和加剧，正如焦虑症中所见。许多数据表明，对恐惧学习机制的研究是我们理解焦虑症的最大希望。事实上，类似的网络是动物和人类恐惧学习的基础（Phelps & LeDoux '05）。此外，这些网络显示出患有焦虑症的人类的异常活动模式（Bremner '08）。因此，为了阐明这些疾病的病理生理学，我们必须进一步了解恐惧学习网络。该提案旨在做到这一点，重点关注终纹床核（BNST），这是恐惧回路中相对被忽视但至关重要的节点。 ！