Functional Organization of the Bed Nucleus of the Stria Terminalis

终纹床核的功能组织

• 批准号: 8862539
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8862539
• 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.

描述(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，但对其知之甚少。在这个过程中，我们的目标是阐明恐惧泛化的潜在机制，这是焦虑症的一个特征。人们普遍认为，BNST会产生持久的焦虑样状态，以应对弥漫的偶发事件，但事实并非如此 不参与对离散感觉线索的后天恐惧反应的表达，后者取决于杏仁核。相反，我们之前的工作表明，BNST活动通过两种方式促进线索恐惧：通过在威胁刺激结束后很长时间延长恐惧反应(恐惧的时间概括)和允许不同的(安全)线索也引发恐惧(刺激恐惧概括)。由于在ThreA过后很长一段时间内经历恐惧或对安全刺激的反应是焦虑症的特征，了解BNST如何导致恐惧泛化是一个具有相当大翻译意义的问题。因此，这项提议将研究BNST如何通过其与杏仁核的相互联系和对脑干恐惧效应器的投射，促进习得的恐惧反应的泛化。然而，在解决这个问题之前，我们需要提高对BNST的基本生理组织的理解。事实上，众所周知，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种部位。然而，这些不同的属性如何相互关联还是个未知数。因此，在AIMS#1-2中，我们将首先努力通过结合体外逆行标记的BNST细胞的斑片记录、生物细胞素标记、谷氨酸的光标记以及GABAA和谷氨酸能标记的后免疫荧光来获得BNST的形态-生理接线图。因此，将能够根据生理将体内记录的细胞(目标#3)分配到该电路中的位置。在目标#3中，在目标#1-2中获得的数据的指导下，我们将对大鼠的BNST和杏仁核神经元进行细胞外记录。这些大鼠将受到一种不同的恐惧条件反射范式的影响，这种范式再现了人类在恐惧反应中的个体间差异。记录的细胞的投射位置将通过逆行侵袭来确定。通过将单位数据与恐惧反应的个体间差异联系起来，我们将制定关于恐惧的时间性和刺激性概括的潜在机制的可测试预测。最后，在目标4中，我们将通过在体内使用光遗传抑制或刺激选择性地抑制或激活特定的BNST或杏仁核输出来检验这些预测。考虑到动物和人类学习恐惧的基础是相似的网络，拟议中的研究可能会揭示焦虑症的病理生理学。