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）：我们的总体目标是表征终纹床核（BNST）的功能组织，这是一个与焦虑有关的脑区，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，这是焦虑症的标志。人们普遍认为，BNST产生长期持续的焦虑样状态，以应对扩散的突发事件，但它是 不参与对离散感觉线索的习得性恐惧反应的表达，后者取决于杏仁核。与此相反，我们以前的工作表明，BNST活动有助于线索恐惧在两个方面：通过延长恐惧反应后很长一段时间的威胁刺激已经结束（恐惧的时间概括），并允许不同的（安全）线索也触发恐惧（刺激概括的恐惧）。由于经历恐惧后很长一段时间已经通过或响应于安全的刺激是焦虑症的标志，了解BNST如何有助于恐惧泛化是一个具有相当大的翻译意义的问题。因此，这项建议将研究如何BNST，通过其与杏仁核的相互联系和脑干恐惧效应器的预测，有助于学习恐惧反应的泛化。然而，在解决这个问题之前，我们需要提高我们对BNST的基本生理组织的理解。事实上，已知BNST包含多种生理细胞类型，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是未知的。因此，在目标#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、生物胞素标记、谷氨酸的光释放以及GABA能和谷氨酸能标记物的事后免疫荧光来获得BNST的形态生理接线图。因此，将能够根据其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，在目标#1-2中获得的数据的指导下，我们将对大鼠BNST和杏仁核神经元进行细胞外记录。大鼠将接受差异性恐惧条件反射范例，该范例再现了在人类中观察到的恐惧反应的个体间差异。记录细胞的投射位点将通过逆向侵袭来鉴定。通过将单元数据与恐惧反应中的个体间变化相关联，我们将制定关于恐惧的时间和刺激泛化机制的可检验预测。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。考虑到动物和人类的恐惧学习的基础是类似的网络，拟议中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的刺激或环境联系起来的能力是生存所必需的。另一方面，过度的恐惧会导致一个恶性循环，逐渐蔓延和加剧，就像焦虑症一样。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，这些网络在患有焦虑症的人中显示出异常的活动模式（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。这个提议的目的就是要做到这一点，重点是终纹的床核（BNST），这是恐惧回路中一个相对被忽视但至关重要的节点。!