Functional Organization of the Bed Nucleus of the Stria Terminalis

终纹床核的功能组织

• 批准号: 8677977
• 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/8677977
• 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（由申请人提供）：我们的一般目标是表征质末端（BNST）的床核的功能组织，这是一个参与焦虑症的大脑区域，但知之甚少。在此过程中，我们旨在阐明恐惧概括的机制，这是焦虑症的标志。人们通常认为，BNST会对弥漫性突发事件产生持久的焦虑状态，但它是 根据杏仁核的不同，不参与对离散感觉提示的恐惧反应的表达。相比之下，我们以前的工作表明，第BN的活动以两种方式导致了恐惧：通过在威胁刺激结束后很长一段时间（恐惧的时间概括），并允许不同的（安全）线索也引发恐惧（刺激恐惧）。由于Threa经过或针对安全刺激的响应是焦虑症的标志，因此了解BNST如何促进恐惧概括是一个相当大的翻译意义问题。因此，该提案将通过其与杏仁核的相互联系以及对脑干恐惧效应子的投影的相互联系来研究，从而有助于学习恐惧反应的概括。但是，在解决这个问题之前，我们需要提高对BNST基本生理组织的理解。实际上，已知BNST包含多种生理细胞类型，表达了不同的神经递质，并投影到影响恐惧表达的各种部位。但是，这些各种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在体外结合逆行标记的BNST细胞的斑块记录，生物囊蛋白标记，谷氨酸后的光学未分离，并获得粘液后免疫持续效应，以实现BNST的形态生理接线图。结果，将能够根据其生理学将记录在体内记录的细胞（AIM＃3）分配给该电路中的位置。在AIM＃3中，在AIMS＃1-2中获得的数据的指导下，我们将执行大鼠BNST和杏仁核神经元的细胞外记录。老鼠将受到差异恐惧调节范式的范围，该范式在人类中看到的恐惧反应中的个体间变化。记录细胞的投影位点将通过抗侵袭来鉴定。通过将单位数据与恐惧反应中的个体变化联系起来，我们将对恐惧的时间和刺激概括的基础机制进行可测试的预测。最后，在AIM＃4中，我们将使用体内光遗传学抑制或刺激选择性地抑制或激活特定的BNST或杏仁核输出来测试这些预测。鉴于类似的网络是动物和人类学习的恐惧学习，因此拟议的研究可能会揭示焦虑症的病理生理学。