Phenotypic and Functional Determination of Central Extended Amygdala Cell Groups

中央扩展杏仁核细胞群的表型和功能测定

• 批准号: 7586970
• 负责人: HEIDI E DAY
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-11 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586970
• 关键词: Acoustics; Address; Adult; Affinity; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Area; Attention; Behavior; Behavioral; Bilateral; Binding; Brain; Cause of Death; Cell Nucleus; Cells; Central Lateral Nucleus; Central Medial Thalamic Nucleus; Chemosensitization; Corticotropin-Releasing Hormone; Custom; Data; Development; Disease; Dynorphins; Effectiveness; Emotional; Emotions; Endocrine; Enkephalins; Fright; Intercalated Cell; Lateral; Lead; Lesion; Ligands; Literature; Medial; Mediating; Methods; Motor output; Nature; Neurons; Neuropeptide Receptor; Neuropeptides; Output; Peptides; Play; Population; Positioning Attribute; Process; Property; Publishing; Rattus; Reflex action; Role; Services; Source; Specificity; Stress; Structure; Structure of terminal stria nuclei of preoptic region; System; Techniques; Testing; Time; Withdrawal; Work; behavior test; cell type; conditioned fear; design; in vivo; indexing; interest; male; mu opioid receptors; neurochemistry; neuropeptide B; neurotoxic; receptor; research study; response; tool; treatment strategy

DESCRIPTION (provided by applicant): This proposal focuses on a brain area that is part of the central extended amygdala: the central nucleus of the amygdala (CEA). The CEA is involved in a number of responses to fear, stress and anxiety and contains distinct cell populations. However, it is not known whether the cell populations have distinct functions, and it is currently impossible to ascertain this in vivo with the tools available. This proposal aims to test the feasibility of developing a selective neurotoxic lesion of a specific neuronal population in the CEA using the neuropeptide B and W type 1 receptor (NPBW1) as a target. This receptor is very discretely expressed, specifically in the lateral CEA, but not in the surrounding areas. Furthermore, this receptor is expressed on cells of the lateral CEA that contain corticotropin releasing hormone (CRH) and dynorphin, but is not expressed on cells that contain enkephalin, or on cells of the medial CEA, a major source of amygdaloid output neurons. A selective ligand for this receptor (neuropeptide W-30) will be custom conjugated with saporin (by Advanced Targeting Systems). Aim 1 focuses on the development of an effective and selective neurotoxic lesion of the CEA. The ligand will bind to the NPBW1 receptor and when internalized will release saporin into the cell, causing the death of the cell. The utility of this approach has been shown for other receptor systems, including selective targeting of cells of the intercalated nuclei of the amygdala, using the mu opioid receptor as a target. The specificity of the localization of the NPBW1 receptor suggests that this lesioning method will selectively destroy cells containing CRH and dynorphin, but spare both enkephalin containing cells in the lateral CEA, and amygdaloid output cells within the medial CEA that are thought to be critical for modulation of several fear and anxiety responses (e.g. fear potentiated startle response). In Aim 2, the potential functions of CRH/dynorphin cells of the central extended amygdala will be assessed in adult male rats. These experiments will initially evaluate the effects of this neurotoxic lesion of the CEA on A) basal anxiety-like behaviors in the elevated plus maze and defensive withdrawal paradigm, and B) fear-potentiated acoustic startle reflexes. It is hoped that the development of a tool to selectively target a specific population of the CEA will help to define its functions, with an initial emphasis on the roles that the cells may play in fear and anxiety-like responses. It is hoped that with time, this work will ultimately lead to the development of neurotoxic lesions of several distinct cell types in the central extended amygdala, including the bed nucleus of the stria terminalis, and collectively, this will lead to a better understanding of the processing of negative emotions that are associated with the development and exacerbation of many fear and anxiety-related disorders. This proposal aims to selectively remove a specific neuronal population in the brain that is thought to be involved in stress, fear and/or anxiety responses. It is hoped that selectively targeting a specific population (rather than the more global approach currently available) will lead to a better understanding of how the brain processes these negative emotions. This in turn will be helpful in the design of treatment strategies for anxiety and fear-related disorders.

描述（由申请人提供）：该提案重点关注中央扩展杏仁核一部分的大脑区域：杏仁核中央核（CEA）。 CEA 参与对恐惧、压力和焦虑的多种反应，并包含不同的细胞群。然而，尚不清楚细胞群是否具有独特的功能，并且目前不可能用现有的工具在体内确定这一点。该提案旨在测试以神经肽 B 和 W 1 型受体 (NPBW1) 作为靶点，对 CEA 中特定神经元群体开发选择性神经毒性病变的可行性。该受体的表达非常离散，特别是在侧 CEA 中，但在周围区域中不表达。此外，该受体在含有促肾上腺皮质激素释放激素 (CRH) 和强啡肽的外侧 CEA 细胞上表达，但在含有脑啡肽的细胞或内侧 CEA 细胞（杏仁输出神经元的主要来源）上不表达。该受体的选择性配体（神经肽 W-30）将与皂草素（由 Advanced Targeting Systems）定制结合。目标 1 侧重于开发有效且选择性的 CEA 神经毒性损伤。配体将与 NPBW1 受体结合，内化后将皂草素释放到细胞中，导致细胞死亡。这种方法的实用性已被证明可用于其他受体系统，包括使用 mu 阿片受体作为靶点选择性靶向杏仁核嵌入核的细胞。 NPBW1 受体定位的特异性表明，这种损伤方法将选择性地破坏含有 CRH 和强啡肽的细胞，但不会保留外侧 CEA 中含有脑啡肽的细胞，以及内侧 CEA 内的杏仁输出细胞，这些细胞被认为对调节至关重要几种恐惧和焦虑反应（例如恐惧增强的惊吓反应）。在目标 2 中，将在成年雄性大鼠中评估中央延伸杏仁核的 CRH/强啡肽细胞的潜在功能。这些实验将首先评估 CEA 的这种神经毒性损伤对 A）高架十字迷宫和防御性退缩范式中的基础焦虑样行为，以及 B）恐惧增强的听觉惊吓反射的影响。希望开发一种选择性针对 CEA 特定群体的工具将有助于定义其功能，最初强调这些细胞在恐惧和焦虑样反应中可能发挥的作用。希望随着时间的推移，这项工作最终将导致中央延伸杏仁核（包括终纹床核）中几种不同细胞类型的神经毒性病变的发展，总的来说，这将导致更好地理解处理与许多恐惧和焦虑相关疾病的发展和恶化有关的负面情绪。该提案旨在选择性地去除大脑中被认为与压力、恐惧和/或焦虑反应有关的特定神经元群。希望选择性地针对特定人群（而不是目前可用的更全面的方法）能够更好地理解大脑如何处理这些负面情绪。这反过来将有助于设计焦虑和恐惧相关疾病的治疗策略。