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）：该提案的重点是中央延伸杏仁核的一部分的大脑区域：杏仁核的中央核（CEA）。 CEA参与了对恐惧，压力和焦虑的许多反应，并包含不同的细胞群体。但是，尚不清楚细胞群是否具有不同的功能，目前无法使用可用工具在体内确定这一点。该建议旨在测试使用神经肽B和W型1受体（NPBW1）作为靶标的CEA中特定神经元种群选择性神经毒性病变的可行性。该受体非常离散地表达，特别是在侧CEA中，但在周围地区不表达。此外，该受体在包含皮质激素释放激素（CRH）和dynorphin的外侧CEA的细胞上表达，但并未在含有enkephalin的细胞或内侧CEA的细胞上表达，或者在内侧CEA的细胞上，是amygdaloid输出神经元的主要来源。该受体（神经肽W-30）的选择性配体将与saporin（通过高级靶向系统）进行自定义。 AIM 1专注于CEA有效和选择性神经毒性病变的发展。配体将与NPBW1受体结合，并在内部化时会释放出剂量的细胞，从而导致细胞死亡。已显示了其他受体系统的实用性，包括使用MU阿片受体作为靶标的杏仁核插入核的细胞的选择性靶向。 NPBW1受体定位的特异性表明，这种病变方法将有选择地破坏含有CRH和Dynorphin的细胞，但要避免两者中含有CEA中含有细胞的细胞，而内侧CEA中的杏仁核输出细胞被认为是对几种恐惧和焦虑反应的恐惧和焦虑响应（例如，恐惧的恐惧的恐惧响应）。在AIM 2中，将在成年雄性大鼠中评估中央延伸杏仁核的CRH/Dynorphin细胞的潜在功能。这些实验最初将评估CEA神经毒性病变对A）升高的基础焦虑症行为的影响，以及迷宫和防御性戒断范式，b）恐惧受到恐惧的声学惊悚反射。希望开发一种选择性针对CEA特定人群的工具将有助于定义其功能，并最初强调细胞在恐惧和类似焦虑症的反应中可能扮演的角色。希望随着时间的流逝，这项工作最终将导致中央延伸杏仁核中几种不同细胞类型的神经毒性病变的发展，包括斯特里亚末端的床核，并集体地，这将使人们更好地理解与许多恐惧和焦虑症相关的负面情绪的处理。该提案旨在选择性地消除大脑中特定的神经元种群，被认为涉及压力，恐惧和/或焦虑反应。希望有选择地针对特定人群（而不是当前可用的全球方法），将使人们更好地了解大脑如何处理这些负面情绪。反过来，这将有助于设计焦虑和与恐惧有关的疾病的治疗策略。