Oxytocin Modulation of CRF Neurons in the BNST: Implications for Anxiety

催产素对 BNST 中 CRF 神经元的调节：对焦虑的影响

• 批准号: 8723883
• 负责人: Sarah Elizabeth Daniel
• 金额: $ 3.14万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723883
• 关键词: Affect; Agonist; Amygdaloid structure; Anterolateral; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Attenuated; Autistic Disorder; Automobile Driving; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Cells; Clinical; Complex; Corticotropin-Releasing Hormone; Data; Electrophysiology (science); Enkephalins; Etiology; Future; Goals; Hormones; Hypothalamic structure; In Vitro; Infusion procedures; Injection of therapeutic agent; Interneurons; Knowledge; Lead; Mental Depression; Mental disorders; Messenger RNA; Molecular; Mus; Nature; Neurons; Neuropeptides; Neurotransmitters; Outcome; Output; Oxytocin; Oxytocin Receptor; Peptides; Phenotype; Physiological; Population; Post-Traumatic Stress Disorders; Prosencephalon; Proteins; Rattus; Receptor Activation; Receptor Cell; Research; Reverse Transcriptase Polymerase Chain Reaction; Schizophrenia; Site; Social Behavior; Stress; Structure; Structure of terminal stria nuclei of preoptic region; System; Testing; Therapeutic; Time; Transgenic Mice; Type II Epithelial Receptor Cell; Type III Epithelial Receptor Cell; Wild Type Mouse; Work; base; biological adaptation to stress; cell type; neural circuit; neuropeptide Y; novel; patch clamp; protein expression; research study; response; treatment strategy

DESCRIPTION (provided by applicant): The bed nucleus of the stria terminalis (BNST) is a region of the extended amygdala in which multiple neuropeptide systems, including oxytocin and corticotropin releasing factor (CRF), have the potential to interact and regulate anxiety-like behaviors. Although oxytocin is known to be released into the BNST during times of stress, it is unknown what effect oxytocin release in the BNST has on anxiety behavior. We have demonstrated the presence of oxytocin receptors on discrete populations of BNST neurons that contain other neuropeptides involved in modulating the stress response, such as CRF, enkephalin (Enk), and neuropeptide Y (NPY). CRF is the prototypical stress hormone, which is thought to trigger the behavioral stress response, whereas NPY and Enk are thought of as factors that act to attenuate the stress response. Hence, oxytocin release in the BNST may affect two diametrically opposed components of the stress response. However, the electrophysiological response of these neuronal populations to oxytocin receptor activation has yet to be explored. The central hypothesis of this proposal is that oxytocin differentially regulats the activity of oxytocin responsive neurons in the BNST to decrease anxiety behavior. This project will first aim to determine the effect of oxytocin in the BNST on anxiety-like behavior in mice. Using site specific injection of an oxytocin agonist and antagonist into the BNST, anxiety behavior will be tested with the elevated plus maze and open field paradigms. Additionally, this project will aim to characterize the genotypic, electrophysiological, and oxytocin- response profile of cells expressing the oxytocin receptor in the BNST. Using two novel transgenic mice driving fluorescent protein expression in either CRF neurons or oxytocin receptor-expressing neurons to facilitate visually guided patch, I will perform patch-clamp electrophysiology and single cell reverse transcriptase PCR (scRT-PCR) to characterize these cells and their response to oxytocin. The combination of behavioral, electrophysiological, and molecular approaches will help us move away from considering the BNST as a homogenous group of neurons, but rather a complex structure with multiple neurotransmitter systems that interact to affect the physiological and behavioral output of the nucleus. Elucidating oxytocin's interactions with other neurotransmitter systems in the BNST could lead to a greater understanding of the etiology of and therapeutic strategies for anxiety disorders.

描述（由申请人提供）：终纹床核（BNST）是杏仁核延伸的一个区域，其中多种神经肽系统，包括催产素和促肾上腺皮质激素释放因子（CRF），有可能相互作用并调节焦虑样症状。行为。尽管众所周知，在压力期间催产素会释放到 BNST 中，但尚不清楚 BNST 中催产素的释放对焦虑行为有何影响。我们已经证明，在离散的 BNST 神经元群体中存在催产素受体，这些神经元含有参与调节应激反应的其他神经肽，例如 CRF、脑啡肽 (Enk) 和神经肽 Y (NPY)。 CRF 是典型的应激激素，被认为会引发行为应激反应，而 NPY 和 Enk 被认为是减弱应激反应的因素。因此，BNST 中催产素的释放可能会影响应激反应的两个截然相反的组成部分。然而，这些神经元群对催产素受体激活的电生理反应仍有待探索。该提议的中心假设是催产素差异性地调节 BNST 中催产素反应性神经元的活性，以减少焦虑行为。该项目首先旨在确定 BNST 中的催产素对小鼠焦虑样行为的影响。通过在 BNST 中特定部位注射催产素激动剂和拮抗剂，将通过高架十字迷宫和开放场地范例来测试焦虑行为。此外，该项目旨在表征 BNST 中表达催产素受体的细胞的基因型、电生理学和催产素反应特征。使用两只新型转基因小鼠在 CRF 神经元或表达催产素受体的神经元中驱动荧光蛋白表达，以促进视觉引导贴片，我将进行膜片钳电生理学和单细胞逆转录酶 PCR (scRT-PCR) 来表征这些细胞及其反应催产素。行为学、电生理学和分子方法的结合将帮助我们不再将 BNST 视为一组同质的神经元，而是一个具有多个神经递质系统的复杂结构，这些神经递质系统相互作用影响细胞核的生理和行为输出。阐明催产素与 BNST 中其他神经递质系统的相互作用可以使人们更好地了解焦虑症的病因和治疗策略。