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: 8457613
• 负责人: Sarah Elizabeth Daniel
• 金额: $ 3.09万
• 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/8457613
• 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; 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. PUBLIC HEALTH RELEVANCE: This project will be crucial in determining how oxytocin treatment could affect the neural circuitry of anxiety-like behavior, and will inform future studie on the use of oxytocin or molecules that manipulate oxytocin as treatment for anxiety disorders. The proposed research is expected to contribute to an understanding of how oxytocin acts on different cell types in the bed nucleus of the stria terminalis (BNST) and how this affects anxiety behaviors.

描述（由申请人提供）：Stria末端（BNST）的床核是延伸杏仁核的一个区域，其中多种神经肽系统（包括催产素和皮质激素释放因子（CRF））具有相互作用和调节类似焦虑的行为的潜力。尽管已知催产素在压力时期被释放到BNST中，但尚不清楚BNST中催产素释放的影响对焦虑行为有什么影响。我们已经证明了催产素受体在离散的BNST神经元种群上存在，这些神经元包含其他参与调节应激反应的神经肽，例如CRF，Enkephalin（ENK）和Neuropeptide Y（NPY）。 CRF是典型的应激激素，被认为会触发行为应力反应，而NPY和ENK被认为是减轻压力反应的因素。因此，BNST中的催产素释放可能会影响应力反应的两个截然相反的组成部分。但是，这些神经元种群对催产素受体激活的电生理反应尚未探索。该提议的中心假设是催产素差异调节了BNST中催产素反应性神经元的活性，以降低焦虑行为。该项目将首先旨在确定催产素对BNST对小鼠焦虑样行为的影响。使用位点特异性注射催产素激动剂和拮抗剂到BNST中，将通过升高的迷宫和开放式范式测试焦虑行为。此外，该项目的目的是表征表达BNST中催产素受体的细胞的基因型，电生理和催产素反应谱。使用两只新型的转基因小鼠在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的斑块，我将执行贴片钳电生理学和单细胞逆转录酶PCR（SCRT-PCR），以表征这些细胞及其对氧蛋白的反应。行为，电生理和分子方法的结合将有助于我们摆脱将BNST视为同质神经元的同质群体，而是具有多个神经递质系统的复杂结构，它们相互作用以影响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能会使人们对焦虑症的病因和治疗策略有更深入的了解。 公共卫生相关性：该项目对于确定催产素治疗如何影响类似焦虑行为的神经回路至关重要，并将告知未来的Studie oxytocin或分子，这些催产素或分子操纵催产素作为治疗焦虑症的治疗。预计拟议的研究将有助于理解催产素如何在脊柱末端（BNST）的床核中对不同细胞类型的作用，以及这如何影响焦虑 行为。