Neurobiology of Anxiety and Panic Disorders

焦虑和惊恐障碍的神经生物学

• 批准号: 7267326
• 负责人: Anantha Shekhar
• 金额: $ 31.67万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267326
• 关键词: Acute; Afferent Pathways; Animals; Anxiety; Anxiety Disorders; Appendix; Attenuated; Baroreflex; Beds; Behavioral; Brain Stem; Breathing; Carbon Dioxide; Cell Nucleus; Cells; Chronic; Cognitive; Crowding; Cues; DSM-IV; Data; Development; Disruption; Dynorphin A; Dynorphins; Efferent Pathways; Emotional; Endocrine; Excision; Exhibits; Exposure to; FOS gene; Fright; Funding; Gene Silencing; Genes; Glutamate Decarboxylase; Glutamates; Goals; Heart Rate; Hormone Antagonists; Human; Hypothalamic structure; Infusion procedures; Injection of therapeutic agent; Interneurons; Lesion; Life; Manuscripts; Measures; Mediating; Melanocyte stimulating hormone; Microinjections; Modeling; Molecular; N-Methylaspartate; Neural Pathways; Neurobiology; Neurons; Neurotransmitters; Nucleus solitarius; Numbers; Panic; Panic Attack; Panic Disorder; Pathology; Pathway interactions; Patients; Peptide Receptor; Peptides; Perception; Physiological; Rate; Rattus; Recurrence; Reflex action; Regulatory Pathway; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Site; Small Interfering RNA; Social Interaction; Sodium Lactate; Staging; Stimulus; Structure of terminal stria nuclei of preoptic region; Symptoms; Techniques; Testing; Work; base; bicuculline methiodide; conditioned fear; decarboxylase inhibitor; disability; gamma-Aminobutyric Acid; hypocretin; immunoreactivity; mRNA Expression; melanin-concentrating hormone; melanin-concentrating hormone receptor; orexin A; pressure; prodynorphin; programs; research study; respiratory; response

DESCRIPTION (provided by applicant): Panic disorder is a severe anxiety disorders characterized by significant disability. Rats in which GABA inhibition is chronically disrupted in the dorsomedial hypothalamus/perifornical (DMH/PeF) region, exhibit heightened anxiety and panic-like responses, defined as increases in heart rate (HR), mean arterial pressure (BP), respiratory rate (RR), and anxiety as measured by the social interaction (SI) test, following exposure to subthreshold cues such as 0.5 M sodium lactate and 7.5% CO2, agents known to provoke panic attacks in subjects suffering from panic disorder. During the last funding period, we have extensively characterized the afferent pathways for the lactate stimulus, demonstrated some of the regulatory mechanisms within the DMH, and identified the efferent targets of the DMH that are implicated in the panic-like response. The goal of this competitive renewal (MH 52619) is to further elucidate the pathways and neurotransmitters involved in the different components of panic response using pharmacological, functional neuroanatomical, and molecular studies. Overall Hypothesis of the work is that disruption of GABA inhibition in the DMH/PeF region of rats induces a 'panic-prone' state, as a result of pathological activation of a select group of glutamate/peptidergic projection neurons, most prominently orexin/dynorphin A (ORX/DYN) positive cells. This results in aberrant stimulation of a number of efferent targets from the DMH. During this funding period, we will study the pathways involved in activating the bed nucleus of the stria terminalis (BNST) to result in anxiety-like responses and specific brain stem projection targets such as the nucleus tractus solitarius (NTS) in causing inhibition of parasympathetic and activation of sympathetic pathways to increase HR and BP following lactate infusions in these panic-prone rats. We will test these hypotheses with experiments using neuronal immunohistochemical studies; systemic injections of ORX and other peptide receptor antagonists; targeted lesioning of the ORX neurons in the DMH/PeF; measuring the changes in pre-proORX (ppORX), proDynorphin (pDYN) and other peptide mRNA expressions using RTPCR; and acute ppORX and/or pDYN gene knockdown with siRNA, within the DMH. We will study the efferent sites with infusions of pharmacological agents, gene silencing using siRNA as well as neuroanatomical techniques. Finally, we will study the role of local versus extrinsic GABA neurons by GAD-67/65 gene silencing in the DMH/PeF region.

描述(申请人提供)：惊恐障碍是一种严重的焦虑症，以严重残疾为特征。在下丘脑背内侧/穹隆周围(DMH/PEF)区域GABA抑制被慢性扰乱的大鼠，在暴露于阈值下线索(如0.5M乳酸钠和7.5%二氧化碳)后，表现出高度的焦虑和恐慌样反应，定义为心率(HR)、平均动脉压(BP)、呼吸频率(RR)和社交互动(SI)测试测量的焦虑。在过去的资助期间，我们广泛地描述了乳酸刺激的传入途径，展示了DMH内的一些调节机制，并确定了DMH与恐慌性反应有关的传出靶点。这一竞争性更新(MH 52619)的目标是通过药理学、功能神经解剖学和分子研究来进一步阐明参与惊恐反应不同组成部分的通路和神经递质。这项工作的总体假设是，破坏大鼠DMH/PEF区的GABA抑制会导致一种易于恐慌的状态，这是由于选定的一组谷氨酸/肽能投射神经元的病理激活，最显著的是食欲素/强啡肽A(ORX/Dyn)阳性细胞。这导致DMH对许多传出靶点的异常刺激。在这一资助期间，我们将研究激活终纹床核(BNST)以导致焦虑样反应的途径，以及特定的脑干投射靶点，如孤束核(NTS)，在这些容易恐慌的大鼠注入乳酸后，导致副交感神经抑制和激活交感神经通路以增加心率和血压。我们将通过以下实验来验证这些假设：神经元免疫组织化学研究；全身注射ORX和其他多肽受体拮抗剂；靶向损伤DMH/PEF中的ORX神经元；使用RT PCR测量前ORX前(PpORX)、前Dynorphin(PDYN)和其他多肽mRNA表达的变化；以及在DMH内用siRNA急性敲除ppORX和/或pDYN基因。我们将通过注入药物、使用siRNA和神经解剖学技术来研究传出部位。最后，我们将通过沉默DMH/PEF区的GAD-67/65基因来研究局部和外部GABA神经元的作用。