The role of BNST CGRP in stress-enhanced anxiety behavior and HPA-axis function

BNST CGRP 在应激增强焦虑行为和 HPA 轴功能中的作用

• 批准号: 8222805
• 负责人: Kelly S. Sink
• 金额: $ 5.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2012-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8222805
• 关键词: Acoustics; Adrenal Glands; Affect; Affinity; Amygdaloid structure; Anxiety; Attenuated; Behavior; Behavioral; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cannulas; Cell surface; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Data; Development; FOS gene; Freezing; Fright; Gene Expression; Generalized Anxiety Disorder; Goals; Hormones; Hypothalamic structure; Individual; Infusion procedures; Knowledge; Lateral; Major Depressive Disorder; Measures; Mediating; Mediator of activation protein; Mental disorders; Molecular; Mood Disorders; Neurons; Neuropeptides; Neurosecretory Systems; Neurotransmitters; Odors; Oral Administration; Peptides; Pituitary Gland; Plasma; Post-Traumatic Stress Disorders; Psychopathology; Public Health; RAMP1; Rattus; Receptor Signaling; Recruitment Activity; Reflex action; Regulation; Research; Risk; Role; Serum; Signal Pathway; Signal Transduction; Small Interfering RNA; Specificity; Stress; Structure; Structure of terminal stria nuclei of preoptic region; System; Testing; United States; base; biological adaptation to stress; calcitonin receptor-like receptor; effective therapy; glycosylation; hypothalamic-pituitary-adrenal axis; knock-down; lentiviral-mediated; mRNA Expression; new therapeutic target; public health relevance; receptor; receptor binding; relating to nervous system; response; stress related disorder; stressor; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Individuals exposed to fear-evoking stressors are at increased risk for a number of psychiatric illnesses including post-traumatic stress disorder, major depressive disorder, and generalized anxiety disorder. These debilitating conditions are among the most significant public health problems facing the United States today. Understanding the central neuropharmacological and molecular mechanisms that drive responses to fear- evoking stressors will enable us to identify points of dysregulation that may contribute to development of stress-related disorders and also identify targets for the development of effective treatment options. The bed nucleus of the stria terminalis, which has recently emerged as an important component of stress regulation circuitry, contains dense terminals that release the neuropeptide calcitonin gene-related peptide (CGRP). Very recently, behavioral evidence has implicated CGRP signaling within the BNST in anxiety and also points to the possibility that BNST CGRP may modulate behavioral and neuroendocrine responses to stress. The first goal of this present research, then, is to test the hypothesis that CGRP signaling within the BNST enhances anxiety-like behavioral and hypothalamic-pituitary-adrenal (HPA) axis responses to stress. I will manipulate BNST CGRP signaling using 1) infusion of a CGRP antagonist, 1CGRP8-37 into the BNST via intracranial cannulae and 2) BNST CGRP receptor sensitization by lentiviral-mediated over-expression of RAMP1, the CGRP receptor subunit that confers pharmacological specificity for CGRP and influences glycosylation and trafficking of the CGRP receptor to the cell surface. Following manipulation of BNST signaling, rats will be exposed to a fear-evoking stressor (trimethlythiazoline odor). We will measure fear- and anxiety-like behavior (acoustic startle and defensive freezing), neuroendocrine responses (serum corticosterone and adrenocorticotropin hormone), and changes in mRNA expression of CGRP, and the CGRP receptor components RAMP1 and calcitonin receptor-like receptor (CRLR). Also, because CGRP terminals within the BNST form perisomatic baskets around neurons containing the stress-related neuropeptide corticotropin- releasing factor (CRF), another goal of this research is to determine if CGRP signaling affects activation of BNST CRF-containing neurons to influence anxiety behavior and HPA axis activity. In order to test the hypothesis that BNST CGRP enhances BNST CRF neuron activation to increase CRFr1 receptor signaling in stress-related target structures, rats will be treated with a systemic CRFr1 antagonist (GSK876008) or infected with lentiviral-mediated CRF siRNA to knock down CRF expression within the BNST and then they will be infused with intra-BNST CGRP and tested as described above. The results of these studies could provide the first pieces of evidence to demonstrate BNST CGRP modulation of behavioral and neuroendocrine stress responses and influence on stress-related neurotransmitter signaling pathways. This research may also present a novel therapeutic target in the treatment of stress-related psychiatric disorders. PUBLIC HEALTH RELEVANCE: Individuals exposed to fear-evoking stressors are at increased risk for a number of psychiatric illnesses including post-traumatic stress disorder, major depressive disorder, and generalized anxiety disorder. The bed nucleus of the stria terminalis (BNST), which contains numerous calcitonin gene-related peptide (CGRP) immunopositive terminals, has recently been identified as a pivotal relay of cortical information to neural structures mediating behavioral and neuroendocrine responses to stress. The proposed research will investigate the role of CGRP signaling within the BNST in fear- and anxiety-like behavioral and neuroendocrine stress responses, and may present a novel therapeutic target in the treatment of stress-related psychopathologies.

描述（由申请人提供）：暴露于恐惧的压力源的个人患有多种精神病患者的风险增加，包括创伤后应激障碍，重度抑郁症和普遍焦虑症。这些使人衰弱的状况是当今美国面临的最重要的公共卫生问题之一。了解推动对恐惧压力源的反应的中心神经药理学和分子机制将使我们能够识别失调点，这可能有助于与压力相关疾病的发展，并确定开发有效治疗方案的目标。最近已成为应力调节回路的重要组成部分的质末端的床核包含释放神经肽降钙素基因相关肽（CGRP）的致密末端。最近，行为证据牵涉到BNST内的CGRP信号传导，也指出了BNST CGRP可能调节对压力的行为和神经内分泌反应的可能性。因此，本研究的第一个目标是检验以下假设：BNST内的CGRP信号传导增强了焦虑样的行为和下丘脑 - 垂体 - 肾上腺肾上腺（HPA）轴对压力的响应。我将使用1）通过颅内插管将CGRP拮抗剂，1CGRP8-37输注到BNST中，并通过颅内插管和2）BNST CGRP受体敏感性通过慢性介导的RAMP 1的过表达来处理BNST CGRP8-37，对CGRP受体亚基的过表达，对CGRP受体的特异性和GGRP的特异性影响，并CGRP受体到细胞表面。操纵BNST信号后，大鼠将暴露于令人恐惧的胁迫源（三甲乙烷气味）。我们将衡量恐惧和焦虑般的行为（声音惊吓和防御性冻结），神经内分泌反应（血清皮质酮和肾上腺皮质激素激素）以及CGRP的mRNA表达变化以及CGRP受体成分RAMP 1 RAMP 1 RAMP 1 RACKIN蛋白受体受体样受体（CRLR）。另外，由于BNST内的CGRP末端形成了包含与压力相关的神经肽皮质激素释放因子（CRF）周围的神经元周围的perias骨篮子，因此这项研究的另一个目标是确定CGRP信号是否会影响BNST CRF涉及抗焦虑神经元的激活，以影响焦虑行为和HPA轴轴和HPA轴的活动。为了测试BNST CGRP增强BNST CRF神经元激活以增加与压力相关的目标结构中CRFR1受体信号传导的假设，将用全身性CRFR1拮抗剂（GSK876008）（GSK876008）处理大鼠，或者用牙齿介导的CRF sirn scress表达，然后将其降低为BN，他们将在BN中表现出来。上面描述。这些研究的结果可以提供第一批证据，以证明对行为和神经内分泌压力反应的BNST CGRP调节以及对与压力相关的神经递质信号通路的影响。这项研究还可能为治疗与压力相关的精神疾病的治疗介绍一个新的治疗靶点。 公共卫生相关性：暴露于恐惧的压力源的人对多种精神病患者的风险增加，包括创伤后应激障碍，重度抑郁症和普遍焦虑症。最近已将降钙素基因相关肽（CGRP）免疫阳性末端的床核（BNST）的床核被鉴定为介导行为和神经内分泌对压力的神经结构的枢纽接送。拟议的研究将研究CGRP信号在BNST在恐惧和焦虑样行为和神经内分泌压力反应中的作用，并可能在治疗与压力相关的心理病理学治疗方面具有新的治疗靶点。