Stress and CRF System Effects on Information Processing

压力和 CRF 系统对信息处理的影响

• 批准号: 7231338
• 负责人: MARK A GEYER
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231338
• 关键词: Acute; Affect; Affinity; Agonist; Anxiety; Anxiety Disorders; Behavior; Behavioral; Binding; Brain; Brain region; CRF receptor type 2; Cerebrospinal Fluid; Characteristics; Chemosensitization; Chronic; Clinical Research; Computer information processing; Corticotropin; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; DSM-IV; Data; Dependence; Diagnostic; Disease; Disruption; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Exhibits; FPS-FES Oncogene; Family; Figs - dietary; Fright; Future; Gene Deletion; Goals; Hormones; Intervention; Knock-out; Ligands; Link; Maintenance; Manuals; Measures; Mediating; Mental disorders; Modeling; Mus; Mutant Strains Mice; Neurons; Neuropeptide Gene; Neuropeptides; Neurosecretory Systems; Numbers; Organism; Panic; Panic Disorder; Partner in relationship; Pathology; Patients; Phase; Phenotype; Physiological; Post-Traumatic Stress Disorders; Principal Investigator; Process; Prosencephalon; RRM1 gene; RRM2 gene; Receptor Activation; Receptor Signaling; Recovery; Relative (related person); Reporting; Residual state; Resources; Rodent; Role; Sensory; Shock; Signal Transduction; Stimulus; Stress; Synapses; System; Testing; Time; Transgenes; Traumatic Stress Disorders; Viral; antisauvagine 30; base; biological adaptation to stress; computerized data processing; cortagine; desensitization; foot; hypothalamic-pituitary-adrenal axis; nestin protein; neuropsychiatry; novel; prepulse inhibition; promoter; receptor; relating to nervous system; release factor; research study; response; stressor; urocortin

DESCRIPTION (provided by applicant): The goal of this project is to use murine models to elucidate the mechanisms underlying the effects of stress and the neuropeptide corticotropin releasing factor (CRF) on information processing and response inhibition. Across species, presentation of a neutral, non-startling "prepulse" 30-300 ms before a startling stimulus reduces startle magnitude, termed prepulse inhibition (PPI), theoretically by requiring the organism to allocate attentional resources to process the prepulse and hence filter or "gate" the subsequent startling stimulus. PPI is used clinically as an operational measure of sensorimotor gating that is deficient in a number of neuropsychiatric disorders. Certain anxiety disorders, post-traumatic stress disorder (PTSD) and panic disorder (PD), exhibit deficits in PPI. These disorders also appear to exhibit pathology in the CRF system, either CRF hypersecretion or increased receptor signaling. CRF is a neuropeptide that coordinates many behavioral and neuroendocrine responses to stress via activation of 2 known receptor subtypes, CRF-R1 and CRF-R2. Over-expression of CRF or exogenous administration of CRF in rodents reduces PPI, mimicking the PPI deficits observed in PTSD and PD patients. CRF-induced deficits in PPI in mice appear to be mediated via CRF-R1 receptors while CRF-R2 receptors have opposing effects. To guide future clinical studies of the roles of CRF systems in PTSD and PD, experiments in mice are proposed to elucidate the role of CRF receptors in stress-induced deficits in PPI, and to clarify how these receptors modulate PPI when chronically activated. This project tests hypotheses based on a novel model of relative CRF-R1 and CRF-R2 receptor signaling processes in response to normal and pathological CRF release. Aim 1 identifies the respective contributions of CRF and dopamine receptors in CRF effects on PPI. Aim 2 identifies the CRF receptor mechanisms underlying shock stress effects on startle and PPI. Aim 3 assesses the contribution of CRF-R2 receptors and endogenous ligands to the maintenance of and recovery from CRF-induced deficits in PPI. Aim 4 assesses the neuroanatomical substrates contributing to both acute CRF and chronic CRF effects on information processing. These studies are critical for our basic understanding of the mechanisms of stress effects on information processing and response inhibition, and will elucidate new receptor targets for pharmacotherapeutic intervention in anxiety disorder patients exhibiting information processing deficits.

描述（由申请人提供）：该项目的目的是使用鼠模型来阐明压力和神经肽皮质激素释放因子（CRF）对信息处理和响应抑制的影响。在整个物种中，在惊人的刺激前30-300毫秒的中性，非开始的“预硫”呈现减少了惊吓幅度，从理论上讲称为Prepulse抑制（PPI），这是要求生物体分配注意力资源以处理预硫酸盐的临时资源来处理预硫酸盐，并因此进行过滤或闸门或“门”，然后“门”。 PPI在临床上用作感觉运动门控的操作量度，在许多神经精神疾病中缺乏。某些焦虑症，创伤后应激障碍（PTSD）和恐慌症（PD）在PPI中表现出缺陷。这些疾病在CRF系统中似乎也表现出病理，无论是CRF过度分泌还是受体信号增加。 CRF是一种神经肽，通过激活2种已知的受体亚型CRF-R1和CRF-R2来协调许多行为和神经内分泌对压力的反应。 CRF或啮齿动物中CRF的外源给药的过表达减少了PPI，模仿了PTSD和PD患者中观察到的PPI缺陷。 CRF诱导的小鼠PPI缺陷似乎是通过CRF-R1受体介导的，而CRF-R2受体具有相反的作用。为了指导CRF系统在PTSD和PD中的作用的未来临床研究，提出了在小鼠中进行实验，以阐明CRF受体在PPI中胁迫引起的缺陷中的作用，并阐明这些受体在长期激活时如何调节PPI。该项目基于对正常和病理CRF释放的新型相对CRF-R1和CRF-R2受体信号传导过程的新模型进行测试。 AIM 1确定了CRF和多巴胺受体对CRF对PPI的影响的各自贡献。 AIM 2识别了惊吓和PPI的冲击应力影响的CRF受体机制。 AIM 3评估CRF-R2受体和内源配体对CRF诱导的PPI缺陷的恢复的贡献。 AIM 4评估了导致急性CRF和慢性CRF对信息处理的影响的神经解剖底物。这些研究对于我们对压力对信息处理和反应抑制的影响的基本理解至关重要，并将阐明新的受体靶标，用于表现出信息处理缺陷的焦虑症患者的药物治疗干预。