Locus Coeruleus-Norepinephrine System Regulation of Prepulse Inhibition

蓝斑-去甲肾上腺素系统对前脉冲抑制的调节

• 批准号: 7470561
• 负责人: VAISHALI P BAKSHI
• 金额: $ 25.12万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470561
• 关键词: Agonist; Amphetamines; Amygdaloid structure; Animal Model; Antipsychotic Agents; Attention; Attention deficit hyperactivity disorder; Behavior; Bethanechol; Catecholamines; Clozapine; Cognitive; Computer information processing; Data; Disease; Disruption; Dopamine; Dose; Employee Strikes; Fire - disasters; Functional disorder; Goals; Haloperidol; Hippocampus (Brain); Human; Infusion procedures; Knowledge; Maps; Measures; Mediating; Mental disorders; Methods; Motor; Nature; Neurobiology; Neurons; Norepinephrine; Norepinephrine Receptors; Numbers; Obsessive-Compulsive Disorder; Organism; Pathology; Patients; Pharmaceutical Preparations; Phencyclidine; Play; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Primates; Process; Prosencephalon; Psychotropic Drugs; Public Health; Range; Rattus; Regulation; Research Personnel; Resources; Rodent; Rodent Model; Role; Schizophrenia; Sensory; Serotonin; Shapes; Site; Source; Specificity; Stimulus; Structure; Structure of terminal stria nuclei of preoptic region; System; Techniques; Testing; Thalamic structure; Tic disorder; Traumatic Stress Disorders; United States; atypical antipsychotic; behavioral pharmacology; clinically relevant; design; endophenotype; improved; information display; insight; locus ceruleus structure; neurochemistry; norepinephrine system; novel; prepulse inhibition; prevent; programs; receptor; relating to nervous system; research study; response; selective attention; theories; transmission process

DESCRIPTION (provided by applicant): Project Summary: Prepulse inhibition (PPI) represents a powerful method for understanding a fundamental component of information-processing, sensorimotor gating. PPI refers to the diminution of the startle response when a sudden startling stimulus is preceded 30-500 ms by a barely detectable prestimulus. This basic form of startle plasticity, seen across species from rodents to primates, has been studied extensively as an exemplar of preattentional sensory 'filters' that defend cognitive processes against the information inundation of our sensory world. A prominent theory holds that dysfunction in these filtering systems represents a core endophenotype manifested in schizophrenia, obsessive compulsive disorder, tic disorders, and possibly attention deficit hyperactivity disorder and post traumatic stress disorder. Patients suffering from this diverse range of illnesses share the common feature of an inability to screen out sensory, motor, or cognitive information, and display markedly deficient PPI. Because PPI deficits can be studied across species, PPI has become well-established as a crucial paradigm with which to study deficient sensorimotor gating in animal models of these psychiatric disorders. Much information has accrued regarding the neurochemical systems and circuits underlying PPI, particularly regarding the role of the dopamine and serotonin systems. Nevertheless, there is a striking gap in knowledge about the role of the norepinephrine (NE) system in regulating PPI. Our preliminary evidence indicates that this catecholamine plays a fundamental role in the ability of phencyclidine-like drugs (potent psychotomimetics in humans) to disrupt PPI in rodent models and the unique ability of atypical antipsychotic medications to reverse these PPI deficits. In addition, we have recently discovered that pharmacologically activating the locus coeruleus (LC), the major source of forebrain norepinephrine, markedly disrupts PPI. These data indicate that the LC-NE system represents a critical, yet almost completely overlooked central modulator of PPI. The experiments outlined in this proposal are designed to systematically characterize the role of the LC and its NE-innervated forebrain targets in regulating PPI, and in mediating the actions of psychotomimetic and antipsychotic drugs on PPI. These data may provide insights into novel circuitries underlying the regulation of PPI, and be of great relevance to understanding the neurobiology of the large set of psychiatric disorders of which dysfunctional sensorimotor gating is a central feature. Relevance to Public Health: Information-processing deficits are a major part of several psychiatric illnesses such as schizophrenia. When totaled, these illnesses represent a staggering 9-10% of the United States population. This proposal will study the neurobiology of the information-processing deficits seen in illnesses like schizophrenia in order to ultimately develop new treatments for these diseases.

描述（申请人提供）：项目摘要：Prepulse抑制（PPI）代表了一种理解信息处理，感觉运动门控的基本组成部分的有力方法。 PPI是指突然惊人的刺激在30-500毫秒之前通过几乎无法检测到的prestimulus之前的突然刺激刺激的减少。从啮齿动物到灵长类动物的物种中，这种惊吓可塑性的这种基本形式已被广泛研究为捍卫认知过程的严重感觉“过滤器”的典范，以防止我们的感觉世界的信息淹没。一个突出的理论认为，这些过滤系统的功能障碍代表了精神分裂症，强迫症，抽动疾病以及可能注意力缺陷多动障碍和创伤后应激障碍的核心内表型。患有多种疾病的患者具有无法筛查感觉，运动或认知信息的共同特征，并表现出明显缺乏的PPI。由于可以在各种物种之间研究PPI缺陷，因此PPI已成为重要的范式，以研究这些精神疾病的动物模型中的感觉运动失调。关于PPI潜在的神经化学系统和电路的大量信息，特别是关于多巴胺和5-羟色胺系统的作用。然而，关于去甲肾上腺素（NE）系统在调节PPI中的作用的知识存在明显的差距。我们的初步证据表明，这种儿茶酚胺在苯基二酮样药物（人类中有效的精神病患者）中破坏啮齿动物模型中PPI的能力以及异常抗精神病药逆转这些PPI缺陷的独特能力。此外，我们最近发现，药理学激活前脑去甲肾上腺素的主要来源（LC）显着破坏了PPI。这些数据表明，LC-NE系统代表了PPI的关键但几乎完全被忽略的中央调节器。该提案中概述的实验旨在系统地表征LC及其NE造成的前脑靶标在调节PPI中的作用，以及介导精神病和抗精神病药对PPI的作用。这些数据可能会提供对PPI调节基础的新型电路的见解，并且与理解大量精神疾病的神经生物学具有很大相关性，其功能失调的感觉运动门控是一个核心特征。与公共卫生的相关性：信息处理缺陷是精神分裂症等几种精神病疾病的主要部分。当总计时，这些疾病占美国人口的惊人9-10％。该建议将研究精神分裂症等疾病中信息处理缺陷的神经生物学，以最终为这些疾病开发新的治疗方法。