Locus Coeruleus-Norepinephrine System Regulation of Prepulse Inhibition

描述(由申请人提供)：项目摘要：前脉冲抑制(PPI)是理解信息处理的基本组成部分--感觉运动门控的一种强有力的方法。PPI指的是当突然的令人震惊的刺激在30-500毫秒之前被几乎检测不到的前刺激所引起的惊吓反应的减弱。这种惊吓可塑性的基本形式在从啮齿类动物到灵长类动物的各种物种中都可以看到，它被广泛研究为前注意感觉过滤器的范例，它可以保护认知过程免受我们感官世界信息淹没的影响。一个突出的理论认为，这些过滤系统的功能障碍代表了一种核心的内表型，表现在精神分裂症、强迫症、抽动障碍，可能还有注意力缺陷多动障碍和创伤后应激障碍。患有这种不同疾病的患者有一个共同的特征，即无法筛选出感觉、运动或认知信息，并显示明显的PPI缺陷。由于PPI缺陷可以跨物种研究，PPI已成为研究这些精神疾病动物模型中感觉运动门控缺陷的关键范式。关于PPI背后的神经化学系统和回路，特别是关于多巴胺和5-羟色胺系统的作用，已经积累了很多信息。然而，关于去甲肾上腺素(NE)系统在调节PPI中的作用，人们的认识存在着显著的差距。我们的初步证据表明，这种儿茶酚胺在苯环利定类药物(人类有效的精神分裂药物)扰乱啮齿动物模型中PPI的能力以及非典型抗精神病药物逆转这些PPI缺陷的独特能力中发挥着基础性作用。此外，我们最近发现，药物激活蓝斑(LC)，这是前脑去甲肾上腺素的主要来源，显著扰乱PPI。这些数据表明，LC-NE系统代表了PPI的一个关键的、但几乎完全被忽视的中央调节器。该方案中概述的实验旨在系统地描述LC及其NE神经支配的前脑靶点在调节PPI中的作用，以及在介导精神类药物和抗精神病药物对PPI的作用中的作用。这些数据可能提供对PPI调节的新回路的洞察，并对理解以感觉运动门控功能障碍为中心特征的大量精神障碍的神经生物学具有重要意义。与公共卫生相关：信息处理缺陷是精神分裂症等几种精神疾病的主要组成部分。这些疾病加在一起，占美国人口的9%-10%，令人震惊。这项提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，以最终开发这些疾病的新疗法。

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.