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）是一种强大的方法，用于理解信息处理的基本组成部分，感觉运动门控。PPI指的是当一个突然的惊吓刺激之前30-500 ms有一个几乎检测不到的前刺激时惊吓反应的减弱。这种惊吓可塑性的基本形式，在从啮齿动物到灵长类动物的物种中都可以看到，已经被广泛研究，作为前注意感官“过滤器”的一个范例，它可以保护认知过程免受我们感官世界的信息淹没。一个著名的理论认为，这些过滤系统的功能障碍代表了精神分裂症、强迫症、抽动障碍、注意力缺陷多动障碍和创伤后应激障碍的核心内在表型。患有这些不同疾病的患者具有无法筛选感觉、运动或认知信息的共同特征，并显示明显缺乏PPI。由于PPI赤字可以跨物种研究，PPI已成为一个重要的范例，研究这些精神疾病的动物模型中的感觉运动门控缺陷。关于PPI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，已经积累了许多信息。然而，在去甲肾上腺素（NE）系统在调节PPI中的作用的知识有一个惊人的差距。我们的初步证据表明，这种儿茶酚胺在苯环己哌啶类药物（人类强效拟精神病药物）破坏啮齿动物模型中PPI的能力以及非典型抗精神病药物逆转这些PPI缺陷的独特能力中起着重要作用。此外，我们最近发现，多巴胺激活蓝斑（LC），前脑去甲肾上腺素的主要来源，显着破坏PPI。这些数据表明，LC-NE系统是一个关键的，但几乎完全被忽视的中央调制器的PPI。本提案中概述的实验旨在系统地表征LC及其NE神经支配的前脑靶点在调节PPI中的作用，以及介导拟精神病药物和抗精神病药物对PPI的作用。这些数据可能提供新的电路基础的PPI的监管的见解，并了解功能失调的感觉运动门控是一个中心功能的精神疾病的大集合的神经生物学是非常相关的。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疾病的主要部分。这些疾病总计占美国人口的9-10%。这项提案将研究精神分裂症等疾病中信息处理缺陷的神经生物学，以最终开发出治疗这些疾病的新方法。

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.