ACC Sensitization in Visceral Hypersensitive Rats

内脏过敏大鼠的 ACC 致敏作用

• 批准号: 7033745
• 负责人: YING LI
• 金额: $ 34.2万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033745
• 关键词: avoidance behavior; brain; depression; hypersensitivity; lead; learning; long term potentiation; neural transmission; neurons; pain; role

DESCRIPTION (provided by applicant): Visceral hypersensitivity is common among patients with irritable bowel syndrome (IBS). The anterior cingulate cortex (ACC) is a brain center which mediates affective responses to pain and gut motor function. Imaging of the human brain indicates abnormal processing of visceral sensory signals by the ACC in IBS patients, however the mechanism is unknown. The current proposal is designed to characterize the electrophysiological properties of ACC neurons, and to explore the synaptic plasticity following the induction of visceral hypersensitivity. We hypothesize that persistence of a heightened tonic visceral afferent nociceptive input to the ACC induces ACC neuronal plasticity characterized by an increase in synaptic transmission. The sensitization of ACC neurons may occur as a result of alteration of activity-dependent plasticity (long-term potentiation, LTP and long-term depression, LTD). This heightened synaptic transmission leads to a reduction in pain threshold and an amplification of affective responses to pain. To test this hypothesis, we plan to use two visceral hypersensitive rat models: colonic anaphylaxis (egg albumin) and colorectal irritation (acetic acid). Electrophysiological recording of single ACC neuronal spike firing in response to colorectal distension will be combined with reversal microdialysis to directly infuse drugs to the dendritic area of neurons to demonstrate the enhancement of synaptic glutamatergic transmission in the ACC. We will record the local field potential and characterize the facilitation of LTP and loss of LTD, a key synaptic mechanism of cortical plasticity, following initiation of visceral hypersensitivity. The mechanisms and intracellular signal events underlying the enhanced ACC neuronal excitability and synaptic plasticity will be explored. Finally, we will characterize the role of ACC in pain-related affective processing and elucidate the cellular mechanisms in the induction of learning and memory in ACC neurons. Understanding the processes that lead to ACC neuronal plasticity and its consequences in pain anticipation that precedes avoidance behavior may prove vital to our understanding of the etiology and treatment of CNS abnormalities associated with visceral hypersensitivity. Relevance to public health: Patients with functional Gl disorders commonly demonstrate visceral hypersensitivity. This study seeks to understand the causes and provide clues for the treatment of this condition.

描述（由申请人提供）：内脏超敏反应在肠易激综合征（IBS）患者中很常见。前扣带皮层（ACC）是介导对疼痛的情感反应和肠道运动功能的脑中心。人脑成像显示IBS患者ACC对内脏感觉信号的异常处理，但机制尚不清楚。本实验旨在研究ACC神经元的电生理特性，并探讨内脏高敏感性诱导后的突触可塑性。我们推测，持续的高紧张性内脏传入伤害性输入到ACC诱导ACC神经元可塑性的特点是增加突触传递。ACC神经元的敏化可能是活动依赖性可塑性（长时程增强，LTP和长时程抑制，LTD）改变的结果。这种增强的突触传递导致疼痛阈值的降低和对疼痛的情感反应的放大。为了验证这一假设，我们计划使用两种内脏过敏大鼠模型：结肠过敏反应（卵白蛋白）和结肠直肠刺激（乙酸）。通过电生理记录单个ACC神经元对结直肠扩张的反应，结合反向微透析，将药物直接注入神经元的树突区域，以证明ACC中突触突触突触能传递的增强。我们将记录局部场电位，并表征LTP的易化和LTD的丧失，LTD是皮层可塑性的关键突触机制，内脏高敏感性开始后。ACC神经元兴奋性和突触可塑性增强的机制和细胞内信号事件将被探讨。最后，我们将描述ACC在疼痛相关的情感处理中的作用，并阐明ACC神经元诱导学习和记忆的细胞机制。了解导致ACC神经元可塑性的过程及其在回避行为之前的疼痛预期中的后果可能对我们理解与内脏高敏感性相关的CNS异常的病因和治疗至关重要。与公共卫生的相关性：功能性GI疾病患者通常表现出内脏高敏感性。这项研究旨在了解原因，并为治疗这种疾病提供线索。