ACC Sensitization in Visceral Hypersensitive Rats

描述(申请人提供)：内脏过敏在肠易激综合征(IBS)患者中很常见。前扣带回皮质(ACC)是调节对疼痛和肠道运动功能的情感反应的大脑中枢。人脑成像显示IBS患者ACC对内脏感觉信号的异常处理，但其机制尚不清楚。目前的建议旨在表征ACC神经元的电生理特性，并探讨内脏超敏反应诱导后突触的可塑性。我们假设，对ACC的持续的紧张性内脏伤害性传入可以诱导以突触传递增加为特征的ACC神经元的可塑性。ACC神经元的敏化可能是由于依赖活动的可塑性改变(长时程增强，LTP和长时程抑制，LTD)的结果。这种突触传递的增强导致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性大鼠模型：结肠过敏(卵白蛋白)和结直肠刺激(冰醋酸)。电生理记录单个ACC神经元放电对结直肠扩张的反应，结合反向微透析，直接向神经元树突区注入药物，以显示ACC突触谷氨酸能传递的增强。我们将记录局部场电位，并描述LTP的易化和LTD的丢失，LTP和LTD的丢失是皮层可塑性的关键突触机制，在内脏超敏启动后。我们将探讨增强ACC神经元兴奋性和突触可塑性的机制和细胞内信号事件。最后，我们将表征ACC在痛相关情感加工中的作用，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，可能被证明对于我们理解与内脏高敏感性相关的中枢神经系统异常的病因和治疗至关重要。与公共健康相关：功能性Gl障碍患者通常表现为内脏过敏。本研究旨在了解其发病原因，并为其治疗提供线索。

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.