Central Nervous System Control of Intraocular and Intracranial Pressure

摘要 青光眼是世界范围内致盲的主要原因，但青光眼患者中视网膜神经节细胞损伤的原因是： 视神经乳头（optic nerve head，ONH）尚未完全了解。眼内压（IOP）升高被认为是主要的 青光眼的病因，但最近的研究表明，降低颅内压（ICP）也有助于 青光眼病理生理学IOP和ICP是动态的，有证据表明它们至少部分地 在中枢神经系统（CNS）控制下。了解控制IOP的神经生理学机制 颅内压的变化是了解青光眼发病机制和进展的关键。我们的实验室已经证明 化学刺激下丘脑背内侧区和穹窿周围区 (DMH/PeF）引起IOP和ICP增加;然而， 这些措施的高峰。这导致跨ONH压差（即IOP减去ICP）的变化 这比单独的IOP或ICP的变化更大。此外，定义这种CNS途径和 参与IOP和ICP调节的神经递质可能为新的青光眼治疗提供靶点， 稳定人体跨椎板压差的能力 这项资助的主要重点是检查控制IOP和ICP的CNS通路，这是IOP和ICP的主要驱动因素。 人体的跨层压差。我们的中心假设是IOP的中枢调节和 ICP至少部分地由位于DMH/PeF区域的神经元控制。为了验证这一点，我们提出了3 具体目标：1）我们将对在定点治疗后IOP和ICP的增加进行定性分析。 使用各种神经递质的选择性拮抗剂对DMH/PeF区域进行立体定位化学刺激 受体。2)我们将试图定义中枢神经系统的传入输入和传出目标的 DMH/PeF神经元可能通过使用定向立体定位显微注射来控制IOP和ICP， 刺激中枢神经系统的各个核团，记录IOP和ICP的变化。3)我们将研究 某些特定的神经递质在调节IOP和ICP昼夜变化中的作用， 基于和基于药理学的神经递质系统抑制，同时使用无线电遥测记录 IOP和ICP。

Abstract Glaucoma is a leading cause of blindness worldwide, yet the reason for retinal ganglion cell damage within the optic nerve head (ONH) is not fully understood. Elevated intraocular pressure (IOP) is considered the primary cause of glaucoma, but recent studies suggest that decreased intracranial pressure (ICP) also contributes to glaucoma pathophysiology. IOP and ICP are dynamic, and evidence suggests that they are at least partially under central nervous system (CNS) control. Understanding the neurophysiologic mechanisms that control IOP and ICP variations is critical to understanding glaucoma pathogenesis and progression. Our lab has shown for the first time that chemical stimulation of the dorsomedial hypothalamus and surrounding perifornical area (DMH/PeF) in rodents evokes increases in IOP and ICP; however, there is a temporal shift in the time for each of these measures to peak. This results in a change in the trans-ONH pressure difference (i.e. IOP minus ICP) that is greater than the change in IOP or ICP alone. Further, defining this CNS pathway and the neurotransmitters involved in IOP and ICP regulation may provide targets for novel glaucoma therapies aimed at stabilizing the human translaminar pressure difference. The primary focus of this grant is to examine the CNS pathways controlling IOP and ICP, the primary drivers of the translaminar pressure difference in humans. Our central hypothesize is that central regulation of IOP and ICP is controlled, at least in part, neurons located in the DMH/PeF region. To test this we have proposed 3 specific aims: 1) We will pharmacologically characterize the increases in IOP and ICP after site-directed stereotaxic chemical stimulation of the DMH/PeF region using selective antagonists to various neurotransmitter receptors. 2) We will attempt to define the central nervous system afferent inputs to and efferent targets of the DMH/PeF neurons that might control IOP and ICP by using site-directed stereotaxic microinjections to stimulate various central nervous system nuclei and record the changes in IOP and ICP. 3) We will examine the role of certain specific neurotransmitters in regulating circadian changes in IOP and ICP by molecular- based and pharmacologic-based inhibition of the neurotransmitter system while using radio-telemetry to record IOP and ICP.