Central Nervous System Control of Intraocular and Intracranial Pressure

摘要 青光眼是世界范围内导致失明的主要原因，但青光眼视网膜神经节细胞损伤的原因 对视神经头(ONH)的认识还不完全。眼压升高被认为是主要的 引起青光眼，但最近的研究表明，颅内压下降也是导致 青光眼病理生理学。眼压和颅内压是动态的，有证据表明，它们至少部分是 在中枢神经系统(CNS)控制下。了解控制眼压的神经生理机制 而颅内压的变化对于了解青光眼的发病机制和进展是至关重要的。我们的实验室已经证明了 第一次化学刺激下丘脑背内侧及穹隆周围区域 啮齿类动物(DMH/PEF)引起眼压和颅内压升高；然而，两者的时间都有时移 这些措施将达到顶峰。这会导致跨眼压差的变化(即眼压减去颅内压)。 这比单纯眼压或颅内压的变化更大。此外，定义这一中枢神经系统通路和 参与眼压和颅内压调节的神经递质可能为针对青光眼的新疗法提供靶点 来稳定人体的跨层压差。 这项拨款的主要重点是研究控制眼压和颅内压的中枢神经系统通路，这是眼压和颅内压的主要驱动因素。 人体的跨层压差。我们的中心假设是眼压和眼压的中央调节 至少部分地控制了位于DMH/PEF区的神经元。为了测试这一点，我们提出了3个 具体目标：1)我们将对眼压和颅内压的升高进行药理学表征 不同神经递质选择性拮抗剂对DMH/PEF区的立体定向化学刺激 感受器。2)我们将尝试定义中枢神经系统的传入和传出目标 DMH/PEF神经元可能通过局部定向立体定向注射控制眼压和颅内压 刺激中枢神经系统各核团，记录眼压和颅内压的变化。3)我们将审查 某些特定神经递质在调节眼压和颅内压昼夜变化中的作用 使用无线电遥测记录时神经递质系统的基于和基于药物的抑制 眼压和颅内压。

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.