Influence of ocular hypertension on neurons and synapses in the visual thalamus

高眼压对视丘脑神经元和突触的影响

• 批准号: 10165730
• 负责人: Matthew John Van Hook
• 金额: $ 36.98万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165730
• 关键词: Affect; Axon; Behavior; Blindness; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cells; Clinic; Clinical; Data; Development; Disease; Disease Progression; Dorsal; Dyes; Early Diagnosis; Electrophysiology (science); Eye; Functional disorder; Gene Expression; Glaucoma; Gliosis; Glutamate Receptor; Goals; Health; Homeostasis; Inherited; Ion Channel; Ion Channel Gating; Label; Lateral Geniculate Body; Learning; Light; Link; Maintenance; Microspheres; Modeling; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neurotransmitter Receptor; Neurotrophic Tyrosine Kinase Receptor Type 2; Ocular Hypertension; Optic Nerve; Optic Nerve Injuries; Output; Pathologic; Permeability; Physiologic Intraocular Pressure; Play; Probability; Process; Receptor Activation; Research; Retina; Retinal Ganglion Cells; Reverse Transcription; Risk Factors; Role; Savings; Signal Transduction; Slice; Stimulus; Stress; Structure; Synapses; Synaptic Transmission; Synaptic Vesicles; System; Testing; Thalamic structure; Therapeutic; Time; Tracer; Training; Translating; Treatment Factor; Vision; Visual; Visual system structure; Work; axonopathy; experimental study; extrastriate visual cortex; in vivo; modifiable risk; mouse model; neuronal excitability; neurotransmitter release; neurotrophic factor; novel; novel strategies; ocular imaging; optogenetics; patch clamp; preservation; pressure; presynaptic; prevent; receptor expression; relating to nervous system; response; retinal damage; retinal ganglion cell degeneration; sight restoration; synaptic function; two photon microscopy; vesicular release; visual information; voltage

The long-term objective of this research is to determine how elevated intraocular pressure, a major risk factor for glaucoma, influences the conveyance of visual signals from the retina to the brain. This is driven by a desire to better understand the link between elevated intraocular pressure (ocular hypertension, OHT) and neuronal dysfunction and degeneration of retinal ganglion cells (RGCs) in order to identify novel means of tracking disease progression, making earlier diagnoses, preventing vision loss, and restoring sight. In glaucoma, OHT ultimately contributes to RGC degeneration by damaging RGC axons as they exit the eye and form the optic nerve. While a substantial body of work has established the multitude of ways that OHT affects the structure, connectivity, and function of RGCs, there is a major gap in our current understanding of how OHT alters their signaling to visual areas of the brain. Neural systems employ homeostatic processes that stabilize their function in response to changing conditions such as development, learning, or disease and OHT-triggered changes to RGC and their axons in the optic nerve are likely to cause early, homeostatic attempts by the visual system to maintain function. The objective of this proposal is to test the hypothesis that OHT triggers homeostatic plasticity in the dorsal lateral geniculate nucleus (dLGN), a key region of the brain receiving visual information from RGCs. This central hypothesis will be tested with three specific aims. Experiments in Aim 1 will determine the influence of OHT on synaptic transmission by RGCs in the dLGN, testing for changes in presynaptic neurotransmitter release efficiency and post-synaptic neurotransmitter receptor composition. Aim 2 will test the hypothesis that OHT triggers an increase in neuronal excitability in the dLGN that maintains neuronal activity in response to axonal dysfunction. Finally, in Aim 3, we will determine the influence of OHT on activation of TrkB, the receptor brain-derived neurotrophic factor (BDNF) and test the hypothesis that altered TrkB activation leads to OHT-dependent changes in neuronal excitability and synaptic function in the dLGN. To accomplish this, we will employ a diverse combination of technical approaches including inducible and inherited mouse models of OHT, brain slice patch-clamp electrophysiology, optogenetics, two-photon microscopy, single-cell dendritic analyses, axonal tracer labeling, quantitative reverse-transcription PCR, and in vivo ocular imaging. Our findings will advance our understanding of neuronal and synaptic homeostasis and its mechanisms and shed light on the processes linking optic nerve injury to vision loss in glaucoma.

这项研究的长期目标是确定眼压升高这一主要危险因素如何 对于青光眼，影响视觉信号从视网膜到大脑的传递。这是由欲望驱动的 更好地了解眼内压升高（高眼压症，OHT）与神经元之间的联系 视网膜神经节细胞（RGC）的功能障碍和退化，以确定新的追踪方法 疾病进展、早期诊断、预防视力丧失和恢复视力。在青光眼、OHT 当 RGC 轴突离开眼睛并形成视神经时，最终会通过损伤 RGC 轴突而导致 RGC 变性 神经。虽然大量工作已经确定了 OHT 影响结构的多种方式， 尽管我们目前对 OHT 如何改变 RGC 的连接性和功能的理解存在重大差距 向大脑视觉区域发出信号。神经系统采用稳态过程来稳定其神经系统 响应不断变化的条件（例如发育、学习或疾病）以及 OHT 触发的功能 视神经中 RGC 及其轴突的变化可能会导致视觉早期尝试稳态 系统来维持功能。该提案的目的是检验 OHT 触发的假设 背外侧膝状核（dLGN）的稳态可塑性，这是大脑接收视觉的关键区域 来自 RGC 的信息。这一中心假设将通过三个具体目标进行检验。目标 1 中的实验 将确定 OHT 对 dLGN 中 RGC 突触传递的影响，测试 突触前神经递质释放效率和突触后神经递质受体组成。目标2 将检验 OHT 触发 dLGN 中神经元兴奋性增加的假设，从而维持 响应轴突功能障碍的神经元活动。最后，在目标 3 中，我们将确定 OHT 对 激活 TrkB（脑源性神经营养因子 (BDNF) 受体）并检验改变的假设 TrkB 激活导致 dLGN 中神经元兴奋性和突触功能发生 OHT 依赖性变化。到 为了实现这一目标，我们将采用多种技术方法组合，包括诱导法和 OHT 遗传性小鼠模型、脑切片膜片钳电生理学、光遗传学、双光子 显微镜、单细胞树突分析、轴突示踪标记、定量逆转录 PCR 和 活体眼部成像。我们的发现将增进我们对神经元和突触稳态的理解 其机制并揭示了视神经损伤与青光眼视力丧失之间的联系过程。