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

这项研究的长期目标是确定如何升高眼内压，一个主要的危险因素， 对于青光眼，影响视觉信号从视网膜到大脑的传递。这是由一种欲望驱动的 为了更好地了解眼内压升高（高眼压症，OHT）和神经元损伤之间的联系， 视网膜神经节细胞（RGC）的功能障碍和变性，以确定新的跟踪手段 疾病进展，早期诊断，预防视力丧失和恢复视力。在青光眼中，OHT 最终通过在RGC轴突离开眼睛并形成视神经时破坏RGC轴突而导致RGC变性 神经。虽然大量的工作已经建立了OHT影响结构的多种方式， 连接和RGC的功能，我们目前对OHT如何改变其功能的理解存在重大差距。 向大脑的视觉区域发出信号。神经系统采用稳态过程， 功能响应不断变化的条件，如发展，学习，或疾病和OHT触发 视神经中RGC及其轴突的变化可能会导致视觉系统的早期自我平衡尝试， 系统保持功能。本提案的目的是检验OHT触发 背外侧膝状体核（dLGN）是大脑接受视觉信号的关键区域， 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。目的2 将检验OHT触发dLGN中神经元兴奋性增加的假设， 神经元活动对轴突功能障碍的反应。最后，在目标3中，我们将确定OHT对 激活TrkB，受体脑源性神经营养因子（BDNF），并测试改变 TrkB激活导致dLGN中神经元兴奋性和突触功能的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，包括诱导和 遗传性OHT小鼠模型，脑片膜片钳电生理学，光遗传学，双光子 显微镜，单细胞树突状细胞分析，轴突示踪标记，定量逆转录PCR， 体内眼部成像。我们的发现将促进我们对神经元和突触稳态的理解， 其机制和揭示的过程中视神经损伤的视力丧失青光眼。

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.