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

这项研究的长期目标是确定眼压升高这一主要危险因素 对于青光眼，会影响视觉信号从视网膜到大脑的传输。这是由一种欲望驱动的 为了更好地了解高眼压(高眼压，OHT)和神经元之间的联系 视网膜神经节细胞(RGC)的功能障碍和变性，以确定新的追踪手段 疾病进展，作出早期诊断，防止视力丧失，恢复视力。青光眼患者，OHT 最终导致RGC变性，因为RGC轴突离开眼睛并形成视神经时受到损害 很有胆量。虽然大量的工作已经确定了OHT影响结构的多种方式， 连接性和RGC的功能，我们目前对OHT如何改变其 向大脑的可视区域发出信号。神经系统使用动态平衡过程来稳定它们的 对不断变化的条件作出反应的功能，如发育、学习或疾病，以及OHT触发 视神经中RGC及其轴突的变化可能导致视觉早期的内稳态尝试 系统维护功能。这项提议的目的是检验OHT触发的假设 大脑接受视觉的关键区域--膝状背外侧核(DLGN)的稳态可塑性 来自RGC的信息。这一核心假设将以三个具体目标进行检验。目标1中的实验 将确定OHT对dLGN中RGCs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 将检验这样的假设，即OHT触发dLGN中神经元兴奋性的增加 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 激活受体脑源性神经营养因子TrkB并检验改变的假说 TrkB的激活导致dLGN神经元兴奋性和突触功能的OHT依赖性改变。至 要实现这一点，我们将采用多种技术方法组合，包括诱导式和 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、轴突示踪剂标记、定量逆转录聚合酶链式反应 活体眼部成像。我们的发现将促进我们对神经元和突触动态平衡的理解 它的机制，并阐明了青光眼视神经损伤与视力丧失之间的联系。

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.