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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

基本信息

批准号：
10636824
负责人：
Matthew John Van Hook
金额：
$ 38.13万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636824
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 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 Work axonopathy experimental study extrastriate visual cortex in vivo modifiable risk mouse model neural neuronal excitability neurotransmitter release neurotrophic factor novel novel strategies ocular imaging optogenetics patch clamp postsynaptic preservation pressure presynaptic prevent receptor expression response retinal damage retinal ganglion cell degeneration sight restoration synaptic function two photon microscopy vesicular release visual information voltage

项目摘要

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.

本研究的长期目标是确定眼压升高这一主要的危险因素是如何引起的