HRS targeting of ON and OFF ganglion cells

HRS 靶向 ON 和 OFF 神经节细胞

• 批准号: 8561456
• 负责人: Shelley Fried
• 金额: $ 34.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8561456
• 关键词: Action Potentials; Axon; Blinded; Brain; Calcium ion; Cell model; Cells; Clinical; Computer Simulation; Degenerative Disorder; Development; Devices; Electrodes; Elements; Evaluation; Exhibits; Gated Ion Channel; Goals; Household; Ion Channel; Lead; Light; Macular degeneration; Measures; Mediating; Methods; Mus; Neurons; Outcome; Output; Pattern; Physiologic pulse; Physiological; Physiology; Potassium Channel; Process; Property; Prosthesis; Pulse Rates; Reading; Reporting; Resolution; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Retinitis Pigmentosa; Scheme; Series; Shapes; Signal Transduction; Stimulus; Testing; Training; Vision; blind; cell type; ganglion cell; improved; neural circuit; public health relevance; relating to nervous system; research study; response; retinal neuron; sodium ion; voltage

Retinal prosthetics strive to restore vision to those blinded by outer retinal diseases such as macular degeneration and retinitis pigmentosa. There has been considerable progress in recent years with reports of previously-blind subjects identifying household objects, navigating in limited ways through unfamiliar landscapes and even reading. Despite this progress however, the overall quality of elicited vision is still remains somewhat limited. For example, even the fastest subjects can only read a few simple words per minute and the average reading rate across all subjects is considerably lower. In addition, the resolution from these devices is typically much lower than that predicted by electrode spacing. One of the factors thought to reduce the quality of prosthetic vision is the methods utilized to stimulate retinal neurons. In the healthy retina, approximately a dozen different types of ganglion cells (retinal output neurons) each utilize different signaling patterns to communicate with the brain. For example, ON ganglion cells generate bursts of spiking at the onset of a light stimulus while OFF cells are silent or even reduce spiking (if a non-zero baseline rate is present). In contrast, stimulation from prosthetic electrodes is thought to create highly similar patterns of spiking in many ganglion cells, including both ON and OFF ganglion cells simultaneously and thus transmit a signal to the brain that is non-physiological. Recently, we tested a series of amplitude-modulated waveforms: 2000 pulse per second (PPS) constant-amplitude train with an occasional increase (or decrease) in amplitude, i.e. an increase from 50 ¿A (baseline) to 60 ¿A over the course of 150 ms followed by a return to 40 ¿A over the subsequent 150 ms. As expected, such waveforms elicited bursts of spikes in ON BT cells for each occurrence of the transient increase. Surprisingly however, responses in OFF BT cells were quite different and consisted of a reduction in spiking during the transient increase in stimulus amplitude. Thus the same stimulus waveform elicits an increase in spiking in ON brisk transient (BT) cells and a simultaneous decrease in spiking in OFF BT cells. This closely matches the physiological response pattern for these two cell types raising the possibility that this approach may have advantages over existing stimulation methods. Our goal in this proposal is to investigate these differences further by exploring their sensitivity to the parameters of stimulation with the goal of optimizing the underlying stimulation process. Additional preliminary experiments indicate that the response to 2000 PPS originates in the ganglion cell (i.e. it is not mediated by the synaptic circuitry). Therefore, we hypothesize that the response differences arise from intrinsic differences across ganglion cell types probably differences within the axon initial segment (AIS). Therefore, we will study the AIS differences across types in order to develop accurate computational models that can be used to understand and hopefully further enhance the response differences. Finally, we will also study how both responses as well as the underlying biophysical features change as the retina degenerates. 1

视网膜修复术致力于恢复视力，以那些失明的外部视网膜疾病，如黄斑变性 和视网膜色素变性。近年来有相当大的进展， 受试者识别家庭物品，在不熟悉的风景中以有限的方式导航，甚至阅读。 然而，尽管取得了这些进展，但诱发视觉的总体质量仍然有些有限。比如说， 即使是最快的受试者每分钟也只能阅读几个简单的单词， 主题相当低。此外，这些设备的分辨率通常远低于 由电极间距预测。其中一个因素被认为是降低质量的假肢视觉的方法 用于刺激视网膜神经元。在健康的视网膜中，大约有十几种不同类型的神经节细胞 视网膜神经元（视网膜输出神经元）各自利用不同的信号模式与大脑进行通信。例如在 神经节细胞在光刺激开始时产生脉冲，而OFF细胞是沉默的，甚至减少 尖峰（如果存在非零基线速率）。相比之下，来自假体电极的刺激被认为会产生 许多神经节细胞中高度相似的尖峰模式，包括同时开启和关闭的神经节细胞 从而向大脑传递非生理信号。最近，我们测试了一系列调幅 波形：2000脉冲每秒（PPS）恒定幅度序列，偶尔增加（或减少） 振幅，即在150 ms的过程中从50 <$A（基线）增加到60 <$A，然后返回到40 <$A 如预期的，这样的波形在ON BT小区中引起尖峰的突发， 出现一过性升高。然而，令人惊讶的是，OFF BT细胞中的反应是完全不同的， 包括在刺激幅度的瞬时增加期间尖峰的减少。同样的刺激 波形elevented增加尖峰在ON轻快瞬态（BT）细胞和同时减少尖峰在 关闭BT细胞。这与这两种细胞类型的生理反应模式非常吻合， 这种方法可能优于现有的刺激方法。我们在这个提案中的目标是 通过探索它们对刺激参数的敏感性来进一步研究这些差异， 优化潜在的刺激过程。进一步的初步实验表明，对2000年 PPS起源于神经节细胞（即它不受突触电路的介导）。因此，我们假设 反应的差异来自于神经节细胞类型之间的内在差异，可能是神经节细胞内的差异。 轴突起始段（AIS）。因此，我们将研究不同类型的AIS差异，以制定准确的 计算模型，可以用来理解，并希望进一步提高响应差异。 最后，我们还将研究如何反应以及潜在的生物物理特征的变化，作为视网膜 堕落 1