HRS targeting of ON and OFF ganglion cells

HRS 靶向 ON 和 OFF 神经节细胞

• 批准号: 8906871
• 负责人: Shelley Fried
• 金额: $ 33.4万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8906871
• 关键词: Action Potentials; Axon; Biophysical Process; Blinded; Brain; Calcium ion; Cell model; Cells; Clinical; Computer Simulation; Development; Devices; Electrodes; Elements; Evaluation; Exhibits; Gated Ion Channel; Goals; Health; Household; Ion Channel; Lead; Light; Macular degeneration; Measures; Mediating; Methods; Mus; Neurons; Ocular Prosthesis; Outcome; Output; Pattern; Physiologic pulse; Physiological; Physiology; Potassium Channel; Process; 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; biophysical properties; blind; cell type; ganglion cell; improved; neural circuit; relating to nervous system; research study; response; retinal neuron; retinal prosthesis; sodium ion; voltage

DESCRIPTION (provided by applicant): 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 remais 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 uA (baseline) to 60 uA over the course of 150 ms followed by a return to 40 uA 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.

描述（由申请人提供）：视网膜假肢努力将视力恢复到被视网膜外疾病（例如黄斑变性和色素性视网膜炎）盲目的视力。 近年来，关于以前盲人识别家庭对象的报道，通过不熟悉的景观甚至阅读以有限的方式导航。 尽管取得了这种进步，但引起视觉的总体质量仍然有些有限。 例如，即使是最快的主题，每分钟只能读几个简单的单词，并且所有受试者的平均阅读率都大大降低。 另外，这些设备的分辨率通常远低于电极间距预测的分辨率。 被认为降低假肢质量的因素之一是用于刺激视网膜神经元的方法。 在健康的视网膜中，大约有十几种不同类型的神经节细胞（视网膜输出神经元）使用不同的信号模式与大脑进行通信。 例如，在神经节细胞上，在静止刺激的开始时会产生尖峰的爆发，而在静止的细胞中，甚至减少了尖峰（如果存在非零基线速率）。 相比之下，被认为是在许多神经节细胞中产生高度相似的尖峰模式的刺激，包括同时开关的神经节细胞，从而将信号传递给大脑，这是非生理学的。 最近，我们测试了一系列振幅调节的波形：每秒2000脉冲（PPS）恒定振幅序列，并偶尔增加（或减小）振幅的增加（或减小），即在150 ms的过程中从50 UA（基线）增加到60 UA，然后在随后的150毫秒内返回40 UA。 正如预期的那样，这种波形引起了每次瞬态增加的BT细胞中的尖峰爆发。 但是，令人惊讶的是，OFF BT细胞的反应完全不同，包括刺激振幅瞬时增加的尖峰降低。 因此，相同的刺激波形引起了尖峰在短暂的（BT）细胞上的尖峰，并且同时减少了OFF BT细胞的尖峰。 这与这两种细胞类型的生理反应模式非常匹配，从而提出了这种方法可能比现有刺激方法具有优势的可能性。 我们在此提案中的目标是通过探索它们对刺激参数的敏感性，以优化基础刺激过程来进一步研究这些差异。 其他初步实验表明，对2000 pps的响应起源于神经节细胞（即，它不是由突触回路介导的）。 因此，我们假设响应差异是由神经节细胞类型之间的固有差异引起的，这可能是轴突初始段（AIS）内的差异。 因此，我们将研究各种类型的AIS差异，以开发可用于理解并希望进一步增强响应差异的准确计算模型。 最后，我们还将研究随着视网膜退化而随着视网膜变性的变化以及潜在的生物物理特征如何变化。