Infrared Photoactivation of Inner-Ear Hair Cells

描述（由申请人提供）：我们最近已经表明，脉冲红外辐射（IR）施加到半规管嵴壶腹在体内引起戏剧性的和高度可控的一级传入神经元的反应。许多传入相位锁定到刺激，并为每个IR脉冲激发动作电位。这允许IR刺激用于控制由第8神经传递到大脑的动作电位的时间和速率。即使在长期刺激下，细胞反应也是稳健的。我们在体外使用心肌细胞的数据表明，IR引起线粒体Ca 2+通量通过单向转运体和Na+/Ca 2+交换。目前尚不清楚线粒体IR兴奋性是否也是毛细胞感觉上皮对IR敏感性的基础，或者是否有其他机制在起作用。IR的作用机制将通过检查4个具体目标来确定。我们将1）在广泛的参数空间内建立脉冲IR和热的剂量反应函数，2）量化细胞电生理和[Ca 2 +]对IR的反应，3）记录传入神经末梢的突触后电位和电流，由IR施加到毛细胞，和4）检查IR兴奋性的线粒体成分。结果有望确定毛细胞红外光敏性的基本机制。了解该机制将对脉冲IR如何用于基础科学产生直接影响（例如，诱发线粒体Ca 2+瞬变与膜去极化电流）。研究结果也有可能对开发新的IR治疗干预措施和利用IR作用机制的假体装置产生重大影响。

DESCRIPTION (provided by applicant): We have recently shown that pulsed infrared radiation (IR) applied to the semicircular canal crista ampullaris in vivo evokes dramatic and highly controllable responses of first order afferent neurons. Many afferents phase lock to the stimulus and fire an action potential for each IR pulse. This allows IR stimuli to be used to control the timing and rate of action potentials transmitted by the 8th nerve to the brain. The cellular response is robust, even under long-term stimulation. Our in vitro data using cardiomyocytes indicates that IR evokes mitochondrial Ca2+ flux via the uniporter and the Na+/Ca2+ exchanger. It is not know if mitochondrial IR excitability also underlies the exquisite sensitivity of hair-cell sensory epithelia to IR, or if some other mechanism is at play. The mechanism of IR action will be determined through examination of 4 specific aims. We will 1) establish dose-response functions for pulsed IR and heat across a broad parameter space, 2) quantify cellular electrophysiological and [Ca2+] responses to IR, 3) record postsynaptic potentials and currents in afferent nerve endings evoked by IR applied to hair cells, and 4) examine the mitochondrial component of IR excitability. Results are expected to determine the fundamental mechanism of IR photosensitivity in hair cells. Knowing the mechanism will have immediate impact on how pulsed IR is used for basic science (e.g. to evoke mitochondrial Ca2+ transients vs. membrane depolarizing currents). Results also have potential for significant impact on the development of new IR therapeutic interventions and prosthetic devices that take advantage of the mechanism of IR action.