Pulsed infrared excitability of inner ear: molecular mechanisms and therapeutics

 描述（由申请人提供）：我们已经证明脉冲红外辐射（IR）利用内耳细胞的内源敏感性，并且不需要对细胞进行药理学或遗传操作。大鼠新生前庭和螺旋神经节神经元对细胞内 [Ca]i 瞬变做出反应，该瞬变可能是由 2 个红外脉冲夹带的。药理学数据进一步表明，IR 可能会激活内质网 Ca2 释放，并且强烈依赖于线粒体 Ca2 循环，并且即使在不含 Ca22 的细胞外溶液中，这种反应也会持续存在。我们将检查 ER 和线粒体对脉冲 IR 的反应。结果将提供关于 IR 神经元兴奋性和关键细胞内 Ca2 储存在 IR 影响中的功能作用的重要新信息。这些知识将适用于各种细胞类型，包括毛细胞和神经元。细胞内细胞器和信号通路的精确光控制可以激发或抑制单个神经元活动，无需化学修饰，可以在神经科学中提供直接的高影响力应用。阐明细胞内 Ca2+ 在内耳突触突触传递中的作用将为理解其在维持生理功能和病理学中的作用奠定基础。我们还将开发新的光学探针，用于局部刺激内耳毛细胞和神经元。最后，我们将在体内检查红外线诱发的前庭眼球运动和肌源性反应，并将探索对未来神经假体应用有效且安全的激光参数。研究结果将带来红外光刺激在基础科学中的新应用，并可能使患有前庭损失、听力损失、耳鸣和疼痛的患者受益。这种光刺激技术将极大地增强内耳领域的研究，并可能在神经科学中具有广泛的应用。

 DESCRIPTION (provided by applicant): We have shown that pulsed infrared radiation (IR) utilizes endogenous sensitivity of cells in the inner ear and does not require pharmacological or genetic manipulation of the cells. Rat neonatal vestibular and spiral ganglion neurons responded with intracellular [Ca]i transients that could be entrained by the 2+ infrared pulses. Pharmacological data further show that IR likely activates the endoplasmic reticulum Ca2+ release with strong dependence on mitochondrial Ca2+ cycling, and the responses persist even in Ca2+-free extracellular solution. We will examine responses of ER and mitochondria to pulsed IR. Results will provide significant new information about IR neuronal excitability and functional role of key intracellular Ca2+ stores in the effects of IR. This knowledge will apply across cell types, including hair cells and neurons. The precise photocontrol of intracellular organelles and signaling pathways with the possibility to excite or inhibit individual neuron activity, without chemical modifications, could provide immediate high impact applications in neuroscience. Clarifying the role of intracellular Ca2+ in synaptic transmission in inner ear synapses will lay the groundwork for understanding its role in maintaining physiological function and in pathology. We will also develop new optical probes for localized stimulation of inner ear hair cells and neurons. Finally we will examine IR evoked vestibular eye movement and myogenic responses in vivo and will explore the laser parameters effective and safe for future neuroprosthetic application(s). The results will lead to new applications of IR optical stimuli in basic science and potentially benefit patients suffering from vestibular loss, hearing loss, tinnits and pain. This optical stimulation technique will greatly enhance research in the inner ear field and likely have broad applications in neuroscience.