Modulation of sensory hair cells by dopamine

描述(申请人提供)：前庭听觉刺激的感觉由来自初级感觉器官的上行传入神经元和来自大脑的下行调制传出神经元共同控制。二十多年来，我们已经知道释放多巴胺(DA)的传出神经支配前庭听觉器官，但DA对初级机械感觉细胞-毛细胞-的影响却知之甚少。斑马鱼具有许多独特的技术特征，使其特别适合于研究神经元电路，包括遗传易操纵性、高繁殖力、透明度、低细胞数量和表面毛细胞，这些都支持出色的活体成像和电生理学。我会用斑马鱼的后侧 LINE(PLL)器官作为脊椎动物前庭听觉系统的模型，以了解多巴胺能传出回路。PLL由神经肥大组成：仅有12个毛细胞组成的孤岛，感知流体动力学，类似于内耳的细胞被内淋巴运动激活。支配斑马鱼耳朵和PLL的多巴胺能神经元起源于下丘脑，这是一个调节动态平衡、睡眠和昼夜节律的器官。这个方案中的实验旨在阐明DA是如何调节毛细胞的。根据初步数据，我假设下丘脑通过激活毛细胞表达的兴奋性DA受体来调节斑马鱼对前庭听觉刺激的敏感性。这些实验的结果将大大有助于我们理解中枢神经系统如何通过直接调节初级感觉细胞来控制对感觉刺激的感知。

DESCRIPTION (provided by applicant): The perception of vestibulo-auditory stimuli is controlled by both ascending afferent neurons from primary sensory organs, and descending modulatory efferent neurons from the brain. For over two decades we have known that efferents that release dopamine (DA) innervate vestibulo-auditory organs, yet the influence of DA on the primary mechanosensory cells-hair cells-is poorly understood. Zebrafish have many technical characteristics that make them uniquely suited to study neuronal circuits, including genetic tractability, high fecundity, transparency, low cell number, and superficial hair cells which all support excellent in vivo imaging and electrophysiology. I will use the zebrafish posterior lateral line (pLL) organ as a model for vertebrate vestibulo-auditory systems to understand the dopaminergic efferent circuit. The pLL is composed of neuromasts: islands of only ~12 hair cells that sense hydrodynamics, analogous to cells of the inner ear that are activated by movement of endolymph. Dopaminergic neurons that innervate the ear and pLL of zebrafish originate in the hypothalamus, an organ that regulates homeostasis, sleep, and circadian rhythms. The experiments in this proposal are designed to elucidate how DA modulates hair cells. Based on preliminary data, I hypothesize that the hypothalamus modulates the sensitivity of zebrafish to vestibulo-auditory stimuli by activating excitatory DA receptors expressed by hair cells. Results from these experiments will substantially contribute to our understanding of how the central nervous system can control perception of sensory stimuli by directly modulating primary sensory cells.