Miniature Microdrive for Intracellular Recordings in Freely Behaving Mice

描述（由申请人提供）：由细胞外电极测量的动作电位是计算冰山的一角，在其下方操作着巨大的电化学信号系统，该电化学信号系统涉及快速神经递质、神经调质、激素、结合这些信号分子的受体以及这些受体所在的神经元的固有膜特性。 因此，通常用于研究自由行为动物神经活动的细胞外电极对广泛的大脑活动是盲目的。 这种不敏感性限制了我们对正常大脑功能背后的神经机制的理解，也限制了对神经系统和神经精神疾病背后的神经活动紊乱的了解。 克服这一限制需要能够克服从自由行为动物大脑中的神经元获得细胞内记录的艰巨挑战的技术。 该提案试图通过实现三个具体目标来克服这一挑战：1）开发微型微驱动器，其中细胞内电极可以快速加载并灵活地定位在大脑表面上。 2)为了简化驱动器的大小和质量，使鼠标可以轻松携带至少两个设备，促进神经元和大脑区域之间的功能连接的评估。 3)在自由行为小鼠的听觉皮层中进行细胞内记录，因为它们在已知强烈调节听觉反应的条件下处理听觉刺激。 这项技术的完善将广泛有益于神经科学界，其在小鼠中的应用将为分析紊乱的神经活动如何成为疾病的基础打开大门。 ! 公共卫生相关性：该提案旨在开发一种微型细胞内记录装置，可用于对自由移动动物的神经活动进行高灵敏度记录。 这项技术的发展可以提供一个强大的工具，阐明神经元活动，使正常的脑功能和紊乱的神经元活动的基础疾病。 !

DESCRIPTION (provided by applicant): The action potentials measured by an extracellular electrode are the tip of a computational iceberg, beneath which operates a vast electrochemical signaling system involving fast neurotransmitters, neuromodulators, hormones, the receptors that bind these signaling molecules, and the intrinsic membrane properties of the neurons in which these receptors reside. Consequently, the extracellular electrodes commonly used to study neural activity in freely behaving animals are blind to a wide spectrum of brain activity. This insensitivity limits our understanding of the neural mechanisms underlying normal brain function and also limits insights into disordered neural activity that underlies neurological and neuropsychiatric diseases. Surmounting this limitation requires technology that can overcome the formidable challenge of obtaining intracellular recordings from neurons in the brain of a freely behaving animal. This proposal seeks to overcome this challenge by accomplishing three Specific Aims: 1) To develop a miniature microdrive in which the intracellular electrode can be rapidly loaded and flexibly positioned over the brain surface. 2) To miniaturize the size and mass of the drive so that a mouse can readily carry at least two devices, facilitating an assessment of functional connectivity between neurons and brain areas. 3) To make intracelular recordings in the auditory cortex of freely behaving mice as they process auditory stimuli in conditions that are known to strongly modulate auditory responses. The refinement of this technology will be widely beneficial to the neuroscience community and its application in the mouse will open the door to analyzing how disordered neural activity underlies diseases. ! PUBLIC HEALTH RELEVANCE: This proposal seeks to develop a miniature intracellular recording device that can be used to make highly sensitive recordings of neural activity in freely moving animals. Development of this technology can provide a powerful tool for elucidating neuronal activity that enables normal brain function and disordered neuronal activity underlying diseases. !