High resolution microelectrode arrays for mapping and manipulation of brain microcircuits

了解大脑如何产生行为是我们面临的主要科学挑战之一。在过去的几十年里，细胞神经科学家在研究神经元如何接收输入和产生动作电位以及在体外制剂中识别不同类型的神经元方面取得了突破。另一方面，系统神经科学家从清醒受试者不同大脑区域的单个神经元记录了与行为不同方面相关的神经元反应。一个问题，仍然缺乏研究是如何在脑切片的细胞内记录的孤立的单个神经元的内在属性转化为复杂的模式，全球，多区域，神经元活动记录在行为。我们的愿景是，从小区域（微电路或小集合）内单个神经元的相互作用中，出现了具有特定微电路签名的内在活动模式。这些局部内在模式然后在全球网络的水平上相互作用，以产生作为感觉运动处理、认知和一般行为基础的全球大脑模式。然而，为了验证这一假设，必须获得至少三个层次的探索，单个神经元，局部微电路和全球大脑网络。我们目前拥有的技术可以让我们探索单个神经元和整个大脑网络。然而，局部微电路的探索一直具有挑战性。微电路由大脑区域或区域内互连的脑细胞（神经元）组成（即，局部集合），其生成对感觉刺激、运动命令和认知状态的特征进行编码的信号。由于目前可用的技术缺乏空间和时间分辨率，很难详细探讨它们。 该提案旨在获得一种用于电生理实验的新技术，该技术允许高时间和空间分辨率记录和操纵特定脑微电路中的神经元活动。我们的团队（Martinez-Trujillo，Inoue，Muller，Allman，Schmid和Laviolette）将利用一种新的高通道计数系统来测量数千个细胞的电活动，并在大脑切片和类器官（来自干细胞的脑组织）中产生刺激模式，以回答有关特定微电路在大脑计算中的作用的问题。使用这个系统，我们将能够将单个神经元活动与微电路动力学联系起来，并解开活动的时空模式，这些模式有助于在潜在行为中使用的全局神经代码中发挥特定的作用。该技术将与现有的专业知识产生实质性的协同作用，并在我们集团和西方社区的不同研究人员之间产生合作。此外，它将提高我们了解自己的能力，促进新技术的发展，并培养高素质的科学家。

Understanding how the brain generates behavior is one of the major scientific challenges we are faced with. Over the last decades cellular neuroscientists have made breakthroughs studying how neurons receive input and generate trains of action potentials as well as identifying different types of neurons in ex vivo preparations. On the other hand, system neuroscientists recording from single neurons across different brain areas in awake subjects have related neuronal responses to different aspects of behavior. One issue that remains poorly investigated is how the intrinsic properties of isolated single neurons documented during intracellular recordings in brain slices translate into the intricate patterns of global, multiarea, neuronal activity documented during behavior. Our vision is that from the interaction of single neurons within small regions (microcircuits or small ensembles) intrinsic activity patterns emerge that hold the signature of that specific microcircuit. Such local intrinsic patterns then interact at the level of global networks to produce global brain patterns underlying sensory-motor processing, cognition and behavior in general. However, to test this hypothesis, one must gain access to at least three levels of exploration, single neurons, local microcircuits, and global brain networks. We currently have technologies that allows us to explore single neurons and entire brain networks. However, the exploration of local microcircuits has been challenging. Microcircuits consist of interconnected brain cells (neurons) within a brain area or region (i.e., local ensembles) that generate signals encoding the features of sensory stimuli, motor commands and cognitive states. It has been difficult to explore them in detail due to the lack of spatial and temporal resolution of so far available techniques. This proposal aims at acquiring a novel technology for electrophysiological experiments that allows high temporal and spatial resolution recordings and manipulation of neuronal activity in specific brain microcircuits. Our team (Martinez-Trujillo, Inoue, Muller, Allman, Schmid and Laviolette) will leverage a new, high-channel-count system to measure the electrical activity from thousands of cells and generate stimulation patterns in brain slices and organoids (brain tissue derived from stem cells) to answer questions on the role of specific microcircuits in the computations performed by the brain. Using this system, we will be able to link single neuron activity to microcircuit dynamics and unravel the spatiotemporal patterns of activity that contribute to the specific areas role in the  global neural codes used underlying behaviour. The technology will substantially synergize with existing expertise and generate collaborations amongst different investigators within our group and the Western community. Furthermore, it will enhance our ability to understand ourselves, to foster new technologies, and to train highly qualified scientists.