A universal and 3D-printed rat calvarium replacement system to enable for pan-cortical and sub-cortical recordings and optogenetics

通用 3D 打印大鼠颅骨替换系统，可实现全皮层和皮层下记录和光遗传学

• 批准号: 10054940
• 负责人: Brendon O Watson
• 金额: $ 42.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054940
• 关键词: 3-Dimensional; 3D Print; Address; Anatomy; Animals; Behavior; Biology; Brain; Brain Diseases; Brain region; Calcium; Cell Nucleus; Cells; Chronic stress; Communities; Complex; Complication; Coupled; Custom; Data; Devices; Disease; Distant; Dorsal; Electrodes; Electrophysiology (science); Elements; Engineering; Event; Fiber Optics; Foundations; Functional Magnetic Resonance Imaging; Future; Goals; Health; Hippocampus (Brain); Human; Image; Implant; Implanted Electrodes; Lead; Major Depressive Disorder; Measures; Mechanics; Medial Dorsal Nucleus; Methods; Modeling; Nature; Neocortex; Neurobiology; Neurons; Neurophysiology - biologic function; Neurosciences; Operative Surgical Procedures; Output; Patients; Play; Positioning Attribute; Rattus; Records Controls; Research; Resolution; Rodent; Rodent Model; Role; Sampling; Secure; Silicon; Site; Sleep; Stress; Structure; Surface; Synapses; Synaptic Transmission; System; Techniques; Technology; Testing; Thalamic structure; Vision; Work; base; biological adaptation to stress; cranium; design; experimental study; flexibility; implantation; innovation; insight; millisecond; neocortical; neuroregulation; new technology; new therapeutic target; novel; novel strategies; optogenetics; relating to nervous system; response; temporal measurement; tool

Abstract While altered broad-scale brain dynamics are a key brain signature of major depressive disorder (MDD) and despite the plethora of powerful neuroscientific tools available in rodents, we actually do not currently have the capacity to assess these broad-scale neocortical dynamics in rodents with synaptic-timescale temporal and single neuron resolution. This is a key gap in the capacity of neuroscientists to study MDD-related biology via rodent models including the sustained threat model. Electrophysiologic and optogenetic approaches would be ideal to study how neocortical dynamics are orchestrated at baseline and are perturbed in disease, since many mechanisms may be synaptic in nature and both methods can operate at synaptic-timescales. We are a team of neuroscientists and mechanical engineers and we aim to develop a system to allow implantation of previously- impractical complex combinations of electrodes and optic fibers to record and manipulate the rat brain. The basis of our approach is a 3-dimensionally printed (3D printed) replacement for the dorsal rat skull – an “Interface Plate” - which we have already successfully attached to two rats with good survival. Unlike a natural skull the Interface Plate is custom designed and fabricated and so can be adapted to guide and secure many devices to the animal using a novel surgical approach including pre-surgical assembly. We aim to optimize our design for the Interface Plate to enable two experiments that will be novel and crucial to studies of sustained threat-related disturbances in neocortical dynamics. The first aim will use our 3D printed positioning and guide system to place 128 electrodes broadly across the entire dorsal neocortex. This will enable the first ever mapping of electrical activity at sub-millisecond resolution across the entire dorsal neocortex enabling us to capture events ranging from synaptic transmission to oscillations to neuromodulation, behavior and brain state transitions. We will additionally place electrodes at both superficial and deep layers to gather data about relative roles of these evolutionarily-conserved anatomical layers. In a second aim we will adapt our Interface Plate to enable recording in neocortex while simultaneously recording and optogenetically stimulating regions that play key roles in coordinating neocortex including the dorsal hippocampus, the medial dorsal nucleus of the thalamus (MDN) and the thalamic reticular nucleus (TRN). In this aim, 8 (and later 32) electrodes will be implanted in cortex for recording while into dorsal hippocampal CA1, MDN and TRN we will implant silicon probes with 64 recording channels and a coupled optic fiber. This will facilitate experiments examining and testing the roles of non- neocortical structures in coordinating the cortex both in and out of sustained threat conditions. The experiments enabled here will provide fundamental new data regarding the neocortex in health and disease. This work will also lead to the creation of a customizable and flexible new tool which we will make openly available to enable complex experiments in freely behaving animals for anyone in the neuroscience community.

抽象的 虽然广泛的大脑动力学改变是重度抑郁症（MDD）和 尽管啮齿类动物有大量强大的神经科学工具，但我们目前实际上还没有 通过突触时间尺度时间和时间来评估啮齿类动物的这些大范围的新皮质动态的能力 单神经元分辨率。这是神经科学家通过以下方式研究 MDD 相关生物学能力的一个关键差距： 啮齿动物模型，包括持续威胁模型。电生理学和光遗传学方法将是 非常适合研究新皮质动力学在基线时如何协调以及在疾病中如何受到干扰，因为许多 机制本质上可能是突触的，并且两种方法都可以在突触时间尺度上操作。我们是一个团队 由神经科学家和机械工程师组成，我们的目标是开发一种系统，允许植入先前的- 电极和光纤的复杂组合来记录和操纵大鼠大脑是不切实际的。这 我们方法的基础是用 3D 打印（3D 打印）替代大鼠背侧头骨——一个“界面” “板”——我们已经成功地将其附着在两只存活良好的老鼠身上。与天然头骨不同的是， 接口板是定制设计和制造的，因此可用于引导和固定许多设备 该动物使用一种新颖的手术方法，包括手术前组装。我们的目标是优化我们的设计 接口板可实现两项实验，这对于持续威胁相关的研究来说是新颖且至关重要的 新皮质动力学紊乱。第一个目标将使用我们的 3D 打印定位和引导系统来放置 128 个电极广泛分布于整个背侧新皮质。这将实现有史以来第一次电力测绘 整个背侧新皮质以亚毫秒分辨率的活动使我们能够捕捉范围广泛的事件 从突触传递到振荡，再到神经调节、行为和大脑状态转换。我们将 另外，在表层和深层放置电极，以收集有关这些电极相对作用的数据 进化上保守的解剖层。第二个目标是我们将调整接口板以实现记录 在新皮质中，同时记录和光遗传学刺激区域，这些区域在 协调新皮质，包括背侧海马、丘脑背内侧核（MDN）和 丘脑网状核（TRN）。为了实现这一目标，将在皮质中植入 8 个（后来是 32 个）电极 在背侧海马 CA1、MDN 和 TRN 中进行记录，我们将植入具有 64 个记录的硅探针 通道和耦合光纤。这将有助于实验检查和测试非 新皮质结构在持续威胁条件下协调皮质。实验 此处启用将提供有关健康和疾病中新皮质的基本新数据。这项工作将 还导致创建一个可定制且灵活的新工具，我们将公开提供该工具以实现 为神经科学界的任何人进行自由行为动物的复杂实验。

项目成果

Manufacturing Processes of Implantable Microelectrode Array for In Vivo Neural Electrophysiological Recordings and Stimulation: A State-Of-the-Art Review.

用于体内神经电生理记录和刺激的植入式微电极阵列的制造工艺：最先进的综述。

• DOI: 10.1115/1.4063179
• 发表时间: 2022
• 期刊: Journal of micro- and nano-manufacturing
• 作者: Yi,Dongyang;Yao,Yao;Wang,Yi;Chen,Lei
• 通讯作者: Chen,Lei

3D Printed Skull Cap and Benchtop Fabricated Microwire-Based Microelectrode Array for Custom Rat Brain Recordings.

• DOI: 10.3390/bioengineering9100550
• 发表时间: 2022-10-14
• 期刊: BIOENGINEERING-BASEL
• 影响因子: 4.6
• 作者: Yi, Dongyang;Hartner, Jeremiah P.;Ung, Brian S.;Zhu, Harrison L.;Watson, Brendon O.;Chen, Lei
• 通讯作者: Chen, Lei

Flexible High-Resolution Force and Dimpling Measurement System for Pia and Dura Penetration During In Vivo Microelectrode Insertion Into Rat Brain.

• DOI: 10.1109/tbme.2021.3070781
• 发表时间: 2021-08
• 期刊: IEEE transactions on bio-medical engineering
• 作者: Chen L;Hartner J;Dong T;Li A;Watson B;Shih A
• 通讯作者: Shih A

Repurposing Cholinesterase Inhibitors as Antidepressants? Dose and Stress-Sensitivity May Be Critical to Opening Possibilities.

• DOI: 10.3389/fnbeh.2020.620119
• 发表时间: 2020
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3
• 作者: Fitzgerald PJ;Hale PJ;Ghimire A;Watson BO
• 通讯作者: Watson BO