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Characterization of in vivo neuronal and inter-neuronal responses to transcranial focused ultrasound

体内神经元和神经元间对经颅聚焦超声反应的表征

基本信息

批准号：
10337754
负责人：
BIN HE
金额：
$ 198.49万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-25 至 2024-08-31
项目状态：
已结题

项目摘要

Non-invasive neuromodulation approaches have been developed to enable the modulation of neural tissue without necessitating invasive surgical procedures. Low-intensity transcranial focused ultrasound (tFUS) neuromodulation has proven its efficacy and precision in modulating the brain, from the neuron to circuit level. However, there is an urgent unmet need to elucidate the in vivo neuronal and inter-neuronal effects of the tFUS neuromodulation, thus advancing the translational application of tFUS neuromodulation on humans. We propose to investigate the in vivo neuronal cell-type specific response and long-term plasticity effects of tFUS by systematically examining tFUS parameters in both anesthetized and awake rat models using a novel, cutting-edge 128-element random ultrasound array for rodents. The proposed experimental investigations are built upon our preliminary explorations and rigorous understanding of how different low-intensity tFUS parameters lead to unequal responses among unique in vivo neuron populations and the sustained alteration of synaptic connectivity in anesthetized rodent models using intracranial recordings. We will address the following specific aims. Aim 1. Characterization of intrinsic in vivo cell-type specific response of somatosensory cortical circuits to tFUS stimulation on anesthetized rat models. We will characterize the cell-type specific neural responses to tFUS stimulation in somatosensory cortical circuits using multi-channel electrophysiological recordings in an in vivo anesthetized rat model. We will further increase the precision of our interrogations through cell-type specific optogenetic rat models. Aim 2. Investigation of intrinsic in vivo cell-type specificity of tFUS in awake head-fixed rats. Uninhibited by anesthesia effects, the awake head fixed model is ideal for the investigation of tFUS neuromodulation on the spatial and temporal activation of different cell types, as well as the propagation of brain activities across local neural networks in the awake brain. Aim 3. Frequency specific modulation of tFUS to induce plasticity in anesthetized and awake head-fixed rats. We will systematically study the long-term effects of tFUS stimulation on synaptic connectivity. We will test the hypotheses that 1) tFUS stimulation is able to encode frequency specific information inducing sustained synaptic plasticity in the hippocampus, and 2) the pattern of the tFUS stimulation parameters has a significant effect on the degree of change. The successful completion of the proposed research promises to uncover the in vivo cellular mechanism of tFUS by investigating in vivo cell- type specific responses to ultrasound stimulation at somatosensory cortex and the induction of long-term effects at both the hippocampus and somatosensory cortex. We will systematically characterize, model, validate and understand the in vivo neuronal and inter-neuronal responses to tFUS stimulation, not only to propel the translation of neuromodulation therapies to clinical utility but also further the understanding of the specific neural circuits in healthy brains.

非侵入性神经调节方法已经被开发出来，能够在不需要侵入性外科手术的情况下调节神经组织。低强度经颅聚焦超声(TFUS)神经调节已证明其在从神经元到电路水平的大脑调节方面的有效性和精确度。然而，迫切需要阐明tFUS神经调节在体内的神经元和神经元间的作用，从而促进tFUS神经调节在人类中的翻译应用。我们建议通过在麻醉和清醒的大鼠模型中系统地检测tFUS参数来研究tFUS在体内神经细胞类型的特异性反应和长期可塑性效应。我们的实验研究是建立在我们的初步探索和对不同低强度tFUS参数如何导致体内独特的神经元群体之间的不同反应以及使用颅内记录的麻醉啮齿动物模型中突触连接的持续改变的严格理解的基础上的。我们将解决以下具体目标。目的1.在麻醉大鼠模型上研究体感皮层环路对tFUS刺激的内在细胞型特异性反应。我们将使用多通道电生理记录在体内麻醉大鼠模型中表征体感皮层回路中对tFUS刺激的细胞类型的特定神经反应。我们将通过细胞类型特定的光遗传大鼠模型进一步提高我们的审讯精度。目的2.研究清醒头位固定大鼠体内tFUS固有的细胞类型特异性。清醒的头部固定模型不受麻醉效应的限制，是研究tFUS神经调节不同类型细胞的空间和时间激活以及大脑活动通过清醒大脑中的局部神经网络传播的理想模型。目的3.tFUS频率特异性调节诱导麻醉和清醒头位固定大鼠的可塑性。我们将系统地研究tFUS刺激对突触连接的长期影响。我们将检验以下假设：1)tFUS刺激能够编码频率特定的信息，诱导海马区持续的突触可塑性；2)tFUS刺激参数的模式对变化的程度有显著影响。这项拟议研究的成功完成有望通过研究体感皮质对超声波刺激的体内细胞类型特异性反应以及在海马区和体感皮层诱导的长期效应来揭示tFUS的体内细胞机制。我们将系统地描述、建模、验证和理解体内神经元和神经元间对tFUS刺激的反应，不仅推动神经调节疗法向临床应用的转化，而且还将进一步了解健康大脑中特定的神经回路。