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.

已经开发出非侵入性神经调节方法来使神经组织的调节无需进行侵入性手术程序。低强度经颅聚焦超声（TFU）神经调节已证明其在调节大脑的功效和精确度，从神经元到电路水平。然而，紧急不需要阐明TFU神经调节的体内神经元和神经元效应，从而推进了TFUS神经调节在人类上的翻译应用。我们建议通过使用新型的，新型的128个元素的随机超声阵列在麻醉和清醒的大鼠模型中系统地检查TFUS参数，以研究TFU的体内神经元细胞类型的特异性响应和长期可塑性效应。拟议的实验研究建立在我们的初步探索和对不同的低强度TFU参数如何导致唯一的体内神经元种群之间不相等的反应以及使用内部记录的麻醉啮齿动物模型中突触连通性的持续改变。我们将解决以下特定目标。 AIM 1。体内细胞类型的内在体体特异性响应对麻醉大鼠模型上TFUS刺激的特异性反应。我们将使用多渠道麻醉大鼠模型中的多通道电生理记录来表征细胞类型对体感皮质电路中TFUS刺激的反应。我们将通过细胞类型特定的光遗传大鼠模型进一步提高询问的精度。 AIM 2。研究醒着头部固定大鼠TFU的内在体内细胞类型特异性。麻醉效果不受阻碍，清醒的固定模型是研究不同细胞类型的空间和时间激活TFU神经调节的理想选择，以及在清醒大脑中局部神经网络中大脑活动的传播。 AIM 3。频率特定的TFU调制以诱导麻醉和清醒的头部固定大鼠的可塑性。我们将系统地研究TFU刺激对突触连通性的长期影响。我们将测试以下假设：1）TFUS刺激能够编码特定的特定信息，以诱导海马中持续的突触可塑性，而2）TFUS刺激参数的模式对变化程度具有显着影响。拟议的研究的成功完成有望通过研究体体性皮质上对超声刺激的体内细胞特异性反应，并在海马体和体感皮质中诱导长期影响，从而揭示TFU的体内细胞机制。我们将系统地表征，建模，验证和理解对TFUS刺激的体内神经元和神经元反应，不仅是为了推动神经调节疗法转化为临床实用性，而且进一步了解了健康大脑中特定神经电路的理解。