Noninvasive low-intensity focused ultrasound-enabled sonogenetic method to induce plasticity in adult visual cortex.

非侵入性低强度聚焦超声声遗传学方法可诱导成人视觉皮层的可塑性。

• 批准号: 9924788
• 负责人: Grace M Hwang
• 金额: $ 39.57万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924788
• 关键词: Adult; Automobile Driving; BRAIN initiative; Behavioral; Brain; Cephalic; Data; Deep Brain Stimulation; Development; Devices; Dorsal; Electric Stimulation; Focused Ultrasound; Gene Expression; Genes; Genetic; Goals; Head; Human; Image; Institutes; Knowledge; Laboratories; Lateral Geniculate Body; Lead; Long-Term Potentiation; Measures; Methodology; Methods; Mus; Muscle; Nervous System Physiology; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Ocular Dominance; Pattern; Photic Stimulation; Physics; Property; Rattus; Recovery; Recovery of Function; Reporting; Rodent; Rogaine; Running; Sensory; Specificity; Structure; Synapses; Synaptic plasticity; Techniques; Testing; Thalamic structure; Time; Ultrasonography; Universities; Vision; Visual; Visual Cortex; area striata; awake; base; behavioral outcome; cell type; critical period; deafening; design; experience; functional plasticity; in vivo; interest; neural circuit; novel; optogenetics; postnatal; relating to nervous system; response; restoration; sensory cortex; simulation; tool; transmission process; two-photon

PROJECT SUMMARY Development of non-invasive tools for activating deep brain structures is critical for causally manipulating neural function in humans. Furthermore, such method, if able to elicit long-term plastic changes in neural circuits, will aid in functional recovery of neural function. One of the promising non-invasive neural modulation technique that has a potential to activate deep brain structures in a focal manner is ultrasound. Several groups have demonstrated that ultrasound can lead to neural activation, alter sensory responses, or cause behavioral outcomes. In this proposal, we aim to fill a gap in knowledge as to whether focal stimulation of deep brain structures using Low Intensity Focused Ultrasound (LIFU) leads to long-term changes in neural function relevant for functional recovery, especially in the adult brain with limited capacity for plasticity. It is known that the developmental loss of thalamocortical (TC) plasticity precedes the closure of the critical period for cortical plasticity in sensory cortices, which suggests that recovery of TC plasticity may be needed to restore plasticity in the adult brain. In line with this idea, several studies have reported that recovery of adult cortical plasticity is often accompanied by restoration of TC plasticity. A previous study demonstrated that patterned electrical stimulation of the visual thalamus (dLGN) produces long-term potentiation (LTP) of TC inputs to the primary visual cortex (V1) in adult rats. Here we will investigate whether non-invasive LIFU stimulation of dLGN can produce TC plasticity in adult V1. In Aim 1, we will determine whether LIFU stimulation leads to long-term plastic changes of dLGN inputs to layer 4 (L4) of adult V1. To do this, we will use a LIFU stimulation device developed by the Applied Physics Laboratory (APL) at Johns Hopkins University, and combine this with genetic tools to express exogenous genes specifically in activated dLGN neurons. Specifically, we will use genetic methods that can drive the expression of optogenetic tools (i.e. channelrhodopsin-2) selectively to LIFU-stimulated neurons to functionally assess long-term synaptic plasticity, and test the utility of a novel sonogenetic tool that can provide cell-type specificity to LIFU stimulation. In Aim 2, we will investigate whether LIFU stimulation can alter neural response properties of V1 L4 neurons using in vivo 2-photon Ca2+ imaging. Results from our study will determine whether LIFU stimulation can produce long- term plasticity of neural circuits in the adult brain, which can be relevant for designing non-invasive methods for functional recovery. At the very least, our study will provide genetic methodologies that can drive exogenous gene expression in deep brain structures using LIFU stimulation, and will provide information on whether sonogenetics can produce cell-type specific activation of deep brain structures.

项目总结 开发用于激活大脑深层结构的非侵入性工具对因果关系至关重要 操控人类的神经功能。此外，这种方法如果能够引起长期的可塑性变化 神经回路，将有助于神经功能的恢复。一种很有前途的非侵入性神经 有可能以焦点方式激活大脑深层结构的调制技术是超声波。 几个小组已经证明，超声波可以导致神经激活，改变感觉反应，或者 导致行为后果。在这项提议中，我们的目标是填补关于局部刺激是否 低强度聚焦超声(LIFU)对脑深部结构的影响导致神经的长期变化 与功能恢复有关的功能，尤指具有有限可塑性的成人大脑。它是 已知在关键期结束之前丘脑皮质(TC)可塑性的发育丧失 对于感觉皮质的可塑性，这表明TC可塑性的恢复可能需要 恢复成人大脑的可塑性。与这一想法一致的是，几项研究报告称，成年人的康复 皮质可塑性通常伴随着TC可塑性的恢复。先前的一项研究表明 图形电刺激视觉丘脑(DLGN)产生TC的长时程增强(LTP) 成年大鼠初级视皮层(V1)的输入。在这里我们将调查非侵入性利福 刺激dLGN可产生成年V1的TC可塑性。在目标1中，我们将确定理府刺激是否 导致dLGN输入到成人V1的第四层(L4)的长期可塑性变化。要做到这一点，我们将使用利福 由约翰霍普金斯大学应用物理实验室(APL)开发的刺激装置，以及 将其与基因工具相结合，在激活的dLGN神经元中特异性地表达外源基因。 具体地说，我们将使用可以驱动光遗传工具(即 视紫红质-2)选择性地作用于利福刺激的神经元，从功能上评估长期突触的可塑性， 并测试一种新的声学工具的实用性，该工具可以为理府刺激提供细胞类型特异性。在目标2中， 我们将研究理府刺激是否可以改变V1 L4神经元的神经反应特性 活体双光子钙离子成像。我们的研究结果将决定利福刺激是否能产生长时间的 成人脑内神经回路的术语可塑性，这可能与设计非侵入性治疗方法有关 功能恢复。至少，我们的研究将提供可以驱动外源基因的遗传方法 利用利福刺激在脑深部结构中的基因表达，并将提供关于是否 声遗传学可以产生脑深部结构的细胞型特异性激活。