Network Dysfunction and Neuromodulation following TBI

TBI 后的网络功能障碍和神经调节

• 批准号: 9903464
• 负责人: John Allen Wolf
• 金额: $ 35.22万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903464
• 关键词: Affect; Animal Model; Area; Behavior; Brain; Brain region; Cells; Clinical; Clinical Treatment; Code; Cognition; Cognitive; Cognitive deficits; Communication; Data; Development; Diffuse; Diffuse Axonal Injury; Electrodes; Fire - disasters; Frequencies; Future; Goals; Hippocampus (Brain); Human; Injury; Knowledge; Lead; Location; Medial; Memory; Memory Disorders; Memory impairment; Mission; Modeling; National Institute of Neurological Disorders and Stroke; Neurons; Output; Population; Prefrontal Cortex; Public Health; Rattus; Reporting; Research; Role; Series; Short-Term Memory; Signal Transduction; Specificity; Structure; Symptoms; TBI treatment; Technology; Testing; Translating; Traumatic Brain Injury; awake; axon injury; base; clinically relevant; cognitive function; common treatment; design; effective therapy; entorhinal cortex; experimental study; functional restoration; memory encoding; memory recall; memory retrieval; mild traumatic brain injury; network dysfunction; neuron loss; neurophysiology; neuroregulation; persistent symptom; pre-clinical; response; restoration; spatial memory; therapy design; therapy development; treatment strategy

Summary Although memory dysfunction is a frequent symptom of traumatic brain injury (TBI), there are currently no effective treatments available for this persistent deficit. In addition, the neurophysiological basis of this disruption remains unknown, making rational treatment design difficult. Disruption of oscillations in memory encoding structures have been demonstrated in animal models of TBI, with loss of hippocampal theta a prominent finding. Restoration of theta using neuromodulation can also restore aspects of memory function in the hippocampus, suggesting that neurons in the hippocampus are still functional, but that coordination between them has been lost along with this organizing signal. New advances in electrode technology can reveal how encoding in the HC is changed post injury, how multiple neurons interact with oscillations, and how the decrease in HC theta has affected cells that use it to encode for spatial memory. The overall objective of the current application is to determine how the coding of memory in hippocampal and associated circuitry is disrupted following TBI, and how theta neuromodulation restores hippocampal function. Our central hypothesis is that TBI disrupts communication within the larger hippocampal network, including oscillatory interactions required for encoding and recall of memory in these connected regions. This hypothesis is based in part on our preliminary data demonstrating that neurons in the hippocampus do not properly fire synchronously with oscillations following injury. To test the above hypothesis, we will first determine the mechanism of theta disruption in the hippocampus following diffuse TBI and its effect on neuronal behavior. We hypothesize that axonal injury between theta generating structures leads to a loss of oscillatory organization in the hippocampus, and a compensatory response in CA1 neurons affects synchronization to theta. TBI may also lead to disruption in the oscillatory communication in the wider hippocampal network, including medial prefrontal cortex (mPFC), leading to spatial working memory dysfunction. We will therefore quantify disruption of neuronal coding and oscillations in this network in awake behaving rats following TBI, and determine the mechanism of neuromodulatory restoration of spatial memory. We will further test this hypothesis in a clinically relevant large animal model of mild TBI that produces diffuse axonal injury to determine whether connectivity disruption is sufficient to affect coordinated neuronal activity in the hippocampal-mPFC memory network. The proposed research will provide the first detailed analysis of disrupted neuronal coding and oscillatory interactions between brain regions underlying memory following TBI and their relationship to axonal injury. These experiments will also identify the effect of neuromodulation on these networks, leading to crucial mechanisms that can be translated in the future to preclinical and clinical TBI treatments. Identification of the mechanisms of neuronal and network disruption underlying memory dysfunction will allow for the development of targeted treatments for this common lingering cognitive deficit following TBI.

概括 尽管记忆功能障碍是创伤性脑损伤（TBI）的常见症状，但目前没有 可用于这种持续赤字的有效治疗方法。另外，这是神经生理的基础 破坏仍然未知，使理性的治疗设计变得困难。记忆中振荡的破坏 在TBI的动物模型中已经证明了编码结构，海马theta a的损失 突出的发现。使用神经调节恢复theta也可以恢复内存功能的各个方面 海马，表明海马中的神经元仍然有效，但该协调性 它们之间与这个组织信号一起丢失了。电极技术的新进步可以 揭示受伤后HC中的编码如何改变，多个神经元如何与振荡相互作用以及如何 HC Theta的减少影响了使用它来编码空间内存的单元。总体目标 当前的应用程序是确定海马和相关电路中内存的编码如何 TBI之后受到破坏，以及theta神经调节如何恢复海马功能。我们的中心假设 TBI是否破坏了较大海马网络中的通信，包括振荡互动 在这些连接区域中编码和回忆记忆所必需的。该假设部分基于 我们的初步数据表明，海马中的神经元与 受伤后的振荡。为了检验上述假设，我们将首先确定theta的机制 弥漫性TBI后海马中的破坏及其对神经元行为的影响。我们假设这一点 theta产生结构之间的轴突损伤导致振荡组织的丧失 海马和CA1神经元中的补偿性反应会影响与theta的同步。 TBI也可能 导致更广泛的海马网络中的振荡通信中断，包括内侧 前额叶皮层（MPFC），导致空间工作记忆功能障碍。因此，我们将量化破坏 在TBI之后，该网络中该网络中的神经元编码和振荡 神经调节恢复空间记忆的机制。我们将在临床上进一步检验该假设 相关的大型轻度TBI动物模型，该模型会产生弥散的轴突损伤，以确定连通性是否存在 破坏足以影响海马MPFC内存网络中协调的神经元活动。这 拟议的研究将对神经元编码和振荡的中断分析提供首次详细分析 TBI之后记忆的基础区域之间的相互作用及其与轴突损伤的关系。 这些实验还将确定神经调节对这些网络的影响，从而导致至关重要 未来可以翻译成临床前和临床TBI处理的机制。识别 神经元和网络中断的机制基础记忆功能障碍将允许开发 TBI后这种常见的挥之不去的认知赤字的有针对性治疗方法。