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 虽然记忆功能障碍是创伤性脑损伤 (TBI) 的常见症状，但目前尚无有效的治疗方法。 针对这种持续的缺陷有有效的治疗方法。此外，这种现象的神经生理学基础 破坏仍然未知，使得合理的治疗设计变得困难。破坏记忆振荡 编码结构已在 TBI 动物模型中得到证实，海马 θ a 缺失 突出的发现。使用神经调节恢复 theta 也可以恢复记忆功能的各个方面 海马体，表明海马体中的神经元仍然具有功能，但协调性 他们之间的联系也随着这种组织信号的消失而消失了。电极技术的新进展可以 揭示损伤后 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记忆的细胞。总体目标 当前的应用是确定海马体和相关电路中的记忆编码是如何进行的 TBI 后的紊乱，以及 θ 神经调节如何恢复海马功能。我们的中心假设 TBI 破坏了更大的海马网络内的通讯，包括振荡相互作用 这些连接区域中的记忆的编码和回忆是必需的。该假设部分基于 我们的初步数据表明海马体中的神经元不能与 受伤后的振荡。为了检验上述假设，我们首先确定 theta 的机制 弥漫性 TBI 后海马体的破坏及其对神经元行为的影响。我们假设 θ生成结构之间的轴突损伤导致振荡组织的丧失 海马体和 CA1 神经元的补偿反应会影响与 θ 的同步。 TBI 也可能 导致更广泛的海马网络中的振荡通讯中断，包括内侧 前额皮质（mPFC），导致空间工作记忆功能障碍。因此，我们将量化破坏 TBI 后清醒行为大鼠中该网络的神经元编码和振荡，并确定 空间记忆的神经调节恢复机制。我们将在临床上进一步检验这一假设 轻度 TBI 的相关大型动物模型，产生弥漫性轴突损伤，以确定连通性是否 破坏足以影响海马-mPFC记忆网络中协调的神经元活动。这 拟议的研究将首次对受损的神经元编码和振荡进行详细分析 TBI 后记忆的大脑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，从而导致关键的 未来可以转化为临床前和临床 TBI 治疗的机制。鉴定 记忆功能障碍背后的神经元和网络破坏机制将允许发展 针对 TBI 后这种常见的挥之不去的认知缺陷的针对性治疗。