Network Dysfunction and Neuromodulation following TBI

TBI 后的网络功能障碍和神经调节

• 批准号: 10655963
• 负责人: John Allen Wolf
• 金额: $ 39.19万
• 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 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655963
• 关键词: Affect; Animal Model; Animals; Area; Behavioral; Brain; Brain region; Clinical Treatment; Code; Cognition; Communication; Complex; Contralateral; Coupling; Data; Electrophysiology (science); Episodic memory; Event; Functional disorder; Future; Goals; Hippocampus; Human; Injury; Interneurons; Knowledge; Learning; Measures; Medial; Memory; Memory Disorders; Memory impairment; Mission; National Institute of Neurological Disorders and Stroke; Neurons; Outcome Measure; Phase; Play; Population; Prefrontal Cortex; Public Health; Rattus; Research; Rodent; Series; Short-Term Memory; Structure; Translating; Traumatic Brain Injury; behavioral outcome; cognitive function; density; design; disabling symptom; effective therapy; experimental study; functional restoration; improved; memory consolidation; memory encoding; memory recall; network dysfunction; neurophysiology; neuroregulation; novel; persistent symptom; rational design; restoration; spatial memory; therapy design; therapy development; treatment strategy

Summary: Although memory dysfunction is a frequent and debilitating symptom of traumatic brain injury (TBI), there are currently no effective treatments available for this often persistent deficit. In addition, the neurophysiological basis of this dysfunction remains unknown, hindering rational treatment design. There is mounting evidence that precisely coordinated communications between brain regions are necessary to encode and recall information in the neuronal ensembles that represent episodic, spatial, and working memory. The hippocampus (HC) is the most well-studied region of memory encoding and is considered to be selectively vulnerable in both human and animal TBI. We and others have demonstrated disruptions of oscillations in the HC following TBI, with the loss of theta a notable finding. Rodent studies have demonstrated that restoration of theta using stimulation (neuromodulation) can restore aspects of HC dependent memory. However, the mechanism remains unknown, as does the complex relationship of these neuronal ensembles to oscillations and their correlation with memory deficits after TBI. Without a deeper understanding of how ensemble coding underlying cognition and memory is disrupted post injury, rational design of neuromodulatory and other therapies remains challenging. Therefore, a critical need exists to determine the underlying mechanisms of the disruption of coding in networks underlying memory formation after TBI, and how a reintroduction of theta restores cognitive function. The overall objective of the current application is to determine how the coding of memory in the hippocampus and associated circuitry is disrupted following TBI, and how theta neuromodulation restores function. Our central hypothesis is that TBI disrupts communication within the larger hippocampal network which disrupts oscillatory interactions required for encoding and recall of memory in networks of synchronized neuronal ensembles. This hypothesis is based in part on our preliminary data demonstrating that neurons in the hippocampus synchronize improperly with oscillations following injury, and that prominent interactions between oscillations are lost. We therefore propose to determine whether TBI affects phase precession, theta sequences, and phase amplitude coupling in area CA1 of the hippocampus during overtrained tasks designed for these measures, as well as whether both hippocampi are affected by a unilateral injury. In addition, we will determine the mechanism of learning and memory dysfunction following TBI by examining neuronal ensemble activity across HC-PFC, quantifying ripple features and replay, and correlating these measures with behavioral memory function relying on HC-PFC networks. We will also examine the mechanism of neuromodulatory restoration of spatial/working memory in rats via simultaneous medial septal stimulation and high-density laminar hippocampal/mPFC recordings. Accomplishment of these goals will provide the first detailed analysis of disrupted neuronal coding and oscillatory interactions between brain regions underlying TBI induced memory dysfunction, identify the effects of neuromodulation on these networks, and lead to clinical treatments for this persistent sequelae of TBI.

概括： 尽管记忆功能障碍是创伤性脑损伤（TBI）的频繁且令人衰弱的症状，但有 目前尚无对这种持续赤字的有效治疗方法。另外，神经生理学 这种功能障碍的基础仍然未知，阻碍了理性的治疗设计。有越来越多的证据表明 必须在大脑区域之间进行精确协调的通信，以编码和回忆信息 代表情节，空间和工作记忆的神经元合奏。海马（HC）是 记忆编码的最精心研究的区域，被认为在人类和 动物TBI。我们和其他人在TBI之后表现出HC中HC中振荡的中断，损失 Theta的一个显着发现。啮齿动物研究表明，使用刺激恢复theta （神经调节）可以恢复HC依赖性内存的各个方面。但是，机制仍然未知， 这些神经合奏与振荡的复杂关系及其与记忆的相关性 TBI之后的缺陷。没有更深入地了解集合编码的基础认知和记忆的方式 受伤后破坏，神经调节和其他疗法的理性设计仍然具有挑战性。因此， 存在关键需求，以确定网络基础编码中断的基本机制 TBI后的记忆形成，以及theta的重新引入如何恢复认知功能。总体目标 当前应用程序是确定海马和相关电路中内存的编码如何 在TBI之后被破坏，以及theta神经调节如何恢复功能。我们的中心假设是TBI 破坏较大的海马网络中的通信，这破坏了所需的振荡相互作用 用于在同步神经元合奏网络中编码和回忆记忆。该假设是基于 在某种程度上，我们的初步数据表明，海马中的神经元与 受伤后的振荡以及振荡之间的显着相互作用消失了。因此，我们提出 确定TBI是否会影响相位序列，theta序列和相位振幅耦合。 在为这些措施设计的过度训练任务中，海马的海马以及两个海马 受单侧伤害的影响。此外，我们将确定学习和记忆的机制 通过检查HC-PFC的神经元合奏活动，在TBI之后的功能障碍，量化波纹特征 并重播，并将这些度量与依靠HC-PFC网络的行为内存函数相关联。我们 还将检查大鼠通过 同时内侧间隔刺激和高密度层流海马/MPFC记录。 这些目标的实现将提供有关神经元编码和振荡性中断的首次详细分析 TBI引起的记忆功能障碍的大脑区域之间的相互作用，确定 这些网络上的神经调节，并导致TBI持续后遗症的临床治疗。