Network Dysfunction and Neuromodulation following TBI

总结： 虽然记忆功能障碍是创伤性脑损伤（TBI）的常见和使人衰弱的症状，但存在以下情况： 目前对于这种经常持续的缺陷没有有效的治疗方法。此外，神经生理学 这种功能障碍的基础仍然未知，阻碍了合理的治疗设计。有越来越多的证据表明 大脑区域之间精确协调的通信是编码和回忆信息所必需的。 代表情景记忆、空间记忆和工作记忆的神经元集合。海马体（hippocampus，HC）是 记忆编码的最充分研究的区域，被认为是在人类和 动物TBI我们和其他人已经证明了TBI后HC振荡的中断， theta是一个值得注意的发现。啮齿类动物的研究表明，使用刺激恢复θ波 （神经调节）可以恢复HC依赖性记忆的方面。然而，其机制仍然未知， 这些神经元集合与振荡的复杂关系以及它们与记忆的相关性也是如此 TBI后的赤字如果没有更深入地理解认知和记忆的整体编码是如何 然而，由于损伤后神经功能的破坏，神经调节和其他疗法的合理设计仍然具有挑战性。因此 迫切需要确定在网络中编码中断的基本机制， TBI后的记忆形成，以及θ的重新引入如何恢复认知功能。总体目标 当前应用的一个关键点是确定海马体和相关电路中的记忆编码是如何 脑外伤后大脑皮层的功能被破坏，以及theta神经调节如何恢复功能。我们的中心假设是 扰乱更大的海马网络内的通讯，从而扰乱所需的振荡相互作用 在同步神经元集合的网络中编码和回忆记忆。这个假设是基于 部分基于我们的初步数据，这些数据表明海马体中的神经元与 损伤后的振荡，以及振荡之间的显著相互作用丢失。因此我们建议 确定TBI是否影响CA 1区的相位进动、θ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，海马体的活动，以及海马体是否 受到单侧损伤的影响。此外，我们将确定学习和记忆的机制 通过检查跨HC-PFC的神经元集合活动，量化涟漪特征， 和重放，并将这些测量与依赖于HC-PFC网络的行为记忆功能相关联。我们 还将研究大鼠空间/工作记忆的神经调节恢复机制， 同时进行内侧隔刺激和高密度层状海马/mPFC记录。 这些目标的实现将提供第一个详细的分析中断的神经元编码和振荡 脑区域之间的相互作用导致TBI诱导的记忆功能障碍，确定 这些网络的神经调节，并导致TBI的这种持续后遗症的临床治疗。

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.