Cellular mechanisms of hippocampal network neuroplasticity generated by brain stimulation

脑刺激产生海马网络神经可塑性的细胞机制

• 批准号: 10247773
• 负责人: JOHN F DISTERHOFT
• 金额: $ 136.68万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247773
• 关键词: Affect; Brain; Brain Injuries; CREB1 gene; Cells; Communication; Dorsal; Down-Regulation; Effectiveness; Electric Stimulation; Electrical Stimulation of the Brain; Electrophysiology (science); Epilepsy; Episodic memory; Frequencies; Goals; Hippocampus (Brain); Human; Implanted Electrodes; In Vitro; Intervention; Intractable Epilepsy; Knowledge; Location; Measures; Memory; Memory impairment; Methods; Neurobiology; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Parietal; Patients; Pattern; Performance; Phase; Property; Rattus; Research; Rodent; Rodent Model; Role; Slice; Synapses; Testing; Up-Regulation; Variant; Viral; activity marker; awake; clinical development; cognitive ability; experimental study; hippocampal pyramidal neuron; improved; in vivo; insight; nervous system disorder; neuronal circuitry; neuronal excitability; neuropsychiatric disorder; neurosurgery; noninvasive brain stimulation; novel; support network; treatment strategy

Project Summary/Abstract The distributed brain network of the hippocampus supports memory and related cognitive abilities. Disruptions of this network occur in many neurological disorders such as epilepsy, brain injury, and neurodegenerative disease. Brain stimulation targeting the human hippocampal network can produce long-lasting improvements of memory ability, with corresponding increases in brain-activity markers of network function. However, mechanisms for this beneficial network-level neuroplasticity caused by brain stimulation remain unknown. Mechanistic knowledge is essential to optimize how and where to stimulate the hippocampal network in order to maximize the resulting memory benefits. This project will investigate the cellular mechanisms for the effects of brain stimulation on the hippocampal network. We will capitalize on the property that activity of regions of the hippocampal network synchronize in the theta frequency band (5-8Hz) to test for mechanistic homology in the effects of stimulation on human versus rodent hippocampal networks. In humans undergoing neurosurgery for intractable epilepsy and in awake, behaving rodents, we predict that electrical stimulation will have greater effects on hippocampal network function when it is delivered with increasing levels of synchronization to the ongoing hippocampal theta activity rhythm. Thus, we will test whether the effects of manipulating the synchrony between brain stimulation and hippocampal theta activity are comparable in humans and rodents. The effects of stimulation will be assessed using measures of hippocampal network functional connectivity and paired-associate memory performance that can be performed similarly in both species. We will then conduct in vitro electrophysiology experiments in rodent brain slices obtained after stimulation in order to identify cellular mechanisms for the effects of stimulation. We predict that stimulation parameters that increase hippocampal network function will increase cellular excitability, as measured via the postburst afterhyperpolarization, of dorsal hippocampal CA1 pyramidal neurons. Viral manipulation of CREB expression, which is necessary for changes in excitability, will be used to causally test the role of dorsal hippocampal CA1 excitability in the effects of stimulation on hippocampal network function. These research objectives are in close alignment with the focus of RFA-NS-18-018 on establishing cellular mechanisms for the effects of brain stimulation on neuronal circuits. Findings will uniquely uncover cellular mechanisms by which brain stimulation beneficially impacts distributed brain networks and corresponding cognitive abilities. These mechanistic insights could propel brain-stimulation treatments for memory impairments caused by disruption of the hippocampal network.

项目总结/摘要 海马体的分布式大脑网络支持记忆和相关的认知能力。中断 这种网络的许多神经系统疾病，如癫痫，脑损伤和神经退行性疾病， 疾病针对人类海马网络的脑刺激可以产生持久的改善 记忆能力的增强，相应的网络功能的大脑活动标志物的增加。然而，在这方面， 由脑刺激引起的这种有益的网络水平神经可塑性的机制仍然未知。 机械知识对于优化如何以及在何处刺激海马网络以 以最大化由此产生的存储器益处。本项目将研究细胞机制的影响 海马体网络上的大脑刺激。我们将利用这些地区的活动， 海马网络在θ频带（5-8Hz）中同步，以测试海马神经元中的机制同源性。 刺激对人类与啮齿动物海马网络的影响。在接受神经外科手术的人类中， 顽固性癫痫和清醒，行为啮齿动物，我们预测，电刺激将有更大的 对海马网络功能的影响，当它与同步水平的增加相结合时， 持续海马theta活动节律。因此，我们将测试操纵 脑刺激和海马体Theta活动之间同步性在人类和啮齿动物中是相当的。 将使用海马网络功能连接的测量来评估刺激的效果， 配对联想记忆的表现，可以在两个物种类似地执行。然后我们将在 在刺激后获得的啮齿动物脑切片中进行体外电生理学实验， 刺激效应的机制。我们预测，刺激参数，增加海马 网络功能将增加细胞的兴奋性，如通过爆发后后超极化测量的， 背侧海马CA 1区锥体神经元。CREB表达的病毒操纵，这对于 兴奋性的变化，将被用来因果检验背海马CA 1兴奋性的作用， 刺激对海马网络功能的影响。这些研究目标与 RFA-NS-18-018的重点是建立脑刺激对 神经回路研究结果将独特地揭示脑刺激有益于 影响分布式大脑网络和相应的认知能力。这些机械论的见解 推动大脑刺激治疗海马网络中断引起的记忆障碍。