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.

项目概要/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。干扰 该网络的一部分发生在许多神经系统疾病中，例如癫痫、脑损伤和神经退行性疾病 疾病。针对人类海马网络的大脑刺激可以产生持久的改善 记忆能力的提高，网络功能的大脑活动标志物的相应增加。然而， 由大脑刺激引起的这种有益的网络级神经可塑性的机制仍然未知。 机械知识对于优化刺激海马网络的方式和地点至关重要 最大限度地提高记忆效果。该项目将研究影响的细胞机制 对海马网络的大脑刺激。我们将利用该地区的活动的财产 海马网络在 theta 频段（5-8Hz）同步，以测试 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 对于顽固性癫痫和清醒的、行为正常的啮齿类动物，我们预测电刺激将会有更大的效果 当海马网络功能随着与大脑的同步水平的增加而传递时，会产生影响 持续的海马θ活动节律。因此，我们将测试操纵的效果是否 人类和啮齿类动物的大脑刺激和海马 θ 活动之间的同步性具有可比性。 将使用海马网络功能连接的测量来评估刺激的效果 配对联想记忆性能在两个物种中都可以类似地执行。然后我们将进行 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，以识别细胞 刺激效应的机制。我们预测增加海马体的刺激参数 网络功能将增加细胞兴奋性，通过后爆发后超极化测量， 背侧海马 CA1 锥体神经元。 CREB ​​表达的病毒操作，这是必要的 兴奋性的变化，将用于因果测试背侧海马 CA1 兴奋性在 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影响的细胞机制 神经元回路。研究结果将独特地揭示大脑刺激有益的细胞机制 影响分布式大脑网络和相应的认知能力。这些机制见解可以 推动大脑刺激治疗因海马网络破坏引起的记忆障碍。