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.

项目摘要/摘要 海马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。针对人海马网络的大脑刺激可以产生持久的改善 内存能力，随着网络功能的脑活动标记的相应增加。然而， 由大脑刺激引起的这种有益网络级神经可塑性的机制尚不清楚。 机械知识对于优化如何以及在何处刺激海马网络至关重要 为了最大程度地利用产生的内存优势。该项目将研究效果的细胞机制 海马网络上的大脑刺激。我们将利用该财产 海马网络在theta频带（5-8Hz）中同步，以测试机械同源性中的同源性 刺激对人与啮齿动物海马网络的影响。在人类接受神经外科手术中 顽固的癫痫和清醒，表现啮齿动物，我们预测电刺激将具有更大的 当海马网络功能随着同步水平的增加而对海马网络功能的影响 正在进行的海马theta活性节奏。因此，我们将测试是否操纵 在人类和啮齿动物中，大脑刺激和海马theta活性之间的同步是可比的。 刺激的效果将使用海马网络功能连通性和 在这两个物种中都可以相似地执行配对的记忆性能。然后我们将进行 刺激后获得的啮齿动物脑切片中的体外电生理实验，以鉴定细胞 刺激作用的机制。我们预测会增加海马的刺激参数 网络功能将增加细胞兴奋性，如通过后爆发后极过过时的， 背部海马CA1锥体神经元。 CREB表达的病毒操纵是必要的 兴奋性的变化将用于因果测试背部海马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 神经元电路。发现将独特地发现细胞机制，通过这些机制，大脑刺激有益地刺激 影响分布式大脑网络和相应的认知能力。这些机械洞察力可能 推动脑刺激治疗因海马网络破坏引起的记忆障碍。