Cellular mechanisms of hippocampal network neuroplasticity generated by brain stimulation

项目摘要/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。中断 发生在许多神经疾病中，如癫痫、脑损伤和神经退行性变 疾病。以人类海马体网络为靶点的脑刺激可以产生长期的改善 随着网络功能的大脑活动标记物的相应增加。然而， 这种由脑刺激引起的有益的网络水平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哪里有序地刺激海马网是必不可少的 以最大化由此产生的内存优势。这个项目将研究这种影响的细胞机制。 大脑刺激对海马网的影响。我们将利用该地区的活动的财产 海马网络在theta频段(5-8赫兹)同步，以测试 刺激对人与啮齿动物海马网的影响。在接受神经外科手术的人类中 顽固性癫痫和清醒的、行为正常的啮齿动物，我们预测电刺激将有更大的 递送时对海马网功能的影响 持续的海马theta活动节律。因此，我们将测试操纵 在人类和啮齿动物中，大脑刺激和海马theta活动之间的同步性是相似的。 刺激的效果将通过测量海马网功能连接性和 配对-联想记忆表现，可以在两个物种中执行类似的操作。然后我们将在 刺激后获得的啮齿类动物脑片的体外电生理实验 刺激效应的机制。我们预测增加海马区的刺激参数 网络功能将增加细胞的兴奋性，如通过爆发后超极化测量的 背侧海马CA1区锥体神经元。病毒操纵CREB的表达，这是必要的 兴奋性的变化，将被用来因果检验背侧海马CA1区兴奋性在 刺激对海马区网络功能的影响。这些研究目标与 RFA-NS-18-018关于建立脑刺激作用的细胞机制的重点 神经回路。这些发现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。这些机械的洞察力可能 推动脑刺激治疗因海马体网络中断而导致的记忆障碍。

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.