Investigation into the synaptic origins of hippocampal replay

项目摘要 这个项目的目的是研究突触机制，使特定的神经活动模式， 恢复原状。在海马回路中，在行为过程中观察到的神经活动的顺序模式 后来在被称为尖波波纹（SPW-R）的振荡活动爆发期间重播。计算 模型显示，重放可能是由于兴奋性神经元上的突触可塑性引起的。 然而，这种兴奋-兴奋连接在海马CA1区很弱，SPW-R重放在那里。 观察因此，CA 1中的SPW-R重放可以从上游区域CA 3继承，其具有密集的 兴奋性复发或者，抑制回路的可塑性可能支持SPW-R的变化 动力学这项资助将使用SPW-R重放来研究神经模式是如何学习和回忆的。 在K99目标中，我将研究神经活动是否足够，突触可塑性是否必要， SPW-R期间随后的神经再激活。我将人工诱导CA1区的活动模式， CA 3，并测试这些模式是否在后续SPW-R中重新激活，以及重新激活是否 仅限于复发密集型CA3。接下来，我将测试SPW-R重放的完整性， CA1区锥体细胞实变。重放中断将指出CA1可塑性在脑缺血中的意想不到的作用。 定义重放序列。授权的R00部分关注重放是否取决于突触 抑制回路的可塑性。首先，我将确定CA1锥体细胞之间的突触连接是否 细胞和中间神经元在体内随着重复配对而变化。接下来，我将阻断CA1区的突触整合 GABA能神经元，以评估重放是否也被破坏。这一发现将展示一种新的作用， 在定义网络动力学时，抑制回路的可塑性。这些实验一起提供了一个直接的测试 一群共同活动的神经元（兴奋性和抑制性）之间的突触可塑性 促进了该种群随后的重新激活。 为了研究突触连接如何影响电路动力学，这项资助首次将细胞类型 特异性控制突触巩固和体内电生理学。拟议的培训将使 在行为、回路动力学和突触功能的水平上研究记忆的职业基础。 拟议的实验旨在告知临床使用药理学和人工神经刺激来帮助 学习和记忆能力的疾病。

Project Summary The aim of this project is to study the synaptic mechanisms that allow particular patterns of neural activity to become reinstated. In hippocampal circuits, the sequential pattern of neural activity observed during behavior is later replayed during oscillatory bursts of activity known as sharp-wave ripples (SPW-Rs). Computational models show that replay could arise due to plasticity of glutamatergic synapses onto excitatory neurons. However, such excitatory-excitatory connections are weak in hippocampal area CA1, where SPW-R replay is observed. Therefore, SPW-R replay in CA1 may be inherited from upstream region CA3, which has dense excitatory recurrents. Alternatively, it is possible that plasticity in inhibitory circuits supports changes in SPW-R dynamics. This grant will use SPW-R replay to study how neural patterns are learned and recalled. In the K99 Aims, I will examine whether neural activity is sufficient and synaptic plasticity necessary for subsequent neural reactivation during SPW-Rs. I will artificially induce patterns of activity in areas CA1 and CA3 and test whether those patterns are reactivated in the proceeding SPW-Rs and whether reactivation is restricted to recurrent-dense CA3. Next, I will test for the integrity of SPW-R replay while blocking synaptic consolidation in CA1 pyramidal cells. Replay disruptions would point to an unexpected role of CA1 plasticity in defining replay sequences. The R00 portion of the grant focuses on whether replay depends on synaptic plasticity in inhibitory circuits. First, I will establish whether the synaptic connectivity between CA1 pyramidal cells and interneurons changes with repetitive pairings in vivo. Next, I will block synaptic consolidation in CA1 GABAergic neurons to assess whether replay is also disrupted. Such a finding would demonstrate a novel role for plasticity in inhibitory circuits in defining network dynamics. Together, these experiments offer a direct test of the hypothesis that synaptic plasticity amongst a population of co-active neurons (excitatory and inhibitory) promotes subsequent reactivation of that population. To study how synaptic connectivity affects circuit dynamics, this grant combines, for the first time, cell-type specific control of synaptic consolidation and in vivo electrophysiology. The proposed training will set the foundation for a career that studies memory on the level of behavior, circuit dynamics, and synaptic function. The proposed experiments aim to inform clinical use of pharmacology and artificial neural stimulation to aid learning and recall in people with diseases that cause memory deficits.