Investigation into the synaptic origins of hippocampal replay

项目摘要 这个项目的目的是研究允许特定模式的神经活动的突触机制 复职。在海马体电路中，在行为过程中观察到的神经活动的顺序模式 后来在称为尖波涟漪(SPW-R)的振荡活动爆发期间重播。计算型 模型显示，重放可能是由于谷氨酸能突触对兴奋性神经元的可塑性。 然而，这种兴奋性-兴奋性联系在SPW-R重播所在的海马区CA1中很弱 观察到的。因此，CA1中的SPW-R重放可能继承自上游区域CA3，其具有密集的 兴奋性复发。或者，抑制电路中的可塑性可能支持SPW-R的变化 动力学。这项资助将使用SPW-R回放来研究神经模式是如何学习和回忆的。 在K99目标中，我将检查神经活动是否充分以及突触可塑性是否必要 在SPW-R期间，随后的神经重新激活。我将人工诱导CA1和CA1区的活动模式 CA3，并测试这些图案是否在之前的SPW-R中重新激活，以及重新激活是否 仅限于复发致密的CA3。接下来，我将测试阻止突触时SPW-R重播的完整性 CA1区锥体细胞固缩。重播中断将指向CA1可塑性在 定义重放序列。拨款的R00部分侧重于重放是否依赖于突触 抑制电路中的可塑性。首先，我将确定CA1锥体之间的突触连接 细胞和中间神经元在体内随着重复配对而变化。接下来，我将阻止CA1中的突触整合 GABA能神经元评估重放是否也被干扰。这样的发现将展示一个新的角色 用于定义网络动力学中抑制电路的可塑性。总而言之，这些实验提供了一个直接的测试 一组共同活跃的神经元(兴奋性和抑制性)之间的突触可塑性 促进随后该人口的重新激活。 为了研究突触连接如何影响电路动力学，这项资助首次结合了细胞类型 突触巩固的特异性控制和体内电生理学。拟议的培训将设置 为在行为、电路动力学和突触功能水平上研究记忆的职业奠定基础。 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 患有导致记忆缺陷的疾病的人的学习和记忆。

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.