Integration of the hippocampal temporal code by post-synaptic neural readers: testing the relevance of fine spike-timing to memory

 描述(由申请人提供)：关于神经活动如何传递信息的基本问题仍然存在。在海马体中，单个细胞的放电率和这些细胞相互之间的时间顺序与经验和计划的空间轨迹相关。这些相关性表明，海马体支持使用速率编码和时间编码的记忆功能，但时间编码和记忆之间缺乏因果联系。为了确定细胞的时间顺序是否将信息传递给大脑的其他部分，有必要从海马体和输出区同时进行记录。在这里，我提出了三个实验，在这些实验中，我将记录并光刺激海马体，同时从其主要的突触后皮质目标之一--下丘脑--进行记录。具体目的1是提供相关证据，证明在没有刺激的情况下，下丘细胞对海马区的时间编码是敏感的。亚核活动的统计模型将测试是否可以用海马区CA1区的活动序列来解释放电频率的显著差异。《特定目标2》将测试亚核的放电模式是否会受到海马区时间编码中断的影响，而海马区的时间编码是由棘波时序上的微小差异定义的。尖峰时序的中断将直接通过表达光激活的视蛋白来兴奋锥体细胞，或者间接地通过表达光激活的视蛋白来沉默中间神经元。如果当海马区的棘波计时被扰乱时，亚束核活动发生变化，这将提供强有力的证据，表明时间代码可以偏向突触后目标的活动，因此可能传递信息。最后，《特定目标3》试图将精细尖峰时序的中断与记忆联系起来。在这项实验中，将使用更广泛的CA1光遗传刺激，并将在依赖于海马体的延迟交替范式中测试记忆。我预测，在延迟期间扰乱海马细胞激发顺序的刺激也会影响记忆。这些实验的目的是证明信息是使用时间代码从海马体传递到下游区域的。确认时间编码和记忆之间的因果联系将极大地扩大对海马体存储容量的估计，并可能为增强记忆的刺激方案提供见解。

 DESCRIPTION (provided by applicant): Basic questions remain as to how information is conveyed by neural activity. In the hippocampus, the firing rate of single cells and the temporal ordering of those cells relative to one another correlate with experienced and planned spatial trajectories. These correlations suggest that the hippocampus supports memory function using both a rate code and a temporal code, but a causal link between temporal coding and memory is lacking. To establish if the temporal ordering of cells conveys information to the rest of the brain, it is necessary to perform simultaneous recordings from the hippocampus and an output region. Here, I propose three experiments in which I will record and optogenically stimulate the hippocampus while recording from one of its main post- synaptic cortical targets, the subiculum. Specific Aim 1 is to provide correlative evidence that, in the absence of stimulation, subicular cells are sensitive to hippocampal temporal coding. Statistical modeling of subicular activity wil test whether a significant amount of variance in firing rate can be explained by sequences of activity in area CA1 of the hippocampus. Specific Aim 2 will test whether subicular firing patterns are affected by disruptions to the hippocampal temporal code that is defined by small differences in spike timing. Spike-timing disruption will be achieved either directly by expressin light-activated opsins that excite pyramidal cells, or indirectly by expressing light-activated opsins that silence interneurons. If alterations in subicular activity occur when spike-timing in the hippocampus is disrupted, this would provide strong evidence that the temporal code can bias the activity of post-synaptic targets and therefore likely conveys information. Finally, Specific Aim 3 seeks to link disruption of fine spike-timing to memory. In this experiment, broader optogenetic stimulation of CA1 will be used and memory will be tested in a delayed alternation paradigm that depends upon the hippocampus. I predict that stimulations during the delay that disrupt the order in which hippocampal cells fire will also affect memory. The aim of these experiments is to show that information is conveyed from the hippocampus to downstream regions using a temporal code. Confirming a causal link between temporal coding and memory would greatly expand estimates of the hippocampal storage capacity and may offer insights into stimulation protocols that enhance memory.