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）：基本的问题仍然是如何通过神经活动传递信息。 在海马体中，单个细胞的放电率和这些细胞相对于彼此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，海马支持使用率代码和时间代码的记忆功能，但时间编码和记忆之间的因果关系是缺乏的。 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，有必要从海马和输出区域同时进行记录。 在这里，我提出了三个实验，在这些实验中，我将记录并光致刺激海马体，同时记录其主要的突触后皮质靶点之一，下托。 具体目的1是提供相关证据，在没有刺激的情况下，海马下托细胞是敏感的海马时间编码。 海马下托活动的统计模型将检验放电率的显著变化是否可以用海马CA1区的活动序列来解释。 具体目标2将测试海马下托放电模式是否受到海马时间代码中断的影响，海马时间代码由尖峰时间的微小差异定义。 尖峰定时中断将通过表达激发锥体细胞的光激活视蛋白直接实现，或通过表达沉默中间神经元的光激活视蛋白间接实现。 如果海马体中的尖峰定时被破坏时，海马下托活动发生改变，这将提供强有力的证据表明，时间代码可以偏向突触后靶点的活动，因此可能传递信息。 最后，具体目标3试图将精细尖峰时间的中断与记忆联系起来。 在该实验中，将使用CA 1的更广泛的光遗传学刺激，并且将在依赖于海马体的延迟交替范例中测试记忆。 我预测，在延迟期间，扰乱海马细胞放电顺序的刺激也会影响记忆。 这些实验的目的是表明，信息从海马传递到下游区域使用时间代码。 阐明时间编码和记忆之间的因果关系将大大扩展海马存储容量的估计，并可能提供对增强记忆的刺激方案的见解。

 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.