Long-term kinetics of CA1 hippocampal place codes

描述（由申请人提供）：关于神经元集合如何存储长期记忆的许多基本问题仍然没有答案。由于体内生理记录方法的局限性，关于存储信息的神经集成表示是否在数周或更长时间尺度上进化的数据是有限的。这项拨款提议在哺乳动物CA1海马表征物理空间和空间记忆的背景下研究这些问题。我们将利用CA1“位置细胞”的既定特性，当哺乳动物被试处于细胞的“位置场”中时，CA1“位置细胞”会表现出更高的峰值率。一些理论认为，位置细胞应该保留稳定的位置场，以长期保留熟悉的空间环境。其他研究表明，位置细胞表征的逐渐进化可能有助于情景记忆，通过使用不同的细胞组合对同一环境中发生的不同事件进行编码。是否CA1表征熟悉的地方是稳定的或不只是部分探索经验。

DESCRIPTION (provided by applicant): Many fundamental questions about how ensembles of neurons store long-term memories remain unanswered. Due to the limitations of in vivo physiological recording methods, data is limited regarding whether neural ensemble representations of stored information evolve over time scales of weeks or more. This grant proposes to examine such questions in the context of the mammalian CA1 hippocampal representation of physical space and spatial memory. We will capitalize on the established properties of CA1 'place cells', which exhibit elevated spike rates when the mammalian subject is physically situated within a cell's 'place field'. Some theories suggest place cells should retan stable place fields for long-term retention of familiar spatial environments. Other work suggests gradual evolution of place cell representations might aid episodic memory, by encoding different events occurring in the same environment using distinct combinations of cells. Whether CA1 representations of familiar places are stable or not has only been partially explored empirically. To date, the data on place fields' stability has generally been restricted to small numbers of cell recorded over at most a week. These studies have shown the existence of place cells with stable place fields, but the data have been too sparse to assess how place cell codes evolve at the population level. We will deve- lop general methods for tracking long-term coding dynamics by combining multiple, recent technical advances. Our approach will allow the first large-scale studies of how CA1 place cell codes evolve over weeks and yield a powerful means by which neuroscientists can address many unanswered questions about long-term memory. We will combine 4 recently developed optical imaging techniques, which together afford the first chance to track the dynamics of genetically identified CA1 cells over multiple weeks in the live brain. Our two aims are: Aim 1: Establish a methodology for time-lapse imaging of CA1 neural dynamics over weeks, across hundreds of genetically targeted neurons in freely behaving mice. This will provide an enabling approach for tracking how information is stored and represented by large ensembles of genetically defined neurons. Aim 2: Quantitatively assess the long-term kinetics of CA1 ensemble place codes. We wil track how CA1 representations of space evolve in subjects visiting a familiar environment repeatedly for 60 days. We will compare two competing ideas, that individual cells retain stable place fields upon re-visitation of a familiar environment; or alternatively that individual cells' coding properties gradually evolve over time. We will thus quantify the constancy or changes in individual cells' coding properties, and in ensemble features such as the density of place cell coverage and fraction of observed cells involved in representing a given arena. The results will shed light on how CA1 represents and stores information over durations pertinent to long-term memory. If our work succeeds, many previously unanswerable questions wil be addressable by similar means. Our approach should be widely applicable to other brain areas and forms of memory.