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，关于所存储信息的神经系综表示是否随数周或更长时间尺度演变的数据是有限的。这项拨款建议在哺乳动物CA 1海马表示物理空间和空间记忆的背景下研究这些问题。我们将利用CA 1“位置细胞”的既定特性，当哺乳动物受试者物理上位于细胞的“位置场”内时，CA 1“位置细胞”表现出升高的尖峰速率。一些理论认为，位置细胞应该重新形成稳定的位置场，以便长期保持熟悉的空间环境。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编码发生在同一环境中的不同事件。熟悉地点的CA 1表征是否稳定，只有部分经验探索。 迄今为止，关于位置场稳定性的数据通常仅限于最多一周内记录的少量细胞。这些研究表明，存在稳定的位置场的位置细胞，但数据过于稀疏，无法评估位置细胞代码如何在种群水平上进化。我们将结合多个最新的技术进步，开发跟踪长期编码动态的一般方法。我们的方法将允许第一次大规模研究CA 1位置细胞密码如何在数周内进化，并产生一种强大的手段，使神经科学家可以解决许多关于长期记忆的未解之谜。 我们将结合联合收割机4个最近开发的光学成像技术，它们一起提供了第一次机会，以跟踪动态的遗传识别的CA 1细胞在活的大脑中多个星期。我们的两个目标是：目标1：建立一种方法，在自由行为小鼠的数百个遗传靶向神经元上，对数周内的CA 1神经动力学进行延时成像。这将为跟踪信息是如何存储和由遗传定义的神经元的大集合表示提供一种使能方法。目的2：定量评估CA 1系综位置代码的长期动力学。我们将跟踪如何CA 1表示空间的主题访问一个熟悉的环境反复60天的演变。我们将比较两种相互竞争的观点，即个体细胞在重新访问熟悉的环境时保持稳定的位置场;或者个体细胞的编码特性随着时间的推移逐渐演变。因此，我们将量化个体细胞编码特性的恒定性或变化，以及整体特征，如位置细胞覆盖的密度和参与代表给定竞技场的观察细胞的分数。 研究结果将揭示CA 1如何在与长期记忆相关的持续时间内表示和存储信息。如果我们的工作成功，许多以前无法回答的问题将通过类似的方法得到解决。我们的方法应该广泛适用于其他大脑区域和记忆形式。 公共卫生相关性：在神经科学中，目前的限制是无法在数周或更长时间内可靠地跟踪单个神经元的动力学和编码特性。我们的工作旨在创造一种大脑成像技术，使研究人员能够长时间监测自由行为小鼠大脑深处基因靶向神经元的动态。然后，我们将使用这种成像技术来检查支持海马体中空间和长期空间记忆表征的神经代码数周的演变，海马体是与许多神经精神疾病（包括几种记忆疾病）有关的关键大脑区域。

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. PUBLIC HEALTH RELEVANCE: In neuroscience, a current limitation is the inability to reliably track the dynamics and coding properties of individual neurons over periods of weeks or more. Our work seeks to create a brain-imaging technique that will alllow researchers to monitor the dynamics of genetically targeted neurons over long time periods deep in the brains of freely behaving mice. We will then use this imaging technique to examine the evolution over weeks of the neural codes that support the representation of space and long-term spatial memory in the hippocampus, a key brain area implicated in many neuropsychiatric disorders including several diseases of memory.