Circuit-level mechanisms of memory consolidation

了解记忆是神经科学的中心目标，对治疗阿尔茨海默病和其他痴呆症具有潜在的深远影响。记忆的形成需要“离线巩固”，即在睡眠期间选择性地稳定代表新获得的经验的神经元轨迹。在提取后，巩固的记忆经历了一个额外的重新巩固过程，进一步稳定了它们的长期表达。特定大脑区域的损伤会导致选择性行为损伤。例如，海马体编码关于特定事件和地点的新记忆(情节记忆和空间记忆)。我们缺乏对新记忆如何获得长期表达的全面了解，但海马电活动的两种不同模式可以促进巩固过程：尖波纹波(SWR)和齿状棘波。短波反射已经得到了很多科学的关注，而干扰短波反射会损害记忆。相比之下，人们对齿状棘波知之甚少，这是一个误导性的术语，指的不是单个齿状颗粒细胞(DGC)的动作电位，而是招募许多DGC的大型群体事件。从来没有人通过压制齿状棘波来确定它们在记忆中的作用。我们提议的实验将解决我们知识中的这一重要缺口，使用尖端技术在学习后睡眠中检测和沉默小鼠大脑中的齿状棘波，从而揭示它们对记忆巩固的贡献。我们的方法将利用复杂的遗传方法，可以将光敏蛋白输送到特定的神经元(例如DGC)。当受到光刺激时，这些蛋白质会使这些神经元静默或激活。我们将使用齿状棘波的实时检测来触发光刺激，使我们能够精确控制睡眠期间的神经元活动。我们将评估齿状棘波对两种不同形式的记忆的贡献，这两种形式都需要海马体。首先，我们将研究齿状棘波沉默对联想记忆的影响，例如，学习线索A预测结果X。通常，学习简单的联想不需要海马体，但如果关系变得模糊(例如，在试验的子集上，结果X只跟随线索A)，那么海马体就变得必要了。其次，我们将研究沉默齿状棘波对非联想记忆的影响，例如，使用记忆线索的相对新颖性或熟悉性来指导行为选择。巩固被认为是联想记忆的关键，但不是非联想记忆。如果抑制齿状棘波也会影响非联想记忆，这将意味着在记忆中扮演更一般的角色，而不是在巩固本身。此外，在控制条件下，我们将在睡眠期间使DGC静默，但在齿状尖峰期间不会，看看这是否也影响记忆巩固。下一步，我们将确定驱动齿状尖峰的神经元输入。我们将使用最近开发的一种技术来选择性地瞄准直接投射到DGC的新皮质中的神经元，并确定激活或沉默这些新皮质细胞是如何改变齿状棘波的。最后，我们将测试在“重新巩固”期间抑制已经巩固的记忆如何影响其长期表达。我们将使用一种特殊的转基因小鼠品系，这种品系可以在特定学习过程中活跃的细胞中选择性地驱动一种光敏神经元抑制物的表达。在稍后的时间，我们将重新激活这一记忆，使记忆处于不稳定状态，然后确定在这种重新激活后抑制齿状棘波如何影响这一记忆的重新巩固。总的来说，我们的实验将为全面理解记忆长期表达的电路水平机制做出重大贡献。

Understanding memory is a central goal of neuroscience, with potentially far-reaching consequences for treating Alzheimer's disease and other dementias. Memory formation requires 'offline consolidation', whereby the neuronal traces representing newly-acquired experiences are selectively stabilised during sleep. Following their retrieval, consolidated memories undergo an additional process of reconsolidation that further stabilizes them for long-term expression.Damage to particular brain regions results in selective behavioural impairments. The hippocampus, for example, encodes new memories about specific events and places (episodic and spatial memories). We lack a comprehensive understanding of how new memories gain long-term expression but two distinctive patterns of hippocampal electrical activity could promote consolidation processes: sharp-wave ripples (SWRs) and 'dentate spikes'. SWRs have received much scientific attention, and disrupting SWRs impairs memory. In contrast, little is known about dentate spikes, a misleading term that refers not to the action potentials of individual dentate granule cells (DGCs) but to a large population event that recruits many DGCs. No one has ever silenced dentate spikes to determine their role in memory. Our proposed experiments will address this important gap in our knowledge, using cutting-edge technology to detect and silence dentate spikes in the mouse brain in post-learning sleep, thereby revealing their contribution to memory consolidation.Our approach will utilise sophisticated genetic approaches that can deliver light-sensitive proteins into particular neurons (e.g. DGCs). When stimulated by light, these proteins will silence or activate those neurons. We will use real-time detection of dentate spikes to trigger light-stimulation, giving us precise control over neuronal activity during sleep.We will assess the contribution of dentate spikes to two distinct forms of memory, both of which require the hippocampus. First we will investigate the effects of dentate spike silencing on associative memory, e.g. learning that cue A predicts outcome X. Ordinarily, learning simple associations does not require the hippocampus, but if the relationship is made ambiguous (e.g. such that outcome X only follows cue A on a subset of trials), the hippocampus then becomes necessary. Second, we will investigate the effects of silencing dentate spikes on non-associative memories, e.g. using the relative novelty or familiarity of mnemonic cues to guide behavioural choices. Consolidation is thought to be critical for associative but not non-associative memories. If silencing dentate spikes also affects non-associative memory, this would suggest a more general role in memory, rather than in consolidation per se. Moreover, in control conditions we will silence DGCs during sleep but NOT during dentate spikes to see whether this also affects memory consolidation.Next, we will determine the neuronal inputs driving dentate spikes. We will use a recently developed technique to selectively target neurons in the neocortex that project directly to DGCs and determine how activating or silencing those neocortical cells alters dentate spikes.Finally, we will test how inhibiting an already consolidated memory during 'reconsolidation' affects its long-term expression. We will use a special genetically-modified mouse line that can drive the expression of a light-sensitive neuronal inhibitor selectively in cells that were active during a particular learning episode. At a later time we will reactivate this memory, which places the memory in a labile state, and then determine how inhibiting dentate spikes following this reactivation affects the reconsolidation of this memory.Collectively, our experiments will make a major contribution to a comprehensive understanding of the circuit-level mechanisms underlying the long-lasting expression of memory.