Memory formation in the human medial temporal lobe

当今的科学挑战之一是了解记忆是如何储存在大脑中的。可以考虑一些简单的事情，比如回忆第一次见到一个人的情景。我们的大脑毫不费力地创造了这样的记忆，但这涉及到我们仍然不了解的复杂神经元过程。例如，人们可能会问：新人的神经元表征是如何形成的，这种表征是如何在未来几年巩固和储存的？为了回答这些问题，我们最好能记录下受试者执行记忆任务时神经元的活动。然而，有一个主要的限制：我们通常不能记录人类单个神经元的活动。问题在于，为了记录单个神经元的活动，我们必须在大脑内部引入小电极，出于明显的伦理原因，这是不可能做到的，因此，我们只能通过脑电图或功能磁共振成像等技术，从头骨外部获取神经元活动的记录。然而，这些方法不能提供关于单个神经元活动的信息，因此不能揭示记忆形成的精确神经机制。另一种方法是通过在动物的大脑中植入电极来记录单个神经元，但可以研究的实验和问题的类型是有限的，因为动物不能给出它们的想法和回忆的反馈，需要大量的训练，与现实生活中记忆形成的自然条件相距甚远。在非常特殊的情况下，单个神经元的记录可以在人类身上进行。这是癫痫患者的情况，他们因临床原因植入颅内电极。在研究这些受试者的神经元活动时，我们发现了被称为“概念细胞”的东西。“詹妮弗·安妮斯顿神经元”)：也就是说，神经元以一种非常有选择性和抽象的方式对特定的人或物体做出反应，比如詹妮弗·安妮斯顿、卢克·天行者或比萨斜塔。例如，一个神经元对7张詹妮弗·安妮斯顿的不同照片做出反应，而不是对80张其他人或物体的照片做出反应。这意味着神经元对“詹妮弗·安妮斯顿”这个概念做出反应，而不是对呈现的每张图片的不同细节做出反应。鉴于它们位于已知对记忆至关重要的区域，我们认为这些神经元与记忆功能有关——这与我们倾向于记住概念而忘记无关细节的事实相一致。然而，我们仍然不知道他们是如何开始对特定概念做出反应的（例如，我们第一次见到的人），以及这些新的记忆表征最终是如何巩固的。该项目将利用记录人类单个神经元的独特机会，与其他动物不同，人类可以对自己的想法和回忆给出详细的反馈。我们将通过跟踪神经元在记忆产生和巩固过程中的放电来探索记忆形成的神经机制。特别是，我们将分析当受试者在重复呈现后熟悉最初未知的面孔时神经元的活动。为了在更自然的情况下研究记忆的形成，我们还将跟踪受试者在观看最初不熟悉但非常吸引人的电影（来自60年代希区柯克的电视剧）时神经元的活动，从而研究神经元是如何对熟悉的不同电影角色进行编码的。实验将每天重复两次（在几个小时的休息后），并在连续几天内进行，以评估神经元反应的稳定性。此外，实验还将辅以特定的问卷调查，以确定神经元编码的记忆的本质，例如它们的情感显著性或特定回忆的触发。总之，我们将首次描述与创造和巩固新记忆有关的神经机制。

One of today's scientific challenges is to understand how memories are stored in the brain. Consider something as simple as remembering meeting a person for the first time. Our brain creates such memories effortlessly, but this involves complex neuronal processes that we still do not understand. One could, for example, ask: How is the neuronal representation of the new person formed, and how is this representation consolidated and stored for years to come? To answer these questions, we would ideally like to record the activity of neurons while subjects perform memory tasks. However, there is a major limitation: we usually cannot record the activity of individual neurons in humans. The problem is that to record the activity of individual neurons we must introduce small electrodes inside the brain, something that cannot be done for obvious ethical reasons and, consequently, we have only access to recordings of neuronal activity from outside the skull, using techniques such as EEG or fMRI. However, these methods cannot give information about the activity of individual neurons and can therefore not unravel the precise neural mechanisms of how memories are formed. An alternative approach is to record individual neurons by implanting electrodes in animals' brains, but the types of experiments and questions that can be studied are limited, as animals cannot give feedback of their thoughts and recollections and need extensive training, far from the natural conditions of real-life memory formation.In very specific cases, recordings of individual neurons can be performed in humans. This is the case of epileptic subjects, who are implanted with intracranial electrodes for clinical reasons. While studying the activity of neurons in these subjects, we discovered what have been named "Concept Cells" (a.k.a. "Jennifer Aniston neurons"): namely, neurons that respond in a remarkably selective and abstract manner to specific persons or objects, like Jennifer Aniston, Luke Skywalker or the Tower of Pisa. For example, one neuron responded to 7 different pictures of Jennifer Aniston and not to 80 pictures of other persons or objects. That means the neuron responded to the concept "Jennifer Aniston" and not to the different details of each of the pictures presented. Given that they are located in an area that is known to be critical for memory, we have argued that these neurons are involved in memory functions - in agreement with the fact that we tend to remember concepts and forget irrelevant details. However, we still do not know how they start responding to specific concepts (e.g. the person we meet for a first time) and how these new memory representations may eventually consolidate. The project will exploit the unique opportunity of recording individual neurons in humans, who, in contrast to other animals, can give detailed feedback of their thoughts and recollections. We will explore the neural mechanisms of memory formation by tracking the firing of neurons while memories are created and consolidated. In particular, we will analyze the activity of neurons while the subjects familiarize themselves with initially unknown faces after repeated presentations. To study memory formation in more natural situations, we will also track the activity of neurons while the subjects watch initially unknown and very engaging movies (from a Hitchcock TV series from the 60s), thus studying how the neurons encode the different movie characters as they become familiar. Experiments will be repeated twice a day (after a few hours' break) and in consecutive days, to assess the stability of the neurons' responses. Furthermore, experiments will be complemented with specific questionnaires to determine the nature of memories encoded by the neurons, such as their emotional saliency or the triggering of specific recollections.In summary, we will describe for the first time the neural machinery that is involved in creating and consolidating new memories.