Sensory sequence representation and discrimination in cortical circuits

我们在空间和时间上体验世界。为了理解环境，我们需要能够区分序列，也就是说，暂时形成模式的刺激。听觉和触觉刺激只能根据它们的时间结构来理解——这是大脑特别擅长破译和记忆的线索，例如当我们学习一首新歌或某种节奏时。产生和解码脑电活动序列的能力在整个大脑中无处不在。此外，在抑郁症和精神分裂症等精神疾病中，序列学习和时间持续时间加工受到损害。然而，尽管序列选择性具有这种中心地位，但人们对其在大脑中的底物知之甚少。从一个连续的时间模式第一次反映在神经元的电活动中，到它被归类为一个“对象”，一个有意义的实体，这一系列的事件仍然是未知的。这是我们对大脑功能理解的一个重大空白。这个项目的目标是了解序列的表征是如何从大脑皮层中神经元群的活动中产生的。大脑皮层是大脑的一部分，它结合来自感官的信息，赋予其意义，将其与先前的经验联系起来，并决定反应。为了展示神经元的电活动如何与序列识别相关，有必要将呈现序列时的神经元反应与显示受试者区分序列的特定行为联系起来。为此，我们创造了一种新的行为任务，在老鼠和人类身上都能成功地完成。老鼠学会了探测传递到它们胡须上的任意刺激序列——触觉上的“歌声”或“话语”。呈现的序列只是在时间模式上有所不同，老鼠学会识别特定的序列来获得奖励。这个实验设计的目的是让我们能够在大脑中寻找序列识别的一般原理，特别是测试对给定序列敏感的神经元是否存在于皮层的感觉区域。我们建议将这种设计与检测和操纵大脑活动的强大新技术结合起来。我们将使用电生理学和双光子成像的方法，已经建立在我们的实验室，记录活动。通过最先进的基因和成像工具，记录将针对大脑皮层的神经元群。这些实验将使我们能够揭示与受控感觉行为相关的神经元活动，并识别对特定序列有选择性的神经元。我们的研究将为神经回路如何随着时间的推移处理信息以产生感觉和知觉提供新的见解。因为在不同的哺乳动物物种中，大脑皮层感觉区域的神经回路是相似的，这一新知识将跨物种相关，也将适用于人类序列学习。这一结果的意义将超越我们对皮层神经元信息流的基本理解。由于序列处理通常在扰乱皮层神经元回路正常建立的疾病中受损，我们的方法将有助于理解这些疾病的功能影响，并为测试脑病理的神经生物学模型提供一种分析方法。

We experience the world in both space and time. To make sense of an environment, we need to be able to distinguish sequences, i.e., stimuli that are temporally patterned. Auditory and tactile stimuli can only be understood in terms of their temporal structure - a cue that the brain is particularly good at deciphering and remembering, for example when we learn a new song or a certain rhythm. The ability to generate and decode sequences of electrical activity is ubiquitous throughout the brain. Moreover, sequence learning and the processing of temporal duration are impaired in psychiatric disorders including depression and schizophrenia. Yet despite this centrality of sequence selectivity, remarkably little is known about its substrates in the brain. The chain of events from when a sequential temporal pattern is first reflected in the electrical activity of neurons to when it is classified as an "object," a meaningful entity, remains unknown. This is a major gap in our functional understanding of the brain. The goal of this project is to understand how representations of sequences emerge from the activity of populations of neurons in the cerebral cortex - the part of the brain that combines information from the senses, assigns it a meaning, relates it to earlier experience and decides on a response. To show how electrical activity in neurons relates to sequence recognition, it is necessary to link neuronal responses during presentation of a sequence to a specific behaviour showing that the subject distinguishes the sequence. To this end, we have created a novel behavioural task that is successfully performed by mice as well as by humans. Mice learn to detect arbitrary sequences of stimulation delivered to their whisker - tactile "songs" or "words." The sequences presented differ only in their temporal patterning, and mice learn to recognise a particular sequence for a reward. This experimental design is designed to allow us to search for general principles of sequence recognition in the brain, and specifically to test whether neurons sensitive to a given sequence reside in sensory areas of the cortex. We propose to combine this design with powerful new techniques for examining and manipulating brain activity. We will use methods of electrophysiology and two-photon imaging, already established in our laboratory, to record activity. Recordings will be targeted to groups of neurons in the cerebral cortex by means of state-of-the-art genetic and imaging tools. These experiments will allow us to uncover the neuronal activity related to the controlled sensory behaviour and identify neurons that are selective to a particular sequence. Our research will provide new insights into how neuronal circuits process information over time to give rise to sensation and perception. Because the neuronal circuitry in sensory areas of the cerebral cortex is similar in different mammalian species, this new knowledge will be relevant across species and will apply to human sequence learning as well. The outcome will have implications beyond improving our fundamental understanding of information flow through cortical neurons. As sequence processing is often impaired in disorders that perturb the normal establishment of neuronal circuits in the cortex, our approach will help the understanding of the functional effects of those disorders, and provide an assay for testing neurobiological models of brain pathologies.