Sensory sequence representation and discrimination in cortical circuits

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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.