All-optical readout and manipulation of neural circuits in the intact mammalian brain

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Neurons in the brain store, process, and transmit information via electrical impulses. How does the spatiotemporal pattern of electrical impulses in the brain drive perception, or enable performance of an action? Such crucial questions have yet to be answered despite substantial recent progress in neuroscience. We propose to develop novel approaches to answer these fundamental questions, in order to reveal how our brains work to perform complex computational feats surpassing what human engineers can create. Such understanding may give us deep insights into the workings of the cerebral cortex, and will aid the fight against debilitating disorders of the brain.Previous research on how the electrical activity drives behaviour has taken two complementary approaches: correlating neuronal activity with what is happening in the environment, and stimulating neuronal activity while recording behavioural responses. In the first approach, many of the basic calculations performed by an animal's sensory system can be characterized by altering the environment and recording the response of neurons in the brain. Recent technical advances now enable recording of movies showing the activity of large groups of neurons at once. Such data are often highly informative, but nonetheless cannot reveal whether the recorded activity is solely responsible for one's perception, or may have just coincidentally occurred at the time of the recording. The second approach is to stimulate neuronal activity and record responses from an animal. While these experiments complement the first approach by providing more direct evidence, they show only that activating certain neurons is sufficient. For example, a neuron that is sufficient to drive an action in the lab may not necessarily be the neuron that is normally active when the animal behaves naturally. This subtle difference is crucial in understanding the neural code because the goal is to understand how the brain works under normal conditions, not how it is able to work under artificial conditions in the laboratory.The goal of this proposal is to bring these two approaches together by closing the loop between recording and manipulating neural activity and linking with behaviour. We have developed an optical approach which allows us to use light to both record and manipulate the activity of many neurons simultaneously on the level of individual electrical impulses. We will further develop this strategy for 'all-optical' readout and manipulation of entire neural circuits during behaviour. This will involve optimizing a toolkit for in vivo 'all-optical' interrogation incorporating custom optics, novel genetically engineered probes, and software built on large-scale computing platforms. This approach will allow us to perform 'real-time' readout and manipulation of functionally defined sets of neurons, allowing us to probe and interrogate the neural code 'on the fly' during behaviour. We will test this approach using experiments in the sensory cortex of a mouse performing a sensory discrimination task, in which we can manipulate neurons in precisely targeted manner and examine the influence on behaviour. The strategy outlined in this application will provide a new technology platform that is applicable to many fundamental problems in neuroscience with the potential for translation to clinical applications.