Toward causal neuroscience: capture and manipulate emergent neuronal ensembles

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DESCRIPTION (provided by applicant): It is hypothesized that animals' perceptual, emotional, or behavioral processes are governed/caused by specific patterns of brain activities, or firings of selected populations (ensembles) of neurons across multiple regions in the nervous system. Indeed recent advancements in optic imaging and multi-electrode recording technology have begun to reveal the inordinately complex dynamics of large populations of neurons in awake, behaving vertebrates such as larval zebrafish and rodents. However, these visualization/recording experiments could not definitively establish the causal relationships between the activities of neuronal ensembles and their functions. A toolkit that enables neuroscientists to be not only observers, but also actuators of the observed ensembles is critically needed for "causal neuroscience". The difficulty to developing such a toolkit lies in th complexity of the mammalian brain, which contains billions of neurons and trillions of synapses. Thus, individual neurons are likely to participate in different active ensembles at different time points. Hence the ensembles associated with a given behavioral or perceptual process are emergent properties arising out of the complicated interactions among millions of neurons. Therefore, ensembles are unlikely to be genetically pre-determined, and molecule or cell-type based methods are not useful for "labeling and manipulating" them. To overcome this difficulty, we will develop a novel toolkit consisting of two key components: (1) a mouse line designed to express, transiently and selectively, a very unstable foreign receptor only in activated neurons, and (2) engineered non-toxic, pseudo-typed viruses that can only infect neurons expressing this foreign receptor. In this way, timed-injection of the pseudo-typed viruses will allow us to specifically and permanently "capture" the recently activated ensembles (which are the ones expressing the viral receptor). The engineered viruses can int