The mammalian brain consists of hundreds of millions to billions of nerve cells (neurons) that form complex networks. How perception, cognition, and action are reflected by the activities of neurons is a central question in modern neuroscience. The investigators have previously developed a genetic method to mark neurons that are activated by a specific sensory experience or behavioral episode, so they can visualize their connections and measure their activities. In this research, the investigators will develop new methods to improve the signal-to-noise ratio to more effectively identify the active neurons, and to mark two separate experiences differentially in the same animal so they can directly compare physiological properties of two populations of neurons, such as those before and after learning. The success of these approaches will enable scientists to compare brain representations of different stimuli and behavior, and what changes occur after learning.
The method used to mark active neurons (TRAP, for targeted recombination in active populations) utilizes the property of immediate early genes, whose transcription is activated by neuronal activity. This was achieved using mouse genetics to place a drug-inducible Cre recombinase under the control of immediate early gene promoters, such that experience in the drug-active period turns on Cre reporter transgenes permanently. This research will utilize a combination of viral transduction and mouse genetics to differentially label neurons that are activated by two separate experiences. In addition, a strategy of using light to locally silence inhibitory neurons will be used to enhance excitation-to-inhibition ratio, and thereby enhance TRAP efficiency, in a much narrower time window during the drug-active period. The new transgenic mice and viral vectors will be deposited in public repositories after validation.
