Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2015.Cataloged from PDF version of thesis.Includes bibliographical references (pages 212-230).Memories thread and unify our overall sense of being. With the accumulation of our knowledge about how memories are formed, consolidated, retrieved, and updated, neuroscience has reached a point where brain cells active during these discrete mnemonic processes can be identified and manipulated at rapid timescales. Here, I begin with historical studies that lead to the modem memory engram theory. Then, I present our recent advances in memory research that combine transgenic and optogenetic approaches to reveal underlying neuronal substrates sufficient for activating mnemonic processes. Our studies' conclusions are threefold: (1) we provide proof of principle evidence demonstrating that learning-related neural changes can be isolated at the level of single cells, and that these cells can then be tagged for subsequent manipulation; (2) a defined subset of hippocampus cells are sufficient to elicit the neuronal and behavioral expression of memory recall, as well as sufficient to modify existing positive and negative memories; (3) and finally, artificially activated memories can be leveraged to acutely and chronically suppress psychiatric disease-related states. We propose that hippocampus cells that show activity-dependent changes during learning construct a cellular basis for contextual memory engrams and that directly activating these endogenous neuronal processes may be an effective means to correct maladaptive behaviors.by Steve Ramirez.Ph. D.