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    578—Animal Learning and Memory: Cortical and Hippocampal Circuits III

    Tuesday, November 12, 2013, 8:00 am - 12:00 noon

    578.14: Inception of a false memory in the hippocampus

    Location: Halls B-H

    1Brain and Cognitive Sciences, MIT, 2MIT, Cambridge, MA

    Abstract Body: Memories are usually excellent guides for cognition and behavior. However, they can also be unreliable, and false memories in particular have had severe legal consequences. Despite these social ramifications, the lack of relevant animal models has largely hindered our understanding of the neural basis of false memories. Here, we describe the inception of a false memory in mice by optogenetically manipulating memory engram-bearing cells in the hippocampus. Mice were allowed to explore a particular environment and dentate gyrus (DG) or CA1 neurons activated by the exposure to this context were labeled with channelrhodopsin-2 (ChR2). These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context in which a foot shock was never delivered compared to: the control groups not expressing ChR2, a group in which light was omitted, and a group that underwent a similar manipulation in CA1. The recall of this false memory was context-specific, activated similar downstream regions engaged during natural fear memory recall, and was also capable of driving an active fear response in a conditioned place avoidance paradigm. The formation of a false memory interfered with the concurrent formation of a natural memory and could have either an additive or competitive effect during the recall of the natural fear memory. Together, our data demonstrate that it is possible to substitute a natural conditioned stimulus (CS) with artificially reactivated DG cells that bear contextual memory engrams to incept an internally represented false fear memory.

    Lay Language Summary: Our research findings are threefold: we first identified single memories in the brain and made the underlying brain cells respond to pulses of light; we then were able to bring back the associated memories at any given moment by activating these cells directly with light; and finally, we artificially activated a specific memory and altered it by associating it with new information, thereby creating a false memory for an event that did not occur.
    When we think back to our first kiss, that time we got into college, or last year’s colorful Bourbon Street experiences at SfN, our brains perform the remarkable task of mental time travel and enrich our lives with a personal narrative. How does neural activity give rise to the seemingly ephemeral content of memory? Moreover, can we causally dissect the underlying neural circuits supporting recollection?
    For decades, the hippocampus has been implicated in processing personally experienced events and storing them for later reminiscence. Most studies to date, however, have focused on inactivating certain brain regions and observing the accompanying side effects at the neuronal, circuit, and behavioral level, therefore testing the necessity of these brain regions. Last year, our team tested a longstanding key hypothesis in neuroscience that asked a question of sufficiency: are the cells active during the formation of a memory sufficient for the reinstatement of that memory? By combining optogenetic and transgenic techniques to label the cells in the hippocampus active during learning with a light-sensitive protein, we were able to optically reactivate these same cells and, remarkably, drive the behavioral expression of the associated memory.
    These findings now enabled us to investigate how these light-activated, internally generated memories can be associated with emotionally salient external events to form new memories. We began by finding and labeling a memory in the hippocampus for a specific environment (context A). We then placed our animals in a second environment (context B) and optically reactivated the memory for the first environment (context A) while delivering mild foot shocks. Here, we were artificially associating the light-reactivated memory for context A with the aversive experience of a foot shock. When we placed our subjects back in context A--the context in which the animals had never experienced an aversive event in real life--they now showed heightened fear responses, thus demonstrating for the first time the formation of a false memory. This false memory was also capable of driving an active fear response and activated similar brain regions involved in true fear memory recall, indicating that, from the animal’s perspective, the false memory seemed to be a real memory.
    False memories riddle both daily life and modern jurisprudence. More than 75% of people wrongfully convicted of a crime and then sentenced to jail--only later to be exonerated by DNA evidence--were victims of faulty eyewitness testimony. Human studies have pointed to the hippocampus as a key region involved in false memory processes, though until now it has not been possible to identify the exact subregions and circuits responsible for generating false memories. Our results propose a neural mechanism for how these cognitive quirks may occur and provide an animal model to causally deconstruct the recollective process.
    In the long run, our findings may permit an optogenetic dissection of neuropsychiatric disorders including post-traumatic stress disorder, anxiety, and depression--all at the level of specific memories. We anticipate that many of the cognitive and behavioral deficits associated with these pathologies can be partially rescued by optically inhibiting the underlying circuitry during their development, or perhaps even reversing the associated deficits by optically editing the valence of any given memory.