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    192—Learning and Memory: Genes, Signaling, and Neurogenesis I

    Sunday, November 10, 2013, 8:00 am - 12:00 noon

    192.12: Time-lapse In vivo imaging of Arc/Arg3.1 expression in adult mouse CA1 hippocampus reveals cellular turnover in the representation of life experience

    Location: Halls B-H

    1Stanford Univ., Stanford, CA; 2Howard Hughes Med. Inst., Stanford, CA; 3Grad. Sch. Med., Univ. of Tokyo, Tokyo, Japan; 4CREST-JST, Tokyo, Japan; 5CNC program, Stanford, CA

    Abstract Body: Mammalian hippocampus plays key roles in the representation of experience and the acquisition and recollection of episodic memories. Long-term modifications to hippocampal neurons’ connectivity and cellular properties underlie these functions, and a key effector is the protein Arc (Arg3.1) that helps regulate AMPA receptor recycling upon increased synaptic activity. In rodent hippocampus, learning and novel experience induce Arc expression; down-regulation or knockout of Arc impair learning and memory. In response to novel experiences, specific subsets of pyramidal cells express Arc, which has led to the hypothesis that patterns of Arc expression provide a representation of experience instrumental to learning and long-term memory.
    Here we investigate the extent to which Arc expression produces a specific hippocampal representation of experience. We developed time-lapse microscopy methods for tracking Arc expression over multiple weeks in the CA1 hippocampal area of adult mice. This involved a genetically encoded Arc transcriptional activity reporter that permitted repeated determinations of Arc expression across hundreds of individual pyramidal cells in the adult brain (Kawashima et al. Soc. Neurosci. Abs. 2012).
    Following transient periods in which we provided the mice enriched environmental conditions, we observed robust increases in Arc expression across substantial subsets of the CA1 pyramidal cell population. Exposures to the same enriched environment on different days elicited spatially correlated patterns of Arc expression in response to the two experiences. Exposures to distinct environments elicited uncorrelated patterns of Arc expression, indicating Arc expression patterns can reflect the similarity of a recent experience to a prior one. Levels of correlation in Arc expression elicited by two exposures to the same environment did not change when the mouse had an intervening enriched experience, in either the same or another environment, suggesting that intervening experiences do not alter the specificity of Arc expression patterns. Multiple exposures to the same environment always elicited robust re-expression of Arc, but the correlations in Arc expression decayed monotonically with the time interval between exposures. This turnover in the cellular membership of CA1 encoding ensembles is consistent with recent time-lapse calcium-imaging data in freely behaving mice revealing a similar effect (Ziv et al., Nat. Neurosci. 2013). Further studies will be necessary to elucidate the extent and mechanisms by which Arc helps shape gradual changes in CA1 neural representations over the time scale of days to weeks.

    Lay Language Summary: Our study shows that populations of neurons in the hippocampus, a crucial brain region for learning and memory, generate representations of the external environment through coordinated changes of their cellular properties. Each such representation appears to be distinct, not only for different environments that a subject has experienced, but also for different exposures to the same environment that a subject has experienced on different occasions. This finding suggests that the brain's representations of experience have their own internal dynamics, which might aid the brain in distinguishing between experiences that are similar in quality but separated in time.
    The hippocampus represents the external environment through the coordinated electrical activity of its neuronal populations. Such coordinated activity translates a subject's experiences of the external world into internal neuronal representations that are important for learning and memory. At the level of individual neurons, electrical activity modifies the ways in which neurons process information in the future. This phenomenon is called neuronal plasticity and it potentially allows cells to store information for the long-term. Through the aggregate occurrences of plasticity across networks of hippocampal neurons, electrical activity may be translated into long-lasting representations of an experience; the specific neurons that undergo plasticity are those especially relevant for storing or representing the particular experience.
    Thanks to new technologies developed in our two laboratories through an international collaboration, we were able to explore this hypothesis for the first time in the hippocampus of live mice. Moreover, our technologies enabled us to carry out our investigations over several weeks, a time scale relevant for long-term memory.
    We allowed mice to explore a novel environment for two hours. Five days later we exposed the mice for two more hours to either the same environment or a different one. Following each exploration episode, we monitored the ensembles of activated neurons by optically imaging the expression of a gene crucial for plasticity, Arc/Arg3.1, in hundreds of neurons in the hippocampus of each mouse. Patterns of Arc/Arg3.1 expression were highly specific for each environment but were similar when the animal was exposed twice to the same environment and different when the animal was exposed to different environments. This shows that the pattern of plasticity-modulated neuronal activation can discriminate between a familiar and a novel environment. In a second set of experiments, we exposed mice repeatedly to the same environment for over a month and imaged the pattern of Arc/Arg3.1 expression after each exposure. Surprisingly, when animals explored the same environment multiple times the pattern of neuronal activation was not always similar to itself but rather evolved over time. This shows that the manner in which neurons represent even one environment is not fixed but gradually changes.
    In this study we establish crucial properties of plasticity-modulated brain activity at the network-level to an unprecedented level of detail. Our results offer new insights regarding how life experiences give rise to long-term cellular changes across large networks of neurons. In addition, the technologies we have developed provide new ways to investigate how cellular plasticity impacts learning during disease progression or aging.