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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    770—Hippocampal Function and Aging

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    770.02: Functional dissection of the role of adult hippocampal neurogenesis in pattern separation

    Location: Halls B-H

    *M. A. KHEIRBEK, L. J. DREW, E. M. BALOUGH, R. HEN;
    Psychiatry & Neurosci., Columbia Univ., New York, NY

    Abstract Body: Adult neurogenesis in the dentate gyrus (DG) has been proposed to play a cognitive function in pattern separation, modulate stress responses and mediate some of the behavioral effects of antidepressants. The majority of our insight into the contribution of adult neurogenesis to behavior comes from long-term manipulations that impact the total number of adult born neurons. To address the on-line role for adult generated DG granule cells (GCs) in behavior, we used optogenetic techniques to selectively modulate the activity of adult generated neurons in a region-specific manner. To this end, we first selectively expressed channelrhodopsin-2 (ChR2) or archaerhodopsin (Arch) in adult generated GCs and then optically modulated these cells in the dorsal or ventral DG. Direct optical inhibition of adult generated GCs in the dorsal DG disrupted the rapid encoding of contextual fear memories, while optical excitation of this cohort of cells impaired both contextual encoding and retrieval. As this manipulation allows for epoch selective modulation of activity in adult generated neurons, we tested whether these cells play a context-limited role in a pattern separation task that requires mice to discriminate between a shocked context and a similar, safe context. Activity in adult-generated GCs in the dorsal DG was suppressed during either exposure to the conditioning context or the similar, safe context. Surprisingly, inhibition of young GCs during exposure to the similar context, but not the conditioning context, impaired discrimination. This suggests that while activity in young GCs was not needed for the maintenance of a learned contextual representation, they were necessary for the disambiguation of similar information from learned information. Thus, adult generated neurons in the dorsal DG are required for the rapid encoding of novel contextual information and to disambiguate novel representations from learned ones.

    Lay Language Summary: To keep memories for different experiences distinct, the hippocampus must encode the distinct features of the environment, and distinguish these features from previously encountered experiences. Here, we show that adult generated neurons in the hippocampus are essential for this process, and are specifically required for distinguishing novel information from already learned information.
    The process of disambiguating new information from similar stored representations, termed “pattern separation,” may be compromised in anxiety disorders such as post-traumatic stress disorder (PTSD). For example, a veteran with PTSD may experience heightened arousal and anxiety to a cue that resembles the traumatic experience (such as a campfire), even when other contextual cues indicate safety (such as absence of combat and a park setting), a phenomenon often referred to as overgeneralization. Our studies have modeled this process in mice, revealing that adult generated neurons of the dentate gyrus are specifically required during encoding of the safe situation (the campfire), to disambiguate it from the fearful one (combat). Having identified how adult generated neurons contribute to pattern separation, we can design more effective, targeted treatments for individuals suffering from PTSD and other anxiety disorders involving impaired contextual discrimination or overgeneralization.
    Our findings are consistent with previous studies indicating that adult generated neurons are important for pattern separation. Yet, before this study, it was not possible to determine the mechanism by which these neurons may facilitate this process. Previous studies have used long-term manipulations such as ablation or genetic expansion of this population of neurons. In this study, we have manipulated the adult-born neurons in the dentate gyrus in real time while the animal was encountering fearful and similar but safe contexts. SFN 2013 will be first time this work has been presented to the public.
    To achieve this, we employed optogenetic techniques in which we use light to either silence or excite adult-born cells in the dentate gyrus. Using this technique, we tested whether these cells play a context-dependent role in a pattern separation task that requires mice to discriminate between a fearful context and a similar, safe context. We suppressed activity in adult-generated cells during either exposure to one of the two contexts: the noxious one in which they received a foot-shock, or the similar context where no shock was administered. Surprisingly, inhibition of adult generated neurons during exposure to the safe context, but not the aversive context, impaired discrimination. This suggests that while activity in young GCs was not needed for the maintenance of a learned contextual representation, they were necessary for the disambiguation of similar information from learned information.
    As our studies reveal that adult neurogenesis influences pattern separation, we hypothesize that targeting adult neurogenesis to improve pattern separation, particularly for situations and contexts that are emotionally charged, may be beneficial for the treatment of anxiety disorders. Specifically, this research suggests that modulating the properties of adult generated neurons after the initial trauma may restrain overgeneralization and may be effective for the treatment of patients who display pattern separation deficits.