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    483—Medial Temporal Lobe Anatomy, Pharmacology and Function

    Monday, November 11, 2013, 1:00 pm - 5:00 pm

    483.04: The role of neurogenesis in the dentate gyrus for spatial pattern separation

    Location: Halls B-H

    1Univ. of Cambridge, Cambridge, United Kingdom; 2Univ. of Buenos Aires, Buenos Aires, Argentina; 3Swansea Univ., Swansea, United Kingdom; 4The Salk Inst., San Diego, CA

    Abstract Body: Pattern separation is a putative computational mechanism for distinguishing between memories, which transforms similar events into discrete non-overlapping representations. The Spontaneous Location Recognition (SLR) task is a behavioural task for rats designed to assess spatial pattern separation specifically during memory encoding. Two studies using this task will be described which indicate a role for plasticity mechanisms within the dentate gyrus (DG) in pattern separation.
    The first study used a lentiviral approach to specifically inhibit neurogenesis in the DG of adult male rats by inhibiting Wnt signaling, which is a principal regulator of adult hippocampal neurogenesis (Lie et al., 2005). This method has been successfully used in other studies to reduce neurogenesis in rats or mice (Clelland et al., 2009; Jessberger et al., 2009). The rats with inhibited DG neurogenesis demonstrated impaired recognition on the SLR task, when objects were placed in similar spatial locations (i.e., when pattern separation was required). This finding suggests that attenuating the production of adult-born DG neurons impairs memory retention when spatial representations require pattern separation.
    The second study was designed to evaluate the long-term effects of increasing neurogenesis, via administration of the peptide hormone ghrelin on spatial pattern separation using the SLR task. Rats treated with ghrelin sub-chronically (14 days, i.p. 10ug/kg, ending 8-10 days prior to testing) had upregulated neurogenesis, and outperformed rats previously treated with saline on the SLR task when objects were placed in similar spatial locations (i.e., when pattern separation was required). This finding suggests that a sub-chronic systemic administration of ghrelin can produce improvements in spatial pattern separation that persist following the end of treatment.
    Together, these experiments provide further evidence for the important role of adult neurogenesis in the DG in spatial pattern separation.

    Lay Language Summary: Our research demonstrates that new brain cells produced during adulthood may play an important role in memory formation, and suggests that healthy lifestyle choices associated with increased brain cell production, such as reducing daily food intake, may have lasting benefits on memory function.
    Arguably, one of the greatest challenges of the 21st century is the escalating health and societal burden associated with age-related cognitive impairment and dementia. By identifying potential targets for cognitive enhancing interventions, this research may eventually aid in the development of treatments for disorders affecting memory.
    Keeping memories distinct and separated is fundamental for successful memory. However, trying to remember two or more events that were similar can be difficult because the events are easily confusable. A process named ‘pattern separation’ is a mechanism within the brain that is believed to be important for keeping such memories distinct and resistant to confusion. Evidence suggests that this process is dependent upon the hippocampus, a structure that is important for memory and is also one of the few brain structures that continues to produce new cells throughout adult life.
    There is an important relationship between metabolic processes and cognitive function that scientists are only beginning to understand. For example, reducing daily food intake has been previously shown to be associated with enhanced performance in learning and memory tasks, as well as increasing the rate of brain cell production in the adult hippocampus. The link between metabolic processes and the brain may involve ghrelin, a stomach-hormone released in the gut in the absence of food. Ghrelin has been shown to positively affect cognitive processes, as well as the structure and production of new adult-born cells.
    Our research demonstrates that preventing new cells from forming in the hippocampus of rats impairs pattern separation. Additionally, we have shown that increasing the total number of new brain cells by administering ghrelin to rats is associated with long lasting improvements in pattern separation, allowing treated animals to distinguish very similar stimuli otherwise indistinguishable and to store distinct memories for very similar events.
    We used a behavioural task to test spatial pattern separation in rats, and investigated the role of adult-born neurons. First, a lentiviral approach was used to specifically attenuate dentate gyrus (DG) neurogenesis in the rat hippocampus. Rats that received this treatment produced 40% fewer new neurons and were impaired when the task required them to distinguish similar locations. We then increased DG neurogenesis in another group of rats, using daily peripheral injections of the gut-hormone ghrelin. The rats treated with ghrelin had more new DG neurons and were able to perform a more challenging version of the task, demonstrating an enhancement effect of the treatment. Together, these results suggest that the level of DG neurogenesis affects pattern separation in the spatial domain, and thus the ability to keep memories for similar locations distinct in the brain.
    Importantly, our study confirms that ghrelin does not need to be administered directly to the brain in order to have beneficial effects on the production of brain cells and cognition. Because ghrelin is an endogenous hormone and can be partially controlled by calorie restriction, it provides a therapeutic framework for designing life style strategies that are cost-effective and non-pharmacological.
    The next step is to understand the specific mechanisms by which ghrelin upregulates neurogenesis and specifically how neurogenesis contributes to pattern separation. This detailed understanding may help identify therapeutic targets for drugs or lifestyle changes that may serve to optimize memory and cognition. This has potential benefits across the lifespan, from children facing educational challenges, to adults coping with age-related cognitive decline or perhaps even dementia.