Adult-Generated Hippocampal Neurons Allow the Flexible Use of Spatially Precise Learning Strategies

Abstract

Despite enormous progress in the past few years the specific contribution of newly born granule cells to the function of the adult hippocampus is still not clear. We hypothesized that in order to solve this question particular attention has to be paid to the specific design, the analysis, and the interpretation of the learning test to be used. We thus designed a behavioral experiment along hypotheses derived from a computational model predicting that new neurons might be particularly relevant for learning conditions, in which novel aspects arise in familiar situations, thus putting high demands on the qualitative aspects of (re-)learning.In the reference memory version of the water maze task suppression of adult neurogenesis with temozolomide (TMZ) caused a highly specific learning deficit. Mice were tested in the hidden platform version of the Morris water maze (6 trials per day for 5 days with a reversal of the platform location on day 4). Testing was done at 4 weeks after the end of four cycles of treatment to minimize the number of potentially recruitable new neurons at the time of testing. The reduction of neurogenesis did not alter longterm potentiation in CA3 and the dentate gyrus but abolished the part of dentate gyrus LTP that is attributed to the new neurons. TMZ did not have any overt side effects at the time of testing, and both treated mice and controls learned to find the hidden platform. Qualitative analysis of search strategies, however, revealed that treated mice did not advance to spatially precise search strategies, in particular when learning a changed goal position (reversal). New neurons in the dentate gyrus thus seem to be necessary for adding flexibility to some hippocampus-dependent qualitative parameters of learning.Our finding that a lack of adult-generated granule cells specifically results in the animal's inability to precisely locate a hidden goal is also in accordance with a specialized role of the dentate gyrus in generating a metric rather than just a configurational map of the environment. The discovery of highly specific behavioral deficits as consequence of a suppression of adult hippocampal neurogenesis thus allows to link cellular hippocampal plasticity to well-defined hypotheses from theoretical models.

Interaction between Neurogenesis and Hippocampal Memory System: New Vistas

“…When testing spatial memory ability, deficits were described in some studies (Snyder et al 2005;Fan et al 2007;Dupret et al 2008;FarioliVecchioli et al 2008;Imayoshi et al 2008;Garthe et al 2009;Lemaire et al 2012), but not in others (Shors et al 2002;Madsen et al 2003;Raber et al 2004;Meshi et al 2006;Saxe et al 2006;Winocur et al 2006;Wojtowicz et al 2008). From our own study, based on a model that consisted in selectively ablating adult hippocampal neurogenesis by overexpressing the proapoptotic protein Bax in neuronal precursors on administration of doxycycline, we concluded that adult-born neurons are required for an allocentric (and not egocentric) strategy and for the flexible use of the acquired information (Dupret et al 2008).…”

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

“…In fact, hippocampal LTD is considered necessary for clearing old memories, and Tau −/− mice show impairments in learning flexibility and various types of hippocampal‐dependent memory (Ikegami et al , 2000; Ahmed et al , 2014; Lei et al , 2014; Ma et al , 2014; Regan et al , 2015). Remarkably, it has been described that granule neurons are important for flexibility of learning strategies (Garthe et al , 2009). …”

Association between exploratory activity and social individuality in genetically identical mice living in the same enriched environment

“…If we accept the idea that the function of new neurons lies in providing flexibility, when new information has to be integrated into pre-established contexts (Dupret et al, 2007;Garthe et al, 2009;Burghardt et al, 2012), a broadly roaming individual might indeed encounter more of such situations than an animal preferring to stay in or near the group. The results of Shemesh et al (2013) suggest that with the experience of complex environments, the inner-group complexity of behaviors actually decreases.…”